Part 13: Blood Disorders

GENERAL APPROACH TO ANEMIAS

Anemia is present in adults if the hematocrit is below 41% (hemoglobin less than 13.6 g/dL [135 g/L]) in males or below 36% (hemoglobin less than 12 g/dL [120 g/L]) in females. Congenital anemia is suggested by the patient’s personal and family history. The most common cause of anemia is iron deficiency. Poor diet may result in folic acid deficiency and contribute to iron deficiency, but bleeding is the most common cause of iron deficiency in adults. Physical examination demonstrates pallor. Attention to physical signs of primary hematologic diseases (lymphadenopathy; hepatosplenomegaly; or bone tenderness, especially in the sternum or anterior tibia) is important. Mucosal changes such as a smooth tongue suggest megaloblastic anemia.

Anemias are classified according to their pathophysiologic basis, ie, whether related to diminished production (relative or absolute reticulocytopenia) or to increased production due to accelerated loss of red blood cells (reticulocytosis) (Table 13–1), and according to red blood cell size (Table 13–2) eFigure 13–1 shows a peripheral blood smear with red blood cells of normal size (visually, approximately the same size as the nucleus of a typical lymphocyte) and shape (biconcave discs with more hemoglobin in the rims surrounding a central pallor). A reticulocytosis occurs in one of three pathophysiologic states: acute blood loss, recent replacement of a missing erythropoietic nutrient, or reduced red blood cell survival (ie, hemolysis). A severely microcytic anemia (mean corpuscular volume [MCV] less than 70 fL) is due either to iron deficiency or thalassemia, while a severely macrocytic anemia (MCV greater than 120 fL) is almost always due to either megaloblastic anemia or to cold agglutinins in blood analyzed at room temperature. A bone marrow biopsy is generally needed to complete the evaluation of anemia when the blood laboratory evaluation fails to reveal an etiology, when there are additional cytopenias present, or when an underlying primary or secondary bone marrow process is suspected.

GENERAL CONSIDERATIONS

Iron deficiency is the most common cause of anemia worldwide. The causes are listed in Table 13–3. Aside from circulating red blood cells, the major location of iron in the body is the storage pool as ferritin or as hemosiderin in macrophages.

The average American diet contains 10–15 mg of iron per day. About 10% of this amount is absorbed in the stomach, duodenum, and upper jejunum under acidic conditions. Dietary iron present as heme is efficiently absorbed (10–20%) but nonheme iron less so (1–5%), largely because of interference by phosphates, tannins, and other food constituents. The major iron transporter from the diet across the intestinal lumen is ferroportin, which also facilitates the transport of iron to apotransferrin in macrophages for delivery to erythroid progenitor cells in the bone marrow prepared to synthesize hemoglobin. Hepcidin, which is increasingly produced during inflammation, negatively regulates iron transport by promoting the degradation of ferroportin. Small amounts of iron—approximately 1 mg/day—are normally lost through exfoliation of skin and gastrointestinal mucosal cells.

With hemorrhage, there is decreased oxygen delivery to the kidneys resulting in stabilization of a hypoxia-inducible factor in the kidneys and increased erythropoietin generation in the kidneys and liver. Erythropoietin stimulates erythropoiesis via an increased synthesis of erythroferrone. In turn, erythroferrone suppresses hepcidin synthesis leading to ferroportin stability and enhanced iron transport across the gastrointestinal lumen.

Menstrual blood loss plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL but may be five times greater in some individuals. Women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day to maintain adequate iron stores, which is not commonly achieved. Women with menorrhagia of this degree will almost always become iron deficient without iron supplementation.

In general, iron metabolism is balanced between absorption of 1 mg/day and loss of 1 mg/day. Pregnancy and lactation upset the iron balance, since requirements increase to 2–5 mg of iron per day. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Decreased iron absorption can also cause iron deficiency, such as in people affected by celiac disease (gluten enteropathy), and it also commonly occurs after gastric resection or jejunal bypass surgery.

The most important cause of iron deficiency anemia in adults is chronic blood loss, especially menstrual and gastrointestinal blood loss. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded. Prolonged aspirin or nonsteroidal anti-inflammatory drug use may cause it even without a documented structural lesion. Celiac disease, even when asymptomatic, can cause iron deficiency through poor absorption in the gastrointestinal tract. Zinc deficiency is another cause of poor iron absorption. Chronic hemoglobinuria may lead to iron deficiency, but this is uncommon. Traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. The cause of iron deficiency is not found in up to 5% of cases.

Pure iron deficiency might prove refractory to oral iron replacement. Refractoriness is defined as a hemoglobin increment of less than 1 g/dL (10 g/L) after 4–6 weeks of 100 mg/day of elemental oral iron. The differential diagnosis in these cases (Table 13–3) includes malabsorption from autoimmune gastritis, Helicobacter pylori gastric infection, celiac disease, and hereditary iron-refractory iron deficiency anemia. Iron-refractory iron deficiency anemia is a rare autosomal recessive disorder due to mutations in the transmembrane serine protease 6 (TMPRSS6) gene, which normally down-regulates hepcidin. In iron-refractory iron deficiency anemia, hepcidin levels are normal to high and ferritin levels are high despite the iron deficiency.

CLINICAL FINDINGS

A. Symptoms and Signs

The primary symptoms of iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, palpitations, and dyspnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, spooning of nails (koilonychia), and cheilosis. Dysphagia due to the formation of esophageal webs (Plummer-Vinson syndrome) may occur in severe iron deficiency. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc) often not rich in iron.

B. Laboratory Findings

Iron deficiency develops in stages. The first is depletion of iron stores without anemia followed by anemia with a normal red blood cell size (normal MCV) followed by anemia with reduced red blood cell size (low MCV). The reticulocyte count is low or inappropriately normal. Ferritin is a measure of total body iron stores. A ferritin value less than 12 ng/mL (27 pmol/L) (in the absence of scurvy) is a highly reliable indicator of reduced iron stores. Note that the lower limit of normal for ferritin is often below 12 ng/mL (27 pmol/L) in women due to the fact that the normal ferritin range is generated by including healthy menstruating women who are iron deficient but not anemic. However, because serum ferritin levels may rise in response to inflammation or other stimuli, a normal or elevated ferritin level does not exclude a diagnosis of iron deficiency. A ferritin level less than 30 ng/mL (67 pmol/L) almost always indicates iron deficiency in anyone who is anemic. As iron deficiency progresses, serum iron values decline to less than 30 mcg/dL (67 pmol/L) and transferrin (the iron transport protein) levels rise to compensate, leading to transferrin saturations of less than 15%. Low transferrin saturation is also seen in anemia of inflammation, so caution in the interpretation of this test is warranted. Isolated iron deficiency anemia has a low hepcidin level, not yet a clinically available test. As the MCV falls (ie, microcytosis), the blood smear shows hypochromic microcytic cells (eFigure 13–2). With further progression, anisocytosis (variations in red blood cell size) and poikilocytosis (variation in shape of red cells) develop. Severe iron deficiency will produce a bizarre peripheral blood smear, with severely hypochromic cells, target cells, and pencil-shaped or cigar-shaped cells. Bone marrow biopsy for evaluation of iron stores is rarely performed. If the biopsy is done, it shows the absence of iron in erythroid progenitor cells by Prussian blue staining. The platelet count is commonly increased, but it usually remains under 800,000/mcL (800 × 10⁹/L).

DIFFERENTIAL DIAGNOSIS

Other causes of microcytic anemia include anemia of chronic disease (specifically, anemia of inflammation), thalassemia, lead poisoning, zinc deficiency, and congenital X-linked sideroblastic anemia. Anemia of chronic disease is characterized by normal or increased iron stores in bone marrow macrophages and a normal or elevated ferritin level; the serum iron and transferrin saturation are low, often drastically so, and the total iron-binding capacity (TIBC) (the blood’s capacity for iron to bind to transferrin) and transferrin are either normal or low. Thalassemia produces a greater degree of microcytosis for any given level of anemia than does iron deficiency and, unlike virtually every other cause of anemia, has a normal or elevated (rather than a low) red blood cell count as well as a reticulocytosis. In thalassemia, red blood cell morphology on the peripheral smear resembles severe iron deficiency.

TREATMENT

The diagnosis of iron deficiency anemia can be made either by the laboratory demonstration of an iron-deficient state or by evaluating the response to a therapeutic trial of iron replacement. Since the anemia itself is rarely life-threatening, the most important part of management is identification of the cause—especially a source of occult blood loss.

A. Oral Iron

Ferrous sulfate, 325 mg once daily or every other day on an empty stomach, is a standard approach for replenishing iron stores. As oral iron stimulates hepcidin production, once daily or every other day dosing maximizes iron absorption compared to multiple doses per day, and with fewer side effects. Nausea and constipation limit compliance with ferrous sulfate. Extended-release ferrous sulfate with mucoprotease is a well-tolerated oral preparation. Taking ferrous sulfate with food reduces side effects but also its absorption. An appropriate response to oral iron is a return of the hematocrit level halfway toward normal within 3 weeks with full return to baseline after 2 months. Iron therapy should continue for 3–6 months after restoration of normal hematologic values to replenish iron stores. Failure of response to iron therapy is usually due to noncompliance, although occasional patients may absorb iron poorly, particularly if the stomach is achlorhydric. Such patients may benefit from concomitant administration of oral ascorbic acid. Other reasons for failure to respond include incorrect diagnosis (anemia of chronic disease, thalassemia), celiac disease, and ongoing blood loss that exceeds the rate of new erythropoiesis. Treatment of H pylori infection, in appropriate cases, can improve oral iron absorption.

B. Parenteral Iron

The indications are intolerance of or refractoriness to oral iron (including those with iron-refractory iron deficiency anemia), gastrointestinal disease (usually inflammatory bowel disease) precluding the use of oral iron, and continued blood loss that cannot be corrected, such as chronic hemodialysis. Historical parenteral iron preparations, such as high-molecular-weight iron dextran, were problematic due to long infusion times (hours), polyarthralgia, and hypersensitivity reactions, including anaphylaxis. Current parenteral iron preparations coat the iron in protective carbohydrate shells or contain low-molecular-weight iron dextran, are safe, and can be administered over 15 minutes to 1 hour. Most iron deficient patients need 1–1.5 g of parenteral iron; this dose corrects for the iron deficit and replenishes iron stores for the future.

The iron deficit is calculated by determining the decrement in red cell volume from normal, recognizing there is 1 mg of iron in each milliliter of red blood cells. Total body iron ranges between 2 g and 4 g: approximately 50 mg/kg in men and 35 mg/kg in women. Most (70–95%) of the iron is present in hemoglobin in circulating red blood cells. In men, red blood cell volume is approximately 30 mL/kg; in women, it is about 27 mL/kg. Thus, a 50-kg woman whose hemoglobin is 9 g/dL (75% of normal) has an iron deficit of 0.25 × 27 mL/kg × 50 kg = 337.5 mL of red blood cells (or 337.5 mg of iron). The parenteral iron dose is the iron deficit plus (usually) 1 extra gram to replenish iron stores and anticipate further iron loses, so in this case 1.4 g.

Ferric pyrophosphate citrate (Triferic) is an FDA-approved additive to the dialysate designed to replace the 5–7 mg of iron that patients with chronic kidney disease tend to lose during each hemodialysis treatment. Ferric pyrophosphate citrate delivers sufficient iron to the marrow to maintain hemoglobin and not increase iron stores; it may obviate the need for intravenous iron in hemodialysis patients.

WHEN TO REFER

Patients should be referred to a hematologist if the suspected diagnosis is not confirmed or if they are not responsive to oral iron therapy.

GENERAL CONSIDERATIONS

Many chronic systemic diseases are associated with mild or moderate anemia. The anemias of chronic disease are characterized according to etiology and pathophysiology. First, the anemia of inflammation is associated with chronic inflammatory states (such as inflammatory bowel disease, rheumatologic disorders, chronic infections, and malignancy) and is mediated through hepcidin (a negative regulator of ferroportin) primarily via elevated IL-6, resulting in reduced iron uptake in the gut and reduced iron transfer from macrophages to erythroid progenitor cells in the bone marrow. This is referred to as iron-restricted erythropoiesis since the patient is iron replete. There is also reduced responsiveness to erythropoietin, the elaboration of hemolysins that shorten red blood cell survival, and the production of other inflammatory cytokines that dampen red cell production. The serum iron is low in the anemia of inflammation. Second, the anemia of organ failure can occur with kidney disease, liver failure, and endocrine gland failure. Erythropoietin is reduced and the red blood cell mass decreases in response to the diminished signal for red blood cell production; the serum iron is normal (except in chronic kidney disease where it is low due to the reduced hepcidin clearance and subsequent enhanced degradation of ferroportin). Third, the anemia of older adults is present in up to 20% of individuals over age 85 years in whom a thorough evaluation for an explanation of anemia is negative. The anemia is a consequence of (1) a relative resistance to red blood cell production in response to erythropoietin, (2) a decrease in erythropoietin production relative to the nephron mass, (3) a negative erythropoietic influence of higher levels of chronic inflammatory cytokines in older adults, and (4) the presence of various somatic mutations in myeloid genes typically associated with myeloid neoplasms. The latter condition is now referred to as clonal cytopenias of undetermined significance, which has a 1–1.5% per year rate of transformation to a myeloid neoplasm, such as a myelodysplastic syndrome (MDS). The serum iron is normal.

CLINICAL FINDINGS

A. Symptoms and Signs

The clinical features are those of the causative condition. The diagnosis should be suspected in patients with known chronic diseases. In cases of significant anemia, coexistent iron deficiency or folic acid deficiency should be suspected. Decreased dietary intake of iron or folic acid is common in chronically ill patients, many of whom will also have ongoing gastrointestinal blood losses. Patients undergoing hemodialysis regularly lose both iron and folic acid during dialysis.

B. Laboratory Findings

The hematocrit rarely falls below 60% of baseline (except in kidney failure). The MCV is usually normal or slightly reduced. Red blood cell morphology is usually normal, and the reticulocyte count is mildly decreased or normal.

1. Anemia of inflammation

In the anemia of inflammation, serum iron and transferrin values are low, and the transferrin saturation may be extremely low, leading to an erroneous diagnosis of iron deficiency. In contrast to iron deficiency, serum ferritin values should be normal or increased. A serum ferritin value less than 30 ng/mL (67 pmol/L) indicates coexistent iron deficiency. Anemia of inflammation has elevated hepcidin levels; however, no clinical test is yet available. A particular challenge is the diagnosis of iron deficiency in the setting of the anemia of inflammation, in which the serum ferritin can be as high as 200 ng/mL (450 pmol/L). The diagnosis is established by a bone marrow biopsy with iron stain. Absent iron staining indicates iron deficiency, whereas iron localized in marrow macrophages indicates pure anemia of inflammation. However, bone marrow biopsies are rarely done for this purpose. Two other tests all support iron deficiency in the setting of inflammation: a reticulocyte hemoglobin concentration of less than 28 pg or a soluble serum transferrin receptor (units: mg/L) to log ferritin (units: mcg/L) ratio of 1–8 (a ratio of less than 1 is virtually diagnostic of pure anemia of chronic disease). If hepcidin levels were available, a normal or elevated level would support a diagnosis of anemia of inflammation. A functional test is hemoglobin response to oral or parenteral iron in the setting of inflammation when iron deficiency is suspected. A note of caution: certain circumstances of iron-restricted erythropoiesis (such as malignancy) will partially respond to parenteral iron infusion even when the iron stores are replete due to the immediate distribution of iron to erythropoietic progenitor cells after the infusion.

2. Other anemias of chronic disease

In the anemias of organ failure and of older adults, the iron studies are generally normal. The anemia of older persons is a diagnosis of exclusion. Clonal cytopenias of undetermined significance are diagnosed by sending a blood sample for myeloid gene sequencing.

TREATMENT

In most cases, no treatment of the anemia of chronic disease is necessary and the primary management is to address the condition causing the anemia. When the anemia is severe or is adversely affecting the quality of life or functional status, then treatment involves either red blood cell transfusions or parenteral recombinant erythropoietin (epoetin alfa or darbepoetin). The FDA-approved indications for recombinant erythropoietin are hemoglobin less than 10 g/dL and anemia due to rheumatoid arthritis, inflammatory bowel disease, hepatitis C, zidovudine therapy in HIV-infected patients, myelosuppressive chemotherapy of solid malignancy (treated with palliative intent only), or chronic kidney disease (estimated glomerular filtration rate of less than 60 mL/min). The dosing and schedule of recombinant erythropoietin are individualized to maintain the hemoglobin between 10 g/dL (100 g/L) and 12 g/dL (120 g/L). The use of recombinant erythropoietin is associated with an increased risk of venothromboembolism and arterial thrombotic episodes, especially if the hemoglobin rises to greater than 12 g/dL (120 g/L). There is concern that recombinant erythropoietin is associated with reduced survival in patients with malignancy. For patients with end-stage renal disease receiving recombinant erythropoietin who are on hemodialysis, the anemia of chronic kidney disease can be more effectively corrected by adding soluble ferric pyrophosphate to their dialysate than by administering intravenous iron supplementation.

WHEN TO REFER

Referral to a hematologist is not usually necessary.

GENERAL CONSIDERATIONS

The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (alpha or beta). Reduced globin chain synthesis causes reduced hemoglobin synthesis and a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. Thalassemias can be considered among the hyperproliferative hemolytic anemias, the anemias related to abnormal hemoglobin, and the hypoproliferative anemias, since all of these factors play a role in pathogenesis. The hallmark laboratory features are small (low MCV) and pale (low mean corpuscular hemoglobin [MCH]) red blood cells, anemia, and a normal to elevated red blood cell count (ie, a large number of the small and pale red blood cells are being produced). Although patients often exhibit an elevated reticulocyte count, generally the degree of reticulocyte output is inadequate to meet the degree of red blood cell destruction (hemolysis) occurring in the bone marrow and the patients remain anemic.

Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. Hemoglobin A is formed from a tetramer of two alpha-globin chains and two beta-globin chains—and is designated alpha2beta2. Two copies of the alpha-globin gene are located on each chromosome 16, and there is no substitute for alpha-globin in the formation of adult hemoglobin. One copy of the beta-globin gene resides on each chromosome 11 adjacent to genes encoding the beta-like globins delta and gamma (the so-called beta-globin gene cluster region). The tetramer of alpha2delta2 forms hemoglobin A₂, which normally composes 1–3% of adult hemoglobin. The tetramer alpha2gamma2 forms hemoglobin F, which is the major hemoglobin of fetal life but which composes less than 1% of normal adult hemoglobin.

The thalassemias are described as thalassemia trait when there are laboratory features without significant clinical impact, thalassemia intermedia when there is an occasional red blood cell transfusion requirement or other moderate clinical impact, and thalassemia major when the disorder is life-threatening and the patient is transfusion-dependent. Most patients with thalassemia major die of the consequences of iron overload from red blood cell transfusions.

Alpha-thalassemia is due primarily to gene deletions causing reduced alpha-globin chain synthesis (Table 13–4). Each alpha-globin gene produces one-quarter of the total alpha-globin quantity, so there is a predictable proportionate decrease in alpha-globin output with each lost alpha-globin gene. Since all adult hemoglobins are alpha containing, alpha-thalassemia produces no change in the proportions of hemoglobins A, A₂, and F on hemoglobin electrophoresis. In severe forms of alpha-thalassemia, excess beta chains may form a beta-4 tetramer called hemoglobin H. In the presence of reduced alpha chains, the excess beta chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to both intramedullary (bone marrow) and peripheral blood hemolysis.

Beta-thalassemias are usually caused by point mutations rather than deletions (Table 13–5). These mutations result in premature chain termination or in problems with transcription of RNA and ultimately result in reduced or absent beta-globin chain synthesis. The molecular defects leading to beta-thalassemia are numerous and heterogeneous. Defects that result in absent beta-globin chain expression are termed beta⁰, whereas those causing reduced but not absent synthesis are termed beta⁺. In beta⁺ thalassemia, the degree of reduction of beta-globin synthesis is consistent within families but is quite variable between families. The reduced beta-globin chain synthesis in beta-thalassemia results in a relative increase in the proportions of hemoglobins A₂ and F compared to hemoglobin A on hemoglobin electrophoresis, as the beta-like globins (delta and gamma) substitute for the missing beta chains. In the presence of reduced beta chains, the excess alpha chains are unstable and precipitate, leading to damage of red blood cell membranes. This leads to both intramedullary (bone marrow) and peripheral blood hemolysis. The bone marrow demonstrates erythroid hyperplasia under the stimuli of anemia and ineffective erythropoiesis (intramedullary destruction of the developing erythroid cells). In cases of severe thalassemia, the marked expansion of the erythroid compartment in the bone marrow may cause severe bony deformities, osteopenia, and pathologic bone fractures.

CLINICAL FINDINGS

A. Symptoms and Signs

The alpha-thalassemia syndromes are seen primarily in persons from southeast Asia and China and, less commonly, in Blacks and persons of Mediterranean origin (Table 13–4). Normally, adults have four copies of the alpha-globin chain. When three alpha-globin genes are present, the patient is hematologically normal (silent carrier). When two alpha-globin genes are present, the patient is said to have alpha-thalassemia trait, a form of thalassemia minor. In alpha-thalassemia-1 trait, the alpha gene deletion is heterozygous (alpha –/alpha –) and affects mainly those of Asian descent. In alpha-thalassemia-2 trait, the alpha gene deletion is homozygous (alpha alpha/– –) and affects mainly Blacks. These patients are clinically normal and have a normal life expectancy and performance status, with a mild microcytic anemia. When only one alpha globin chain is present (alpha –/– –), the patient has hemoglobin H disease (alpha-thalassemia-3). This is a chronic hemolytic anemia of variable severity (thalassemia minor or intermedia). Physical examination might reveal pallor and splenomegaly. Affected individuals usually do not need transfusions; however, they may be required during transient periods of hemolytic exacerbation caused by infection or other stressors or during periods of erythropoietic shutdown caused by certain viruses (“aplastic crisis”). When all four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn (hydrops fetalis). In hydrops fetalis, the only hemoglobin species made is gamma and is called hemoglobin Bart’s (gamma4).

Beta-thalassemia primarily affects persons of Mediterranean origin (Italian, Greek) and to a lesser extent Asians and Blacks (Table 13–5). Patients homozygous for beta-thalassemia (beta⁰/beta⁰ or some with beta⁺/beta⁺) have beta-thalassemia major (Cooley anemia). Affected children are normal at birth, but after 6 months, when hemoglobin synthesis switches from hemoglobin F to hemoglobin A, severe anemia develops that requires transfusion. Numerous clinical problems ensue, including stunted growth, bony deformities (abnormal facial structure, pathologic bone fractures), hepatosplenomegaly, jaundice (due to gallstones, hepatitis-related cirrhosis, or both), and thrombophilia. The clinical course is modified significantly by transfusion therapy, but transfusional iron overload (hemosiderosis) results in a clinical picture similar to hemochromatosis, with heart failure, cardiac arrhythmias, cirrhosis, endocrinopathies, and pseudoxanthoma elasticum (calcification and fragmentation of the elastic fibers of the skin, retina, and cardiovascular system), usually after more than 100 units of red blood cells have been transfused. Iron overloading occurs because the human body has no active iron excretory mechanism. Before the application of allogeneic stem cell transplantation and the development of more effective forms of iron chelation, death from iron overload usually occurred between the ages of 20 and 30 years.

Patients homozygous for a milder form of beta-thalassemia (beta⁺/beta⁺, but allowing a higher rate of beta-globin synthesis) have beta-thalassemia intermedia. These patients have chronic hemolytic anemia but do not require transfusions except under periods of stress or during aplastic crises. They also may develop iron overload because of periodic transfusion. They survive into adult life but with hepatosplenomegaly and bony deformities. Patients heterozygous for beta-thalassemia (beta/beta⁰ or beta/beta⁺) have beta-thalassemia minor and a clinically insignificant microcytic anemia.

Prenatal diagnosis is available, and genetic counseling should be offered and the opportunity for prenatal diagnosis discussed.

B. Laboratory Findings

1. Alpha-thalassemia trait

These patients have mild or no anemia, with hematocrits between 28% and 40%. The MCV is strikingly low (60–75 fL) despite the modest anemia, and the red blood count is normal or increased. The peripheral blood smear shows microcytes, hypochromia, occasional target cells, and acanthocytes (cells with irregularly spaced spiked projections). The reticulocyte count and iron parameters are normal. Hemoglobin electrophoresis is normal. Alpha-thalassemia trait is thus usually diagnosed by exclusion. Genetic testing to demonstrate alpha-globin gene deletion is available.

2. Hemoglobin H disease

These patients have a more marked anemia, with hematocrits between 22% and 32%. The MCV is remarkably low (60–70 fL) and the peripheral blood smear is markedly abnormal, with hypochromia, microcytosis, target cells, and poikilocytosis. The reticulocyte count is elevated and the red blood cell count is normal or elevated. Hemoglobin electrophoresis will show a fast-migrating hemoglobin (hemoglobin H), which comprises 10–40% of the hemoglobin. A peripheral blood smear can be stained with supravital dyes to demonstrate the presence of hemoglobin H (eFigure 13–3).

3. Beta-thalassemia minor

These patients have a modest anemia with hematocrit between 28% and 40%. The MCV ranges from 55 fL to 75 fL, and the red blood cell count is normal or increased. The reticulocyte count is normal or slightly elevated. The peripheral blood smear is mildly abnormal, with hypochromia, microcytosis, and target cells (eFigure 13–4). In contrast to alpha-thalassemia, basophilic stippling is present. Hemoglobin electrophoresis shows an elevation of hemoglobin A₂ to 4–8% and occasional elevations of hemoglobin F to 1–5%.

4. Beta-thalassemia intermedia

These patients have a moderate anemia with hematocrit between 17% and 33%. The MCV ranges from 55 fL to 75 fL, and the red blood cell count is normal or increased. The reticulocyte count is elevated. The peripheral blood smear is abnormal with hypochromia, microcytosis, basophilic stippling, and target cells. Hemoglobin electrophoresis shows up to 30% hemoglobin A, an elevation of hemoglobin A₂ up to 10%, and elevation of hemoglobin F from 6% to 10%.

5. Beta-thalassemia major

These patients have severe anemia, and without transfusion the hematocrit may fall to less than 10%. The peripheral blood smear is bizarre, showing severe poikilocytosis, hypochromia, microcytosis, target cells, basophilic stippling, and nucleated red blood cells. Little or no hemoglobin A is present. Variable amounts of hemoglobin A₂ are seen, and the predominant hemoglobin present is hemoglobin F (eFigure 13–5).

DIFFERENTIAL DIAGNOSIS

Mild forms of thalassemia must be differentiated from iron deficiency. Compared to iron deficiency anemia, patients with thalassemia have a lower MCV, a normal or elevated red blood cell count (rather than low), a more abnormal peripheral blood smear at modest levels of anemia, and usually a reticulocytosis. Iron studies are normal or the transferrin saturation or ferritin (or both) are elevated. Severe forms of thalassemia may be confused with other hemoglobinopathies. The diagnosis of beta-thalassemia is made by the above findings and hemoglobin electrophoresis showing elevated levels of hemoglobins A₂ and F (provided the patient is replete in iron), or beta-gene sequencing. The diagnosis of alpha-thalassemia is made by exclusion since there is no change in the proportion of the normal adult hemoglobin species or confirmed by alpha gene deletion studies. The only other microcytic anemia with a normal or elevated red blood cell count is iron deficiency in a patient with polycythemia vera.

TREATMENT

Patients with mild thalassemia (alpha-thalassemia trait or beta-thalassemia minor) require no treatment and should be identified so that they will not be subjected to repeated evaluations and treatment for iron deficiency. Patients with hemoglobin H disease should take folic acid supplementation (1 mg/day orally) and avoid medicinal iron and oxidative drugs such as sulfonamides. Patients with severe thalassemia are maintained on a regular transfusion schedule (in part to suppress endogenous erythropoiesis and therefore bone marrow expansion) and receive folic acid supplementation. Splenectomy is performed if hypersplenism causes a marked increase in the transfusion requirement or refractory symptoms. Patients with regular transfusion requirements should be treated with iron chelation (oral or parenteral) in order to prevent or delay life-limiting organ damage from iron overload. A new agent, luspatercept, has been FDA approved for transfusion-dependent beta-thalassemia. It is a TGF-beta ligand trap that promotes erythroid maturation and reduces transfusion needs.

Allogeneic stem cell transplantation is the treatment of choice for beta-thalassemia major and the only available cure. Children who have not yet experienced organ damage from iron overload do well, with long-term survival in more than 80% of cases. Autologous gene therapy is showing promise for thalassemia major.

WHEN TO REFER

All patients with thalassemia intermedia or major should be referred to a hematologist. Any patient with an unexplained microcytic anemia should be referred to help establish a diagnosis. Patients with thalassemia minor or intermedia should be offered genetic counseling because offspring of thalassemic couples are at risk for inheriting thalassemia major.

GENERAL CONSIDERATIONS

The sideroblastic anemias are a heterogeneous group of disorders in which hemoglobin synthesis is decreased because of reduced ability to synthesize heme due to an impaired ability to incorporate iron into protoporphyrin IX. Iron accumulates, particularly in the mitochondria. The disorder is generally acquired; it is most often a subtype of a MDS. Other causes include chronic alcoholism, lead poisoning, copper deficiency, medications (isoniazid and chloramphenicol), and chronic infection or inflammation. Inherited forms are usually X-linked, but rare recessive forms have been documented. Modern classification divides sideroblastic anemia into two categories: dyserythropoiesis (ie, hypohepcidinemia) or transfusion-dependence (MDS, thalassemia, etc.).

CLINICAL FINDINGS

Patients have no specific clinical features other than those related to anemia. The anemia is usually moderate, with hematocrits of 20–30%, but transfusions may occasionally be required. In the sideroblastic subtype of MDS, the MCV is usually normal or slightly increased, as it when due to alcohol. In other types, the MCV is usually low (especially in the inherited forms) leading to confusion with iron deficiency. However, the serum iron level is elevated and the transferrin saturation is high. The peripheral blood smear characteristically shows a dimorphic population of red blood cells, one normal and one microcytic. In cases of lead poisoning, coarse basophilic stippling of the red cells is seen and the serum lead levels will be elevated.

The diagnosis is made by examination of the bone marrow. Characteristically, there is marked erythroid hyperplasia, a sign of ineffective erythropoiesis (expansion of the erythroid compartment of the bone marrow without the release of adequate mature red blood cells into the peripheral blood) (eFigure 13–6). The Prussian blue iron stain of the bone marrow shows a generalized increase in iron stores and the presence of ringed sideroblasts (erythroid cells with iron deposits in mitochondria encircling the nucleus). Occasionally, the anemia is severe enough to require red blood cell transfusions. These patients usually do not respond well to recombinant erythropoietin therapy, especially when transfusion requirements are significant. There are occasional responses to oral pyridoxine (50–200 mg/day). Removal of offending toxins and drugs is needed in the secondary acquired forms. A new agent, luspatercept, has been FDA approved for MDS with ringed sideroblasts. It is a TGF-beta ligand trap that promotes erythroid maturation and reduces transfusion needs.

A rare form of sideroblastic anemia is now recognized that is due to copper deficiency (hypocupremia). The anemia is normocytic in two-thirds of cases and macrocytic in the remainder. The zinc level is usually elevated. Neutropenia or thrombocytopenia (or both) may also be present. Some patients have a myelopathy or demyelinating peripheral neuropathy. The bone marrow biopsy is usually interpreted as a "myelodysplastic syndrome" due to the presence of ringed sideroblasts and vacuolization of the myeloid and erythroid progenitors. The causes of hypocupremia include excess total body zinc (due to zinc-imbedded dental fillings or excessive oral zinc intake, eg, due to high levels of zinc in some Asian herbal preparations), or due to gastric bypass surgery. Treatment with copper sulfate (2.5 mg twice daily) is associated with a high hematologic response rate but a low neurologic response rate. Exogenous or endogenous zinc exposure needs to be eliminated.

WHEN TO REFER

Refer to a hematologist if diagnostic or transfusion support is needed.

GENERAL CONSIDERATIONS

Vitamin B₁₂ belongs to the family of cobalamins and serves as a cofactor for two important reactions in humans (eFigure 13–7). As methylcobalamin, it is a cofactor for methionine synthetase in the conversion of homocysteine to methionine, and as adenosylcobalamin for the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. These enzymatic steps are critical for annealing Okazaki fragments during DNA synthesis, particularly in erythroid progenitor cells. Vitamin B₁₂ comes from the diet and is present in all foods of animal origin. The daily absorption of vitamin B₁₂ is 5 mcg.

After being ingested, vitamin B₁₂ is bound to intrinsic factor, a protein secreted by gastric parietal cells in an acid environment. Other cobalamin-binding proteins (called R factors) compete with intrinsic factor for vitamin B₁₂. Vitamin B₁₂ bound to R factors cannot be absorbed. The vitamin B₁₂–intrinsic factor complex travels through the intestine and is absorbed in the terminal ileum by cells with specific receptors for the complex. It is then transported through plasma and stored in the liver. Three plasma transport proteins have been identified. Transcobalamins I and III (differing only in carbohydrate structure) are secreted by white blood cells. Although approximately 90% of plasma vitamin B₁₂ circulates bound to transcobalamins I and III, only transcobalamin II is capable of transporting vitamin B₁₂ into cells.

The liver contains 2–5 mg of stored vitamin B₁₂. Since daily utilization is 3–5 mcg, the body usually has sufficient stores of vitamin B₁₂ so that it takes more than 3 years for vitamin B₁₂ deficiency to occur if all intake or absorption immediately ceases.

Since vitamin B₁₂ is present in foods of animal origin, dietary vitamin B₁₂ deficiency is extremely rare but is seen in vegans—strict vegetarians who avoid all dairy products, meat, and fish (Table 13–6). Pernicious anemia is an autoimmune illness whereby autoantibodies destroy gastric parietal cells (that produce intrinsic factor) and cause atrophic gastritis or bind to and neutralize intrinsic factor, or both. Abdominal surgery may lead to vitamin B₁₂ deficiency in several ways. Gastrectomy will eliminate the site of intrinsic factor production; blind loop syndrome will cause competition for vitamin B₁₂ by bacterial overgrowth in the lumen of the intestine; and surgical resection of the ileum will eliminate the site of vitamin B₁₂ absorption. Rare causes of vitamin B₁₂ deficiency include fish tapeworm (Diphyllobothrium latum) infection, in which the parasite uses luminal vitamin B₁₂; pancreatic insufficiency (with failure to inactivate competing cobalamin-binding proteins [R-factors]); severe Crohn disease, causing sufficient destruction of the ileum to impair vitamin B₁₂ absorption; and perhaps prolonged use of proton pump inhibitors.

CLINICAL FINDINGS

A. Symptoms and Signs

Vitamin B₁₂ deficiency causes a moderate to severe anemia of slow onset; patients may have few symptoms relative to the degree of anemia. In advanced cases, the anemia may be severe, with hematocrits as low as 10–15%, and may be accompanied by leukopenia and thrombocytopenia. The deficiency also produces changes in mucosal cells, leading to glossitis, as well as other vague gastrointestinal disturbances such as anorexia and diarrhea. Vitamin B₁₂ deficiency also leads to a complex neurologic syndrome. Peripheral nerves are usually affected first, and patients complain initially of paresthesias. As the posterior columns of the spinal cord become impaired, patients complain of difficulty with balance or proprioception, or both. In more advanced cases, cerebral function may be altered as well, and on occasion dementia and other neuropsychiatric abnormalities may be present. It is critical to recognize that the nonhematologic manifestations of vitamin B₁₂ deficiency can be manifest despite a completely normal complete blood count.

Patients are usually pale and may be mildly icteric or sallow. Typically, later in the disease course, neurologic examination may reveal decreased vibration and position sense or memory disturbance (or both).

B. Laboratory Findings

The diagnosis of vitamin B₁₂ deficiency is made by finding a low serum vitamin B₁₂ (cobalamin) level. Whereas the normal vitamin B₁₂ level is greater than 300 pg/mL (221 pmol/L), most patients with overt vitamin B₁₂ deficiency have serum levels less than 200 pg/mL (148 pmol/L), with symptomatic patients often having levels less than 100 pg/mL (74 pmol/L). The diagnosis of vitamin B₁₂ deficiency in low or low-normal values (level of 200–300 pg/mL [147.6–221.3 pmol/L]) is best confirmed by finding an elevated level of serum methylmalonic acid or homocysteine. Of note, elevated levels of serum methylmalonic acid can be due to kidney disease.

The anemia of vitamin B₁₂ deficiency is typically moderate to severe with the MCV quite elevated (110–140 fL). However, it is possible to have vitamin B₁₂ deficiency with a normal MCV from coexistent thalassemia or iron deficiency; in other cases, the reason is obscure. Patients with neurologic symptoms and signs that suggest possible vitamin B₁₂ deficiency should be evaluated for that deficiency despite a normal MCV or the absence of anemia. In typical cases, the peripheral blood smear is megaloblastic, defined as red blood cells that appear as macro-ovalocytes, (although other shape changes are usually present) and neutrophils that are hypersegmented (six [or greater]-lobed neutrophils or mean neutrophil lobe counts greater than four) (eFigures 13–8 and 13–9). The reticulocyte count is reduced. Because vitamin B₁₂ deficiency can affect all hematopoietic cell lines, the white blood cell count and the platelet count are reduced in severe cases.

Other laboratory abnormalities include elevated serum lactate dehydrogenase (LD) and a modest increase in indirect bilirubin. These two findings reflect the intramedullary destruction of developing abnormal erythroid cells.

Bone marrow morphology is characteristically abnormal (eFigure 13–10). Marked erythroid hyperplasia is present as a response to defective red blood cell production (ineffective erythropoiesis). Megaloblastic changes in the erythroid series include abnormally large cell size and asynchronous maturation of the nucleus and cytoplasm—ie, cytoplasmic maturation continues while impaired DNA synthesis causes retarded nuclear development. In the myeloid series, giant bands and meta-myelocytes are characteristically seen.

DIFFERENTIAL DIAGNOSIS

Vitamin B₁₂ deficiency should be differentiated from folic acid deficiency, the other common cause of megaloblastic anemia, in which red blood cell folic acid is low while vitamin B₁₂ levels are normal. The bone marrow findings of vitamin B₁₂ deficiency are sometimes mistaken for a MDS or even acute erythrocytic leukemia. The distinction between vitamin B₁₂ deficiency and myelodysplasia is based on the characteristic morphology and the low vitamin B₁₂ and elevated methylmalonic acid levels.

TREATMENT

Initially, patients with vitamin B₁₂ deficiency are usually treated with parenteral therapy. Intramuscular or subcutaneous injections of 100–1000 mcg of vitamin B₁₂ are adequate for each dose (with the higher dose recommended initially). Replacement is usually given daily for the first week, weekly for the next month, and then monthly for life. The vitamin deficiency will recur if patients discontinue their therapy. Oral or sublingual methylcobalamin (1 mg/day) may be used instead of parenteral therapy once initial correction of the deficiency has occurred. Oral or sublingual replacement is effective, even in pernicious anemia, since approximately 1% of the dose is absorbed in the intestine via passive diffusion in the absence of active transport. It must be continued indefinitely and serum vitamin B₁₂ levels must be monitored to ensure adequate replacement. For patients with neurologic symptoms caused by vitamin B₁₂ deficiency, long-term parenteral vitamin B₁₂ therapy is recommended, though its superiority over oral vitamin B₁₂ therapy has not been proven. Because some patients are concurrently folic acid deficient from intestinal mucosal atrophy, simultaneous folic acid replacement (1 mg daily) is advised for the first several months of vitamin B₁₂ replacement.

Patients respond to therapy with an immediate improvement in their sense of well-being. Hypokalemia may complicate the first several days of therapy, particularly if the anemia is severe. A brisk reticulocytosis occurs in 5–7 days, and the hematologic picture normalizes in 2 months. Central nervous system symptoms and signs are potentially reversible if they have been present for less than 6 months. Red blood cell transfusions are rarely needed despite the severity of anemia, but when given, diuretics are also recommended to avoid heart failure because this anemia develops slowly and the plasma volume is increased at the time of diagnosis.

WHEN TO REFER

Referral to a hematologist is not usually necessary.

GENERAL CONSIDERATIONS

“Folic acid” is the term commonly used for pteroylmonoglutamic acid. Folic acid is present in most fruits and vegetables (especially citrus fruits and green leafy vegetables). Daily dietary requirements are 50–100 mcg. Total body stores of folic acid are approximately 5 mg, enough to supply requirements for 2–3 months.

The most common cause of folic acid deficiency is inadequate dietary intake (Table 13–7). Alcoholic or anorectic patients, persons who do not eat fresh fruits and vegetables, and those who overcook their food are candidates for folic acid deficiency. Reduced folic acid absorption is rarely seen, since absorption occurs from the entire gastrointestinal tract. However, medications such as phenytoin, trimethoprim-sulfamethoxazole, or sulfasalazine may interfere with its absorption. Folic acid absorption is poor in some patients with vitamin B₁₂ deficiency due to gastrointestinal mucosal atrophy. Folic acid requirements are increased in pregnancy, hemolytic anemia, and exfoliative skin disease, and in these cases the increased requirements (5–10 times normal) may not be met by a normal diet.

CLINICAL FINDINGS

A. Symptoms and Signs

The clinical features are similar to those of vitamin B₁₂ deficiency. However, isolated folic acid deficiency does not result in neurologic abnormalities.

B. Laboratory Findings

Megaloblastic anemia is identical to anemia resulting from vitamin B₁₂ deficiency. A red blood cell folic acid level below 150 ng/mL (340 nmol/L) is diagnostic of folic acid deficiency. Whether to order a serum or a red blood cell folate level remains unsettled since there are few, if any, data to support one test over the other. Usually the serum vitamin B₁₂ level is normal, and it should always be measured when folic acid deficiency is suspected. In some instances, folic acid deficiency is a consequence of the gastrointestinal mucosal atrophy from vitamin B₁₂ deficiency.

DIFFERENTIAL DIAGNOSIS

The megaloblastic anemia of folic acid deficiency should be differentiated from vitamin B₁₂ deficiency by the finding of a normal vitamin B₁₂ level and a reduced red blood cell (or serum) folic acid level. Alcoholic patients, who often have nutritional deficiency, may also have anemia of liver disease. Pure anemia of liver disease causes a macrocytic anemia but does not produce megaloblastic morphologic changes in the peripheral blood; rather, target cells are present. Hypothyroidism is associated with mild macrocytosis and also with pernicious anemia.

TREATMENT

Folic acid deficiency is treated with daily oral folic acid (1 mg). The response is similar to that seen in the treatment of vitamin B₁₂ deficiency, with rapid improvement and a sense of well-being, reticulocytosis in 5–7 days, and total correction of hematologic abnormalities within 2 months. Large doses of folic acid may produce hematologic responses in cases of vitamin B₁₂ deficiency, but permit neurologic damage to progress; hence, obtaining a serum vitamin B₁₂ level in suspected folic acid deficiency is paramount.

WHEN TO REFER

Referral to a hematologist is not usually necessary.

Acquired pure red cell aplasia is rare. It is an autoimmune disease mediated by T lymphocytes and/or by an IgG antibody against erythroid precursors in the bone marrow. In adults, the disease is usually idiopathic. However, cases have been seen in association with systemic lupus erythematosus, chronic lymphocytic leukemia (CLL), lymphomas, or thymoma. Some medications (phenytoin, chloramphenicol) may cause red cell aplasia. Rarely, anti-erythropoietin antibodies cause pure red cell aplasia in patients who are treated with recombinant erythropoietin. Transient episodes of red cell aplasia are probably common in response to viral infections, especially parvovirus infections. However, these acute episodes will go unrecognized unless the patient has a chronic hemolytic disorder or a chronic immunocompromised state, in which case the hematocrit may fall precipitously.

The only signs are those of anemia unless the patient has an associated autoimmune or lymphoproliferative disorder. The anemia is often severe and normochromic, with low or absent reticulocytes. Red blood cell morphology is normal, and the myeloid and platelet lines are unaffected. The bone marrow is normocellular with markedly reduced or absent erythroid progenitors; all non-erythroid elements are present and normal. The bone marrow karyotype is normal on standard banding cytogenetics. In some cases, chest imaging studies will reveal a thymoma.

The disorder must be distinguished from aplastic anemia (in which the marrow is hypocellular and all cell lines are affected) and from myelodysplasia. This latter disorder is recognized by the presence of morphologic abnormalities that should not be present in pure red cell aplasia.

Possible offending medications should be stopped. Most patients will require red blood cell transfusion support. With thymoma, resection alone results in amelioration of anemia in a low proportion of cases (about 10%). High-dose intravenous immune globulin has produced responses in a small number of cases, mainly during parvovirus infections. For idiopathic cases, the treatment of choice is immunosuppressive therapy with a calcineurin inhibitor (ie, cyclosporine) with durable response rates of 65–87%. A calcineurin inhibitor is usually used in conjunction with surgical resection in cases of thymoma. Monotherapy with corticosteroids produce responses in 30–60% of cases, but relapses are common once corticosteroids are discontinued. Anti-CD20 monoclonal antibody (rituximab) is the treatment of choice in the setting of anti-erythropoietin antibodies. In patients with an associated lymphoproliferative disorder, treating the neoplasm should also treat the anemia.

WHEN TO REFER

All patients should be referred to a hematologist.

The hemolytic anemias are a group of disorders in which red blood cell survival is reduced, either episodically or continuously. The bone marrow has the ability to increase erythroid production up to eightfold in response to reduced red cell survival, so anemia will be present only when the ability of the bone marrow to compensate is outstripped. This will occur when red cell survival is extremely short or when the ability of the bone marrow to compensate is impaired.

Since red blood cell survival is normally 120 days, in the absence of red cell production, the hematocrit will fall at the rate of approximately 1/120 of the hematocrit per day, which translates to a decrease in the hematocrit reading of approximately 2–3% (absolute percentage) per week. For example, a fall of hematocrit from 45% to 36% over 3 weeks need not indicate hemolysis, since this rate of fall would result simply from cessation of red blood cell production. If the hematocrit is falling at a rate faster than that due to decreased production, blood loss or hemolysis is the cause.

Reticulocytosis is an important clue to the presence of hemolysis, since in most hemolytic disorders the bone marrow will respond with increased red blood cell production and earlier release of young red blood cells into the circulation. However, hemolysis can be present without reticulocytosis when a confounding erythropoietic disorder (infection, nutritional deficiency, disturbed marrow) is superimposed on hemolysis; in these circumstances, the hematocrit will fall rapidly. Reticulocytosis does not necessarily imply hemolysis, since it also occurs during recovery from hypoproliferative anemia (replacement of a missing nutrient) or acute bleeding. Hemolysis is correctly diagnosed (when acute bleeding and nutrient replacement are excluded) if the hematocrit is either falling or stable despite reticulocytosis.

Hemolytic disorders are generally classified according to whether the defect is intrinsic to the red cell or due to some external factor (Table 13–8). Intrinsic defects have been described in all components of the red blood cell, including the membrane, enzyme systems, and hemoglobin; most of these disorders are hereditary. Hemolytic anemias due to external factors are immune, microangiopathic hemolytic anemias, and infections of red blood cells.

Certain laboratory features are common to all hemolytic anemias. Haptoglobin, a normal plasma protein that binds and clears free hemoglobin released into plasma, is depressed in hemolytic disorders. However, the haptoglobin level is influenced by many factors and is not always a reliable indicator of hemolysis, particularly in end-stage liver disease (its site of synthesis). When intravascular hemolysis occurs, transient hemoglobinemia ensues. Hemoglobin is filtered through the renal glomerulus and is usually reabsorbed by tubular cells. Hemoglobinuria will be present only when the capacity for reabsorption of hemoglobin by renal tubular cells is exceeded. In the absence of hemoglobinuria, evidence for prior intravascular hemolysis is the presence of hemosiderin in shed renal tubular cells (positive urine hemosiderin). With severe intravascular hemolysis, hemoglobinemia and methemalbuminemia may be present. Hemolysis increases the indirect bilirubin, and the total bilirubin may rise to 4 mg/dL (68 mcmol/L) or more. Bilirubin levels higher than this may indicate some degree of hepatic dysfunction. Serum LD levels are strikingly elevated in cases of microangiopathic hemolysis (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome) and may be elevated in other hemolytic anemias.

GENERAL CONSIDERATIONS

Hereditary spherocytosis is a disorder of the red blood cell membrane, leading to chronic hemolytic anemia. Normally, the red blood cell is a biconcave disk with a diameter of 7–8 mcm. The red blood cells must be both strong and deformable—strong to withstand the stress of circulating for 120 days and deformable so as to pass through capillaries 3 mcm in diameter and splenic fenestrations in the cords of the red pulp of approximately 2 mcm. The red blood cell membrane skeleton, made up primarily of the proteins spectrin and actin, gives the red cells these characteristics of strength and deformability.

In hereditary spherocytosis, the membrane defect is an abnormality in spectrin, actin, or other red blood cell membrane proteins, such as band 3 or protein 4.2; these proteins provide most of the scaffolding for the red blood cell membranes. The result is a decrease in surface-to-volume ratio that results in a spherical shape of the red blood cell. These spherical red blood cells are less deformable and less able to pass through the small fenestrations in the splenic red pulp. Hemolysis takes place because of trapping of red blood cells within the spleen and their premature removal by splenic macrophages.

CLINICAL FINDINGS

A. Symptoms and Signs

Hereditary spherocytosis is an autosomal dominant disease of variable severity. It is often diagnosed during childhood, but milder cases may be discovered incidentally in adult life. Anemia may or may not be present, since the bone marrow may be able to compensate for shortened red cell survival. Severe anemia (aplastic crisis) may occur in folic acid deficiency or when bone marrow erythropoiesis is temporarily impaired by infection. Chronic hemolysis causes jaundice and pigment (calcium bilirubinate) gallstones, leading to attacks of cholecystitis, and medial malleolar skin ulcers. Examination may reveal icterus and a palpable spleen.

B. Laboratory Findings

The anemia is of variable severity, and the hematocrit may be normal. Reticulocytosis is always present. The peripheral blood smear shows the presence of spherocytes, small cells that have lost their central pallor. Hereditary spherocytosis is the only important disorder associated with microcytosis (sometimes normocytic) and an increased MCHC, often greater than 36 g/dL. As with other hemolytic disorders, there may be an increase in indirect bilirubin. The Coombs test is negative (see section on Autoimmune Hemolytic Anemia).

Because spherocytes are red cells that have lost some membrane surface, they are abnormally vulnerable to swelling induced by hypotonic media. Increased osmotic fragility merely reflects the presence of spherocytes and does not distinguish hereditary spherocytosis from other spherocytic hemolytic disorders such as autoimmune hemolytic anemia. In some laboratories, the osmotic fragility test has been supplanted by ektacytometry, which has the advantages of better reliability and the ability to distinguish spherocytes from other red blood cell abnormalities such as elliptocytes. EMA (eosin-5' maleimide) binding by flow cytometry is another diagnostic tool.

TREATMENT

Patients should receive supplementation with daily folic acid, 1 mg. The treatment of choice is splenectomy, which will correct neither the membrane defect nor the spherocytosis but will eliminate the site of hemolysis. The timing of splenectomy is controversial, but certainly after 5 years of life whenever possible and if needed. In mild cases discovered late in adult life, splenectomy may not be necessary.

WHEN TO REFER

Patients in whom hereditary spherocytosis is suspected should have the diagnosis confirmed by a hematologist, and decisions regarding splenectomy should be made in consultation with a hematologist.

GENERAL CONSIDERATIONS

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disorder that results in abnormal sensitivity of the red blood cell membrane to lysis by complement and therefore hemolysis. The underlying cause is an acquired defect in the gene for phosphatidylinositol class A (PIG-A), which results in a deficiency of the glycosylphosphatidylinositol (GPI) anchor for cellular membrane proteins. In particular, the complement-regulating proteins CD55 and CD59 are deficient, which permits unregulated formation of the complement membrane attack complex on red cell membranes and intravascular hemolysis. Free hemoglobin is released into the blood that scavenges nitric oxide and promotes esophageal spasms, male erectile dysfunction, kidney damage, and thrombosis. Patients with significant PNH live about 10–15 years following diagnosis; thrombosis is the primary cause of death.

CLINICAL FINDINGS

A. Symptoms and Signs

Classically, patients report episodic hemoglobinuria resulting in reddish-brown urine. Hemoglobinuria is most often noticed in the first morning urine due to the fall in blood pH while sleeping (hypoventilation) that facilitates this hemolysis. Besides anemia, these patients are prone to thrombosis, especially within mesenteric and hepatic veins, central nervous system veins (sagittal vein), and skin vessels (with formation of painful nodules). As this is a hematopoietic stem cell disorder, PNH may appear de novo or arise in the setting of aplastic anemia or myelodysplasia with possible progression to acute myeloid leukemia (AML). It is common that patients with idiopathic aplastic anemia have a small PNH clone (less than 2%) on blood or bone marrow analysis; this should not be considered true PNH per se, especially in the absence of a reticulocytosis or thrombosis.

B. Laboratory Findings

Anemia is of variable severity and frequency, so reticulocytosis may or may not be present at any given time. Abnormalities on the blood smear are nondiagnostic but may include macro-ovalocytes and polychromasia. Since the episodic hemolysis is mainly intravascular, urine hemosiderin is a useful test. Serum LD is characteristically quite elevated. Iron deficiency is commonly present, related to chronic iron loss from hemoglobinuria.

The white blood cell count and platelet count may be decreased and are always decreased in the setting of aplastic anemia. The best screening test is flow cytometry of blood erythrocytes, granulocytes, and monocytes to demonstrate deficiency of CD55 and CD59. The proportion of erythrocytes deficient in these proteins might be low due to the ongoing destruction of affected erythrocytes. The FLAER assay (fluorescein-labeled proaerolysin) by flow cytometry is more sensitive. Bone marrow morphology is variable and may show either generalized hypoplasia or erythroid hyperplasia or both. The bone marrow karyotype may be either normal or demonstrate a clonal abnormality.

TREATMENT

Many patients with PNH have mild disease not requiring intervention. In severe cases and in those occurring in the setting of myelodysplasia or previous aplastic anemia, allogeneic hematopoietic stem cell transplantation may prove curative. In patients with severe hemolysis (usually requiring red cell transfusions) or thrombosis (or both), treatment with eculizumab is warranted. Eculizumab is a humanized monoclonal antibody against complement protein C5 given every 2 weeks. Binding of eculizumab to C5 prevents its cleavage so the membrane attack complex cannot assemble. Eculizumab improves quality of life and reduces hemolysis, transfusion requirements, fatigue, and thrombosis risk. Eculizumab increases the risk of Neisseria meningitidis infections; patients receiving the antibody should undergo meningococcal vaccination (including vaccines for serogroup B) and take oral penicillin (or equivalent) meningococcal prophylaxis. Ravulizumab is a longer-acting version of eculizumab; it is given every 8 weeks and demonstrates fewer breakthrough hemolytic episodes than eculizumab. Iron replacement is indicated for treatment of iron deficiency when present, which may improve the anemia while also causing a transient increase in hemolysis. For unclear reasons, corticosteroids are effective in decreasing hemolysis.

WHEN TO REFER

Most patients with PNH should be under the care of a hematologist.

GENERAL CONSIDERATIONS

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary enzyme defect that causes episodic hemolytic anemia because of the decreased ability of red blood cells to deal with oxidative stresses. G6PD deficiency leads to excess oxidized glutathione that forces hemoglobin to denature and form precipitants called Heinz bodies. Heinz bodies cause red blood cell membrane damage, which leads to premature removal of these red blood cells by reticuloendothelial cells within the spleen (ie, extravascular hemolysis).

Numerous G6PD isoenzymes have been described. The usual isoenzyme found in American Blacks is designated G6PD-A and that found in Whites is designated G6PD-B, both of which have normal function and stability and therefore no hemolytic anemia. Ten to 15 percent of American Blacks have the variant G6PD isoenzyme designated A–, in which there is both a reduction in normal enzyme activity and a reduction in its stability. The A– isoenzyme activity declines rapidly as the red blood cell ages past 40 days, a fact that explains the clinical findings in this disorder. More than 150 G6PD isoenzyme variants have been described, including some Mediterranean, Ashkenazi Jewish, and Asian variants with very low enzyme activity, episodic hemolysis, and exacerbations due to oxidizing substances including fava beans(class II G6PD activity). The other classes of G6PD isoenzyme activity are class I, extremely low activity with associated chronic, severe hemolysis; class III, 10–60% activity with episodic hemolysis (includes the American Black A– isoform); class IV, 60–150% activity (normal); and class V, greater than 150% activity. Patients with G6PD deficiency seem to be protected from malaria parasitic infection, have less coronary artery disease, and possibly have fewer cancers and greater longevity.

CLINICAL FINDINGS

G6PD deficiency is an X-linked disorder affecting 10–15% of American hemizygous Black males and rare female homozygotes. Female carriers are rarely affected—only when an unusually high percentage of cells producing the normal enzyme are X-inactivated.

A. Symptoms and Signs

Patients are usually healthy, without chronic hemolytic anemia or splenomegaly. Hemolysis occurs episodically as a result of oxidative stress on the red blood cells, generated either by infection or exposure to certain medications. Medications initiating hemolysis that should be avoided include dapsone, methylene blue, phenazopyridine, primaquine, rasburicase, toluidine blue, nitrofurantoin, trimethoprim/sulfamethoxazole, sulfadiazine, pegloticase, and quinolones. Other medications, such as chloroquine, quinine, high-dose aspirin, and isoniazid, have been implicated but are less certain as offenders since they are often given during infections. Even with continuous use of the offending medication, the hemolytic episode is self-limited because older red blood cells (with low enzyme activity) are removed and replaced with a population of young red blood cells (reticulocytes) with adequate functional levels of G6PD. Severe G6PD deficiency (as in Mediterranean variants) may produce a chronic hemolytic anemia.

B. Laboratory Findings

Between hemolytic episodes, the blood is normal. During episodes of hemolysis, the hemoglobin rarely falls below 8 g/dL (80 g/L), and there is reticulocytosis and increased serum indirect bilirubin. The peripheral blood cell smear often reveals a small number of “bite” cells—cells that appear to have had a bite taken out of their periphery, or “blister” cells (eFigure 13–11). This indicates pitting of precipitated membrane hemoglobin aggregates (ie, Heinz bodies) by the splenic macrophages. Heinz bodies may be demonstrated by staining a peripheral blood smear with cresyl violet (eFigure 13–12); they are not visible on the usual Wright-Giemsa–stained blood smear. Specific enzyme assays for G6PD reveal a low level but may be falsely normal if they are performed during or shortly after a hemolytic episode during the period of reticulocytosis. In these cases, the enzyme assays should be repeated weeks after hemolysis has resolved. In severe cases of G6PD deficiency, enzyme levels are always low.

TREATMENT

No treatment is necessary except to avoid known oxidant medications.

GENERAL CONSIDERATIONS

Sickle cell anemia is an autosomal recessive disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences. A single DNA base change leads to an amino acid substitution of valine for glutamate in the sixth position on the beta-globin chain. The abnormal beta chain is designated beta^s and the tetramer of alpha-2beta^s-2 is designated hemoglobin SS (eFigure 13–13). Hemoglobin S is unstable and polymerizes in the setting of various stressors, including hypoxemia and acidosis, leading to the formation of sickled red blood cells. Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. Adenosine binds to its receptor (A2B), resulting in the production of 2,3-biphosphoglycerate and the induction of more sickling, and to its receptor (A2A) on natural killer cells, resulting in pulmonary inflammation. The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction, vascular injury, and pulmonary hypertension.

The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. Hemoglobin F cannot participate in polymer formation, and its presence markedly retards sickling. Factors that increase sickling are red blood cell dehydration and factors that lead to formation of deoxyhemoglobin S (eg, acidosis and hypoxemia), either systemic or local in tissues. Hemolytic crises may be related to splenic sequestration of sickled cells (primarily in childhood before the spleen has been infarcted as a result of repeated sickling) or with coexistent disorders such as G6PD deficiency.

The beta^S gene is carried in 8% of American Blacks, and 1 of 400 American Black children will be born with sickle cell anemia; prenatal diagnosis is available when sickle cell anemia is suspected. Genetic counseling should be made available to patients.

CLINICAL FINDINGS

A. Symptoms and Signs

The disorder has its onset during the first year of life, when hemoglobin F levels fall as a signal is sent to switch from production of gamma-globin to beta-globin. Chronic hemolytic anemia produces jaundice, pigment (calcium bilirubinate) gallstones, splenomegaly (early in life), and poorly healing skin ulcers over the lower tibia. Life-threatening severe anemia can occur during hemolytic or aplastic crises, the latter generally associated with viral or other infection caused by immunoincompetence from hyposplenism or by folic acid deficiency causing reduced erythropoiesis.

Acute painful episodes due to acute vaso-occlusion from clusters of sickled red cells may occur spontaneously or be provoked by infection, dehydration, or hypoxia. Common sites of acute painful episodes include the spine and long appendicular bones. These episodes last hours to days and may produce low-grade fever. Acute vaso-occlusion may cause strokes due to sagittal sinus venous thrombosis or to bland or hemorrhagic central nervous system arterial ischemia. Vaso-occlusion may also cause priapism. Vaso-occlusive episodes are not associated with increased hemolysis.

Repeated episodes of vascular occlusion especially affect the heart, lungs, and liver. The acute chest syndrome is characterized by acute chest pain, hypoxemia, and pulmonary infiltrates on a chest radiograph and must be distinguished from an infectious pneumonia. Ischemic necrosis of bones may occur, rendering the bone susceptible to osteomyelitis due to salmonellae and (somewhat less commonly) staphylococci. Infarction of the papillae of the renal medulla causes renal tubular concentrating defects and gross hematuria, more often encountered in sickle cell trait than in sickle cell anemia. Retinopathy similar to that noted in diabetes mellitus is often present and may lead to visual impairment. Pulmonary hypertension may develop and is associated with a poor prognosis. These patients are prone to delayed puberty. An increased incidence of infection is related to hyposplenism as well as to defects in the alternate complement pathway.

On examination, patients are often chronically ill and jaundiced. There is often hepatomegaly, but the spleen is not palpable in adult life. The heart may be enlarged with a hyperdynamic precordium and systolic murmurs and, in some cases, a pronounced increase in P2. Nonhealing cutaneous ulcers of the lower leg and retinopathy may be present.

B. Laboratory Findings

Chronic hemolytic anemia is present. The hematocrit is usually 20–30%. The peripheral blood smear is characteristically abnormal, with sickled cells comprising 5–50% of red cells. Other findings include reticulocytosis (10–25%), nucleated red blood cells, and hallmarks of hyposplenism such as Howell-Jolly bodies and target cells (eFigure 13–14). The white blood cell count is characteristically elevated to 12,000–15,000/mcL (12–15 × 10⁹/L), and reactive thrombocytosis may occur. Indirect bilirubin levels are high.

The diagnosis of sickle cell anemia is confirmed by hemoglobin electrophoresis (Table 13–9). Hemoglobin S will usually comprise 85–98% of hemoglobin. In homozygous S disease, no hemoglobin A will be present. Hemoglobin F levels are sometimes increased, and high hemoglobin F levels (15–20%) are associated with a more benign clinical course. Patients with S-beta⁺-thalassemia and SS alpha-thalassemia also have a more benign clinical course than straight sickle cell anemia (SS) patients.

TREATMENT

When allogeneic hematopoietic stem cell transplantation is performed before the onset of significant end-organ damage, it can cure more than 80% of children with sickle cell anemia who have suitable HLA-matched donors, with a reasonably good quality of life. Transplantation remains investigational in adults. Other therapies modulate disease severity: hydroxyurea increases hemoglobin F levels epigenetically. Hydroxyurea (500–750 mg orally daily) reduces the frequency of painful crises in patients whose quality of life is disrupted by frequent vaso-occlusive pain episodes (three or more per year). Long-term follow-up of patients taking hydroxyurea demonstrates it improves overall survival and quality of life with little evidence for secondary malignancy. The use of omega-3 (n-3) fatty acid supplementation may also reduce vaso-occlusive episodes and reduce transfusion needs in patients with sickle cell anemia. L-glutamine has been shown to favorably modulate sickle pain crises and acute chest syndrome. A monoclonal antibody (crizanlizumab-tmca) reduces vaso-occlusive episodes by 50%. It blocks P-selectin on activated endothelial cells and thus disrupts the adverse interactions of platelets, red blood cells, and leukocytes with the endothelial wall. Voxelotor inhibits the polymerization of deoxygenated sickle red blood cells and increases the hemoglobin in SS patients age 12 years or older.

Supportive care is the mainstay of treatment for sickle cell anemia. Patients are maintained on folic acid supplementation (1 mg orally daily) and given transfusions for aplastic or hemolytic crises. When acute painful episodes occur, precipitating factors should be identified and infections treated if present. The patient should be kept well hydrated, given generous analgesics, and supplied oxygen if hypoxic. Pneumococcal vaccination reduces the incidence of infections with this pathogen while hydroxyurea and L-glutamine reduce hospitalizations for acute pain. Angiotensin-converting enzyme inhibitors are recommended in patients with microalbuminuria.

Exchange transfusions are indicated for the treatment of severe or intractable acute vaso-occlusive crises, acute chest syndrome, priapism, and stroke. Long-term transfusion therapy has been shown to be effective in reducing the risk of recurrent stroke in children. Phenotypically matched transfused red blood cells are recommended to reduce the risk of red blood cell alloimmunization. It has been recommended that children with SS who are aged 2–16 years have annual transcranial ultrasounds and, if the Doppler velocity is abnormal (200 cm/s or greater), the clinician should strongly consider beginning transfusions to prevent stroke. Iron chelation is needed for those on chronic transfusion therapy.

PROGNOSIS

Sickle cell anemia becomes a chronic multisystem disease, leading to organ failure that may result in early death. With improved supportive care, average life expectancy is now between 40 and 50 years of age.

WHEN TO REFER

Patients with sickle cell anemia should have their care coordinated with a hematologist and should be referred to a Comprehensive Sickle Cell Center, if one is available.

WHEN TO ADMIT

Patients should be admitted for management of acute chest syndrome, for aplastic crisis, or for painful episodes that do not respond to outpatient interventions.

People with the heterozygous hemoglobin genotype AS have sickle cell trait. These persons are hematologically normal, with no anemia and normal red blood cells on peripheral blood smear. A screening test for sickle hemoglobin will be positive, and Hemoglobin electrophoresis will reveal that approximately 40% of hemoglobin is hemoglobin S (Table 13–9). People with sickle cell trait experience more rhabdomyolysis during vigorous exercise but do not have increased mortality compared to the general population. They may be at increased risk for venous thromboembolism. Chronic sickling of red blood cells in the acidotic renal medulla results in microscopic and gross hematuria, hyposthenuria (poor urine concentrating ability), and possibly chronic kidney disease. No treatment is necessary but genetic counseling is recommended.

Patients with homozygous sickle cell anemia and alpha-thalassemia have less vigorous hemolysis and run higher hemoglobins than SS patients due to reduced red blood cell sickling related to a lower hemoglobin concentration within the red blood cell and higher hemoglobin F levels (Table 13–9). The MCV is low, and the red cells are hypochromic.

Patients who are compound heterozygotes for beta^s and beta-thalassemia are clinically affected with sickle cell syndromes. Sickle beta⁰-thalassemia is clinically very similar to homozygous SS disease. Vaso-occlusive crises may be somewhat less severe, and the spleen is not always infarcted. The MCV is low, in contrast to the normal MCV of sickle cell anemia. Hemoglobin electrophoresis reveals no hemoglobin A but will show an increase in hemoglobins A₂ and F (Table 13–9).

Sickle beta⁺-thalassemia is a milder disorder than homozygous SS disease, with fewer pain episodes but more acute chest syndrome than sickle beta⁰-thalassemia. The spleen is usually palpable. The hemolytic anemia is less severe, and the hematocrit is usually 30–38%, with reticulocytes of 5–10%. Hemoglobin electrophoresis shows the presence of some hemoglobin A and elevated hemoglobins A₂ and F (Table 13–9). The MCV is low.

Hemoglobin C is formed by a single amino acid substitution at the same site as in sickle hemoglobin (codon 6 of the beta globin gene) but with lysine instead of valine substituted for glutamate. Hemoglobin C is nonsickling but may participate in polymer formation in association with hemoglobin S. Homozygous hemoglobin C disease produces a mild hemolytic anemia with splenomegaly, mild jaundice, and pigment (calcium bilirubinate) gallstones. The peripheral blood smear shows generalized red cell targeting and occasional cells with angular crystals of hemoglobin C (eFigure 13–15). Persons heterozygous for hemoglobin C are clinically normal.

Patients with hemoglobin SC disease are compound heterozygotes for beta^S and beta^C. These patients, like those with sickle beta⁺-thalassemia, have a milder hemolytic anemia and milder clinical course than those with homozygous SS disease and they live longer. There are fewer vaso-occlusive events, and the spleen remains palpable in adult life. However, persons with hemoglobin SC disease have more retinopathy and more priapism than those with SS disease. The hematocrit is usually 30–38%, with 5–10% reticulocytes, and compared to SS, fewer irreversibly sickled cells on the blood smear. Target cells are more numerous than in SS disease. Hemoglobin electrophoresis will show approximately 45–50% hemoglobin C, 50% hemoglobin S, and no increase in hemoglobin F levels.

Unstable hemoglobins are prone to oxidative denaturation even in the presence of a normal G6PD system. The disorder is autosomal dominant and of variable severity. Most patients have a mild chronic hemolytic anemia with splenomegaly, mild jaundice, and pigment (calcium bilirubinate) gallstones. Less severely affected patients are not anemic except under conditions of oxidative stress.

The diagnosis is suspected by the finding of Heinz bodies combined with a normal G6PD level when checked during a period of hemolytic quiescence. Hemoglobin electrophoresis is usually normal, since these hemoglobins characteristically do not have a change in their migration pattern. These hemoglobins precipitate in isopropanol. Usually no treatment is necessary. Patients with chronic hemolytic anemia should receive folic acid supplementation (1 mg orally) and avoid known oxidative drugs. In rare cases, splenectomy may be required.

GENERAL CONSIDERATIONS

Warm autoimmune hemolytic anemia is an acquired disorder in which an IgG autoantibody is formed that binds to a red blood cell membrane protein and does so most avidly at body temperature (ie, a “warm” autoantibody). The antibody is most commonly directed against a basic component of the Rh system present on most human red blood cells. When IgG antibodies coat the red blood cell, the Fc portion of the antibody is recognized by macrophages present in the spleen and other portions of the reticuloendothelial system. The interaction between splenic macrophages and the antibody-coated red blood cell results in removal of red blood cell membrane and the formation of a spherocyte due to the decrease in surface-to-volume ratio of the surviving red blood cell. These spherocytic cells have decreased deformability and are unable to squeeze through the 2-mcm fenestrations of splenic sinusoids and become trapped in the red pulp of the spleen. When large amounts of IgG are present on red blood cells, complement may be fixed. Direct complement lysis of cells is rare, but the presence of C3b on the surface of red blood cells allows Kupffer cells in the liver to participate in the hemolytic process via C3b receptors. The destruction of red blood cells in the spleen and liver designates this as extravascular hemolysis.

Approximately one-half of all cases of autoimmune hemolytic anemia are idiopathic. The disorder may also be seen in association with systemic lupus erythematosus, other rheumatic disorders, chronic lymphocytic leukemia (CLL), or lymphomas. It must be distinguished from drug-induced hemolytic anemia. When penicillin (or other medications, especially cefotetan, ceftriaxone, and piperacillin) coats the red blood cell membrane, the autoantibody is directed against the membrane-drug complex. Fludarabine, an antineoplastic, causes autoimmune hemolytic anemia through its immunosuppression; there is defective self- versus non–self-immune surveillance permitting the escape of a B-cell clone, which produces the offending autoantibody.

CLINICAL FINDINGS

A. Symptoms and Signs

Autoimmune hemolytic anemia typically produces an anemia of rapid onset that may be life-threatening. Patients complain of fatigue and dyspnea and may present with angina pectoris or heart failure. On examination, jaundice and splenomegaly are usually present.

B. Laboratory Findings

The anemia is of variable degree but may be very severe, with hematocrit of less than 10%. Reticulocytosis is present, and spherocytes are seen on the peripheral blood smear. In cases of severe hemolysis, the stressed bone marrow may also release nucleated red blood cells (eFigure 13–16). As with other hemolytic disorders, the serum indirect bilirubin is increased and the haptoglobin is low. Approximately 10% of patients with autoimmune hemolytic anemia have coincident immune thrombocytopenia (Evans syndrome).

The antiglobulin (Coombs) test forms the basis for diagnosis. The Coombs reagent is a rabbit IgM antibody raised against human IgG or human complement. The direct antiglobulin (Coombs) test (DAT) is performed by mixing the patient’s red blood cells with the Coombs reagent and looking for agglutination, which indicates the presence of antibody or complement or both on the red blood cell surface. The indirect antiglobulin (Coombs) test is performed by mixing the patient’s serum with a panel of type O red blood cells. After incubation of the test serum and panel red blood cells, the Coombs reagent is added. Agglutination in this system indicates the presence of free antibody (autoantibody or alloantibody) in the patient’s serum.

The direct antiglobulin test is positive (for IgG, complement, or both) in about 90% of patients with autoimmune hemolytic anemia. The indirect antiglobulin test may or may not be positive. A positive indirect antiglobulin test indicates the presence of a large amount of autoantibody that has saturated binding sites on the red blood cell and consequently appears in the serum. Because the patient’s serum usually contains the autoantibody, it may be difficult to obtain a “compatible” cross-match with homologous red blood cells for transfusions since the cross-match indicates the possible presence (true or false) of a red blood cell “alloantibody.”

TREATMENT

Initial treatment consists of prednisone, 1–2 mg/kg/day orally in divided doses. Patients with DAT-negative and DAT-positive autoimmune hemolysis respond equally well to corticosteroids. Transfused red blood cells will survive similarly to the patient’s own red blood cells. Because of difficulty in performing the cross-match, possible “incompatible” blood may need to be given. Decisions regarding transfusions should be made in consultation with a hematologist and a blood bank specialist. Death from cardiovascular collapse can occur in the setting of rapid hemolysis. In patients with rapid hemolysis, therapeutic plasmapheresis should be performed early in management to remove autoantibodies. If prednisone is ineffective or if the disease recurs on tapering the dose, splenectomy should be considered, which may cure the disorder. Patients with autoimmune hemolytic anemia refractory to prednisone and splenectomy may also be treated with a variety of agents. Treatment with rituximab, a monoclonal antibody against the B cell antigen CD20, is effective in some cases. The suggested dose is 375 mg/m² intravenously weekly for 4 weeks. Rituximab is used in conjunction with corticosteroids as initial therapy in some patients with severe disease. In patients with past hepatitis B virus (HBV) infection, rituximab should be used with anti-HBV agent prophylaxis since HBV reactivation, fulminant hepatitis, and, rarely, death can occur otherwise. Danazol, 400–800 mg/day orally, is less often effective than in immune thrombocytopenia but is well suited for long-term use because of its low toxicity profile. Immunosuppressive agents, including cyclophosphamide, vincristine, azathioprine, mycophenolate mofetil, alemtuzumab (an anti-CD52 antibody), or cyclosporine, may also be used. High-dose intravenous immune globulin (1 g/kg daily for 2 days) may be effective in controlling hemolysis. The benefit is short-lived (1–3 weeks), and immune globulin is very expensive. The long-term prognosis for patients with this disorder is good, especially if there is no other underlying autoimmune disorder or lymphoproliferative disorder. Treatment of an associated lymphoproliferative disorder will also treat the hemolytic anemia.

WHEN TO REFER

Patients with autoimmune hemolytic anemia should be referred to a hematologist for confirmation of the diagnosis and subsequent care.

WHEN TO ADMIT

Patients should be hospitalized for symptomatic anemia or rapidly falling hemoglobin levels.

GENERAL CONSIDERATIONS

Cold agglutinin disease is an acquired hemolytic anemia due to an IgM autoantibody (called a “cold agglutinin”) usually directed against the I/i antigen on red blood cells. These IgM autoantibodies characteristically will react poorly with cells at 37°C but avidly at lower temperatures, usually at 0–4°C (ie, “cold” autoantibody). Since the blood temperature (even in the most peripheral parts of the body) rarely goes lower than 20°C, only cold autoantibodies reactive at relatively higher temperatures will produce clinical effects. Hemolysis results indirectly from attachment of IgM, which in the cooler parts of the circulation (fingers, nose, ears) binds and fixes complement. When the red blood cell returns to a warmer temperature, the IgM antibody dissociates, leaving complement on the cell. Complement lysis of red blood cells rarely occurs. Rather, C3b, present on the red blood cells, is recognized by Kupffer cells (which have receptors for C3b), and red blood cell sequestration and destruction in the liver ensues (extravascular hemolysis). However, in some cases, the complement membrane attack complex forms, lysing the red blood cells (intravascular hemolysis).

Most cases of chronic cold agglutinin disease are idiopathic. Others occur in association with Waldenström macroglobulinemia, lymphoma, or CLL, in which a monoclonal IgM paraprotein is produced. Acute postinfectious cold agglutinin disease occurs following mycoplasma pneumonia or viral infection (infectious mononucleosis, measles, mumps, or cytomegalovirus [CMV] with autoantibody directed against antigen i rather than I).

CLINICAL FINDINGS

A. Symptoms and Signs

In chronic cold agglutinin disease, symptoms related to red blood cell agglutination occur on exposure to cold, and patients may complain of mottled or numb fingers or toes, acrocyanosis, episodic low back pain, and dark-colored urine. Hemolytic anemia is occasionally severe, but episodic hemoglobinuria may occur on exposure to cold. The hemolytic anemia in acute postinfectious syndromes is rarely severe.

B. Laboratory Findings

Mild anemia is present with reticulocytosis and rarely spherocytes. The blood smear made at room temperature shows agglutinated red blood cells (there is no agglutination on a blood smear made at body temperature). The direct antiglobulin (Coombs) test will be positive for complement only. Serum cold agglutinin titer will semi-quantitate the autoantibody. A monoclonal IgM is often found on serum protein electrophoresis and confirmed by serum immunoelectrophoresis. There is indirect hyperbilirubinemia and the haptoglobin is low during periods of hemolysis.

TREATMENT

Treatment is largely symptomatic, based on avoiding exposure to cold. Splenectomy and prednisone are usually ineffective (except when associated with a lymphoproliferative disorder) since hemolysis takes place in the liver and blood stream. Rituximab is the treatment of choice but in patients with past HBV infection, it must be used with anti-HBV prophylaxis. The dose is 375 mg/m² intravenously weekly for 4 weeks. Relapses may be effectively re-treated. High-dose intravenous immunoglobulin (2 g/kg) may be effective temporarily, but it is rarely used because of the high cost and short duration of benefit. Patients with severe disease may be treated with cytotoxic agents, such as bendamustine (plus rituximab), cyclophosphamide, fludarabine, or bortezomib, or with immunosuppressive agents, such as cyclosporine. As in warm IgG-mediated autoimmune hemolysis, it may be difficult to find compatible blood for transfusion. Red blood cells should be transfused through an in-line blood warmer.

The microangiopathic hemolytic anemias are a group of disorders in which red blood cell fragmentation takes place. The anemia is intravascular, producing hemoglobinemia, hemoglobinuria and, in severe cases, methemalbuminemia. The hallmark of the disorder is the finding of fragmented red blood cells (schistocytes, helmet cells) on the peripheral blood smear (eFigure 13–17).

These fragmentation syndromes can be caused by a variety of disorders (Table 13–8). Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome are the most important of these and is discussed in Chapter 14. Clinical features are variable and depend on the underlying disorder. Thrombocytopenia is uniformly present. Coagulopathy is variably present and depends on the underlying disorder driving the microangiopathy.

Chronic microangiopathic hemolytic anemia (such as is present with a malfunctioning cardiac valve prosthesis) may cause iron deficiency anemia because of continuous low-grade hemoglobinuria.

GENERAL CONSIDERATIONS

Aplastic anemia is a condition of bone marrow failure that arises from suppression of, or injury to, the hematopoietic stem cell. The bone marrow becomes hypoplastic, fails to produce mature blood cells, and pancytopenia develops.

There are a number of causes of aplastic anemia (Table 13–10). Direct hematopoietic stem cell injury may be caused by radiation, chemotherapy, toxins, or pharmacologic agents. Systemic lupus erythematosus may rarely cause suppression of the hematopoietic stem cell by an IgG autoantibody directed against it. However, the most common pathogenesis of aplastic anemia appears to be autoimmune suppression of hematopoiesis by a T-cell-mediated cellular mechanism, so-called idiopathic aplastic anemia. In some cases of idiopathic aplastic anemia, defects in maintenance of the hematopoietic stem cell telomere length (eg, dyskeratosis congenita) or in DNA repair pathways (eg, Fanconi anemia) have been identified and are likely linked to both the initiation of bone marrow failure and the propensity to later progress to myelodysplasia, PNH, or AML. Complex detrimental immune responses to viruses can also cause aplastic anemia.

CLINICAL FINDINGS

A. Symptoms and Signs

Patients come to medical attention because of the consequences of bone marrow failure. Anemia leads to symptoms of weakness and fatigue, neutropenia causes vulnerability to bacterial or fungal infections, and thrombocytopenia results in mucosal and skin bleeding. Physical examination may reveal signs of pallor, purpura, and petechiae (eFigure 13–18). Other abnormalities such as hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present, and their presence should lead to questioning the diagnosis.

B. Laboratory Findings

The hallmark of aplastic anemia is pancytopenia. However, early in the evolution of aplastic anemia, only one or two cell lines may be reduced.

Anemia may be severe and is always associated with reticulocytopenia. Red blood cell morphology is unremarkable, but there may be mild macrocytosis (increased MCV). Neutrophils and platelets are reduced in number, and no immature or abnormal forms are seen on the blood smear. The bone marrow aspirate and the bone marrow biopsy appear hypocellular, with only scant amounts of morphologically normal hematopoietic progenitors. The prior dictum that the bone marrow karyotype should be normal (or germline if normal variant) has evolved and some clonal abnormalities or other genetic aberrations may be present even in the setting of idiopathic aplastic anemia.

DIFFERENTIAL DIAGNOSIS

Aplastic anemia must be differentiated from other causes of pancytopenia (Table 13–11). Hypocellular forms of myelodysplasia or acute leukemia may occasionally be confused with aplastic anemia. These are differentiated by the presence of cellular morphologic abnormalities, increased percentage of blasts, or abnormal karyotype in bone marrow cells typical of MDS or acute leukemia. Hairy cell leukemia has been misdiagnosed as aplastic anemia and should be recognized by the presence of splenomegaly and by abnormal “hairy” lymphoid cells in a hypocellular bone marrow biopsy. Pancytopenia with a normocellular bone marrow may be due to systemic lupus erythematosus, disseminated infection, hypersplenism, nutritional (eg, vitamin B₁₂ or folate) deficiency, or myelodysplasia. Isolated thrombocytopenia may occur early as aplastic anemia develops and may be confused with immune thrombocytopenia.

TREATMENT

Mild cases of aplastic anemia may be treated with supportive care, including erythropoietic (epoetin or darbepoetin) or myeloid (filgrastim or sargramostim or biosimilars) growth factors, or both. Red blood cell transfusions and platelet transfusions are given as necessary, and antibiotics are used to treat infections.

Severe aplastic anemia is defined by a neutrophil count of less than 500/mcL (0.5 × 10⁹/L), platelets less than 20,000/mcL (20 × 10⁹/L), reticulocytes less than 1%, and bone marrow cellularity less than 20%. The treatment of choice for young adults (under age 40 years) who have an HLA-matched sibling is allogeneic bone marrow transplantation. Children or young adults may also benefit from allogeneic bone marrow transplantation using an unrelated donor. Because of the increased risks associated with unrelated donor allogeneic bone marrow transplantation compared to sibling donors, this treatment is usually reserved for patients who have not responded to immunosuppressive therapy.

For adults over age 40 years or those without HLA-matched hematopoietic stem cell donors, the treatment of choice for severe idiopathic aplastic anemia is immunosuppression with equine antithymocyte globulin (ATG) plus cyclosporine. Equine ATG is given in the hospital in conjunction with transfusion and antibiotic support. A proven regimen is equine ATG 40 mg/kg/day intravenously for 4 days in combination with cyclosporine, 6 mg/kg orally twice daily. Equine ATG is superior to rabbit ATG, resulting in a higher response rate and better survival. Eltrombopag, a thrombopoietin mimetic, is now being added to ATG plus cyclosporine with tri-lineage hematologic responses as high as 90%. ATG should be used in combination with corticosteroids (prednisone or methylprednisolone 1–2 mg/kg/day orally for 1 week, followed by a taper over 2 weeks) to avoid ATG infusion reactions and serum sickness. Responses usually occur in 1–3 months and are usually only partial, but the blood counts rise high enough to give patients a safe and transfusion-free life. The full benefit of immunosuppression is generally assessed at 4 months post-equine ATG. Cyclosporine and eltrombopag are maintained at full doses for 6 months and then stopped in responding patients. Androgens (such as fluoxymesterone 10–20 mg/day orally in divided doses or danazol 200 mg orally twice daily) have been widely used in the past, with a low response rate, and may be considered in mild cases. Androgens appear to partially correct telomere length maintenance defects and increase the production of endogenous erythropoietin.

COURSE & PROGNOSIS

Patients with severe aplastic anemia have a rapidly fatal illness if left untreated. Allogeneic bone marrow transplant from an HLA-matched sibling donor produces survival rates of over 80% in recipients under 20 years old and of about 65–70% in those 20 to 50 years old. Respective survival rates drop 10–15% when the donor is HLA-matched but unrelated. Equine ATG-cyclosporine immunosuppressive treatment leads to a response in approximately 70% of patients (including those with hepatitis virus–associated aplastic anemia) and in up to 90% of patients with the addition of eltrombopag. Up to one-third of patients will relapse with aplastic anemia after ATG-based therapy. Clonal hematologic disorders, such as PNH, AML, or myelodysplasia, may develop in one-quarter of patients treated with immunosuppressive therapy after 10 years of follow-up. Factors that predict response to ATG-cyclosporine therapy are patient’s age, reticulocyte count, lymphocyte count, and age-adjusted telomere length of leukocytes at the time of diagnosis.

WHEN TO REFER

All patients should be referred to a hematologist.

WHEN TO ADMIT

Admission is necessary for treatment of neutropenic infection, the administration of ATG, or allogeneic bone marrow transplantation.

GENERAL CONSIDERATIONS

Neutropenia is present when the absolute neutrophil count is less than 1800/mcL (1.8 × 10⁹/L), although Blacks, Asians, and other specific ethnic groups may have normal neutrophil counts as low as 1200/mcL (1.2 × 10⁹/L) or even less. The neutropenic patient is increasingly vulnerable to infection by gram-positive and gram-negative bacteria and by fungi. The risk of infection is related to the severity of neutropenia. The risk of serious infection rises sharply with neutrophil counts below 500/mcL (0.5 × 10⁹/L), and a high risk of infection within days occurs with neutrophil counts below 100/mcL (0.1 × 10⁹/L) (“profound neutropenia”). The classification of neutropenic syndromes is unsatisfactory as the pathophysiology and natural history of different syndromes overlap. Patients with “chronic benign neutropenia” are free of infection despite very low stable neutrophil counts; they seem to physiologically respond adequately to infections and inflammatory stimuli with an appropriate neutrophil release from the bone marrow. In contrast, the neutrophil count of patients with cyclic neutropenia periodically oscillates (usually in 21-day cycles) between normal and low, with infections occurring during the nadirs. Congenital neutropenia is lifelong neutropenia punctuated with infection. Both cyclic neutropenia and congenital neutropenia represent problems in mutations in the neutrophil elastase gene ELANE (also called ELA-2).

A variety of bone marrow disorders and non-marrow conditions may cause neutropenia (Table 13–12). All of the causes of aplastic anemia (Table 13–10) and pancytopenia (Table 13–11) may cause neutropenia. The new onset of an isolated neutropenia is most often due to an idiosyncratic reaction to a medication, and agranulocytosis (complete absence of neutrophils in the peripheral blood) is almost always due to a drug reaction. In these cases, examination of the bone marrow shows an almost complete absence of granulocyte precursors with other cell lines undisturbed. This marrow finding is also seen in pure white blood cell aplasia, an autoimmune attack on marrow granulocyte precursors. Neutropenia in the presence of a normal bone marrow may be due to immunologic peripheral destruction (autoimmune neutropenia), sepsis, or hypersplenism. The presence in the serum of antineutrophil antibodies supports the diagnosis of autoimmune neutropenia but does not prove this as the pathophysiologic reason for neutropenia. Felty syndrome is an immune neutropenia associated with seropositive nodular rheumatoid arthritis and splenomegaly. Severe neutropenia may be associated with clonal disorders of T lymphocytes, often with the morphology of large granular lymphocytes, referred to as CD3-positive T-cell large granular lymphoproliferative disorder. Isolated neutropenia is an uncommon presentation of hairy cell leukemia or MDS. By its nature, myelosuppressive cytotoxic chemotherapy causes neutropenia in a predictable manner.

CLINICAL FINDINGS

Neutropenia results in stomatitis and in infections due to gram-positive or gram-negative aerobic bacteria or to fungi such as Candida or Aspergillus. The most common infectious syndromes are septicemia, cellulitis, pneumonia, and neutropenic fever of unknown origin. Fever in neutropenic patients should always be initially assumed to be of infectious origin until proven otherwise (Chapter 30).

TREATMENT

Treatment of neutropenia depends on its cause. Potential causative medications should be discontinued. Myeloid growth factors (filgrastim or sargramostim or biosimilar myeloid growth factors) help facilitate neutrophil recovery after offending medications are stopped. Chronic myeloid growth factor administration (daily or every other day) is effective at dampening the neutropenia seen in cyclic or congenital neutropenia. When Felty syndrome leads to repeated bacterial infections, splenectomy has been the treatment of choice, but sustained use of myeloid growth factors is effective and provides a nonsurgical alternative. Patients with autoimmune neutropenia often respond briefly to immunosuppression with corticosteroids and are best managed with intermittent doses of myeloid growth factors. Patients with true pure white blood cell aplasia need immunosuppression with ATG and cyclosporine, as in aplastic anemia and pure red blood cell aplasia. The neutropenia associated with large granular lymphoproliferative disorder may respond to therapy with oral methotrexate, cyclophosphamide, or cyclosporine.

Fevers during neutropenia should be considered as infectious until proven otherwise. Febrile neutropenia is a life-threatening circumstance. Enteric gram-negative bacteria are of primary concern and often empirically treated with fluoroquinolones or third- or fourth-generation cephalosporins (see Infections in the Immunocompromised Patient, Chapter 30). For protracted neutropenia, fungal infections are problematic and empiric coverage with azoles (fluconazole for yeast and voriconazole, itraconazole, posaconazole, or isavuconazole for molds) or echinocandins is recommended. The neutropenia following myelosuppressive chemotherapy is predictable and is partially ameliorated by the use of myeloid growth factors. For patients with acute leukemia undergoing intense chemotherapy or patients with solid cancer undergoing high-dose chemotherapy, the prophylactic use of antimicrobial agents and myeloid growth factors is recommended.

WHEN TO REFER

Refer to a hematologist if neutrophils are persistently and unexplainably less than 1000/mcL (1.0 × 10⁹/L).

WHEN TO ADMIT

Neutropenia by itself is not an indication for hospitalization. However, many patients with severe neutropenia may have a serious underlying disease that may require inpatient treatment. Most patients with febrile neutropenia require hospitalization to treat infection.

Myeloproliferative disorders are due to acquired clonal abnormalities of the hematopoietic stem cell (eFigure 13–19). Since the stem cell gives rise to myeloid, erythroid, and platelet cells, qualitative and quantitative changes are seen in all of these cell lines. Classically, the myeloproliferative disorders produce characteristic syndromes with well-defined clinical and laboratory features (Tables 13–13 and 13–14). However, these disorders are grouped together because they may evolve from one into another and because hybrid disorders are commonly seen. All of the myeloproliferative disorders may progress to AML.

The Philadelphia chromosome seen in chronic myeloid leukemia (CML) was the first recurrent cytogenetic abnormality to be described in a human malignancy. Since that time, there has been tremendous progress in elucidating the genetic nature of these disorders, with identification of mutations in JAK2, MPL, CALR, CSF3R, and other genes.

GENERAL CONSIDERATIONS

Polycythemia vera is an acquired myeloproliferative disorder that causes overproduction of all three hematopoietic cell lines, most prominently the red blood cells. Erythroid production is independent of erythropoietin, and the serum erythropoietin level is low. True erythrocytosis, with an elevated red blood cell mass, should be distinguished from spurious erythrocytosis caused by a constricted plasma volume.

A mutation in exon 14 of JAK2 (V617F), a signaling molecule, has been demonstrated in 95% of cases. Additional JAK2 mutations have been identified (exon 12) and suggest that JAK2 is involved in the pathogenesis of this disease and is a potential therapeutic target.

CLINICAL FINDINGS

A. Symptoms and Signs

Headache, dizziness, tinnitus, blurred vision, and fatigue are common complaints related to expanded blood volume and increased blood viscosity. Generalized pruritus, especially following a warm shower or bath, is related to histamine release from the basophilia. Epistaxis is probably related to engorgement of mucosal blood vessels in combination with abnormal hemostasis. Sixty percent of patients are men, and the median age at presentation is 60 years. Polycythemia rarely occurs in persons under age 40 years.

Physical examination reveals plethora and engorged retinal veins. The spleen is palpable in 75% of cases but is nearly always enlarged when imaged. Thrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death in this disorder. Thrombosis appears to be related both to increased blood viscosity and abnormal platelet function. Uncontrolled polycythemia leads to a very high incidence of thrombotic complications of surgery, and elective surgery should be deferred until the condition has been treated. Paradoxically, in addition to thrombosis, increased bleeding can occur. There is also a high incidence of peptic ulcer disease.

B. Laboratory Findings

According to the WHO 2016 criteria, the hallmark of polycythemia vera is a hematocrit (at sea level) that exceeds 49% in males or 48% in females. Red blood cell morphology is normal (Table 13–14; see red cells in eFigure 13–1). The white blood count is usually elevated to 10,000–20,000/mcL (10–20 × 10⁹/L), and the platelet count is variably increased, sometimes to counts exceeding 1,000,000/mcL (1000 × 10⁹/L). Platelet morphology is usually normal. White blood cells are usually normal, but basophilia and eosinophilia are frequently present. Erythropoietin is suppressed and serum levels, usually low. The diagnosis should be confirmed with JAK2 mutation screening. The absence of a mutation in either exon 14 (most common) or 12 should lead the clinician to question the diagnosis.

The bone marrow is hypercellular, with panhyperplasia of all hematopoietic elements, but bone marrow examination is not necessary to establish the diagnosis. Iron stores are usually absent from the bone marrow, having been transferred to the increased circulating red blood cell mass. Iron deficiency may also result from chronic gastrointestinal blood loss. Bleeding may lower the hematocrit to the normal range (or lower), creating diagnostic confusion, and may lead to a situation with significant microcytosis yet a normal hematocrit.

Vitamin B₁₂ levels are strikingly elevated because of increased levels of transcobalamin III (secreted by white blood cells). Overproduction of uric acid may lead to hyperuricemia.

Although red blood cell morphology is usually normal at presentation, microcytosis, hypochromia, and poikilocytosis may result from iron deficiency following treatment by phlebotomy (see eFigure 13–2). Progressive hypersplenism may also lead to elliptocytosis (eg, with red cells the size and shape of those in hereditary elliptocytosis) (eFigure 13–20).

DIFFERENTIAL DIAGNOSIS

Spurious polycythemia, in which an elevated hematocrit is due to contracted plasma volume rather than increased red cell mass, may be related to diuretic use or may occur without obvious cause.

A secondary cause of polycythemia should be suspected if splenomegaly is absent and the high hematocrit is not accompanied by increases in other cell lines. Secondary causes of polycythemia include hypoxia and smoking; carboxyhemoglobin levels may be elevated in smokers (Table 13–15). A renal CT scan or sonogram may be considered to look for an erythropoietin-secreting cyst or tumor. A positive family history should lead to investigation for a congenital high-oxygen-affinity hemoglobin. An absence of a mutation in JAK2 suggests a different diagnosis. However, JAK2 mutations are also commonly found in other myeloproliferative disorders, essential thrombocytosis, and myelofibrosis.

Polycythemia vera should be differentiated from other myeloproliferative disorders (Table 13–14). Marked elevation of the white blood count (above 30,000/mcL [30 × 10⁹/L]) suggests CML. Abnormal red blood cell morphology and nucleated red blood cells in the peripheral blood are seen in myelofibrosis. Essential thrombocytosis is suggested when the platelet count is strikingly elevated.

TREATMENT

The treatment of choice is phlebotomy. One unit of blood (approximately 500 mL) is removed weekly until the hematocrit is less than 45%; the hematocrit is maintained at less than 45% by repeated phlebotomy as necessary. Patients for whom phlebotomy is problematic (because of poor venous access or logistical reasons) may be managed primarily with hydroxyurea. Because repeated phlebotomy intentionally produces iron deficiency, the requirement for phlebotomy should gradually decrease. It is important to avoid medicinal iron supplementation, as this can thwart the goals of a phlebotomy program. A diet low in iron is not necessary but will increase the intervals between phlebotomies. Maintaining the hematocrit at normal levels has been shown to decrease the incidence of thrombotic complications.

Occasionally, myelosuppressive therapy is indicated. Indications include a high phlebotomy requirement, thrombocytosis, and intractable pruritus. There is evidence that reduction of the platelet count to less than 600,000/mcL (600 × 10⁹/L) will reduce the risk of thrombotic complications. Hydroxyurea is widely used when myelosuppressive therapy is indicated. The usual dose is 500–1500 mg/day orally, adjusted to keep platelets less than 500,000/mcL (500 × 10⁹/L) without reducing the neutrophil count to less than 2000/mcL (2.0 × 10⁹/L). The JAK2 inhibitor ruxolitinib is FDA-approved for patients resistant or intolerant to hydroxyurea. In a randomized study comparing best available therapy to ruxolitinib, treatment with ruxolitinib was associated with greater benefit for both hematocrit control without phlebotomy (60%) and splenic volume reduction (38%). Symptom burden improved by greater than 50% in 49% of patients.

A randomized phase 3 trial comparing ropeginterferon alfa-2b, a novel interferon, to hydroxyurea demonstrated improved disease control rates in patients presenting without splenomegaly with 53% vs 38% of patients achieving a complete hematologic response and with improved disease burden at 3 years’ follow up. Toxicity included abnormal liver biochemical tests in the ropeginterferon alfa-2b group, and leukopenia and thrombocytopenia in the standard therapy group, with serious adverse events occurring in 2% in the former and 4% in the latter group. As a result, ropeginterferon alfa-2b was approved by the European Medicines Agency as first-line therapy for patients without symptomatic splenomegaly. Alkylating agents, such as busulfan and pipobroman, have been shown to increase the risk of conversion of this disease to acute leukemia and should be avoided. Lastly, a new and promising therapeutic strategy is induction of apoptosis via the p53 pathway through pharmacologic inhibition of human double minute 2 (mdm2).

Low-dose aspirin (75–81 mg/day orally) has been shown to reduce the risk of thrombosis without excessive bleeding and should be part of therapy for all patients without contraindications to aspirin. Allopurinol 300 mg orally daily may be indicated for hyperuricemia. Antihistamine therapy with diphenhydramine or other H₁-blockers and, rarely, selective serotonin reuptake inhibitors are used to manage pruritus.

PROGNOSIS

Polycythemia is an indolent disease with median survival of over 15 years. The major cause of morbidity and mortality is arterial thrombosis. Over time, polycythemia vera may convert to myelofibrosis or to CML. In approximately 5% of cases, the disorder progresses to AML, which is usually refractory to therapy.

WHEN TO REFER

Patients with polycythemia vera should be referred to a hematologist.

WHEN TO ADMIT

Inpatient care is rarely required.

GENERAL CONSIDERATIONS

Essential thrombocytosis is an uncommon myeloproliferative disorder of unknown cause in which marked proliferation of the megakaryocytes in the bone marrow leads to elevation of the platelet count. As with polycythemia vera, the finding of a high frequency of mutations of JAK2 and others in these patients has advanced the understanding of this disorder.

CLINICAL FINDINGS

A. Symptoms and Signs

The median age at presentation is 50–60 years, and there is a slightly increased incidence in women. The disorder is often suspected when an elevated platelet count is found. Less frequently, the first sign is thrombosis, which is the most common clinical problem. The risk of thrombosis rises with age. Venous thromboses may occur in unusual sites such as the mesenteric, hepatic, or portal vein. Some patients experience erythromelalgia, painful burning of the hands accompanied by erythema; this symptom is reliably relieved by aspirin. Bleeding, typically mucosal, is less common and is related to a concomitant qualitative platelet defect. Splenomegaly is present in at least 25% of patients.

B. Laboratory Findings

An elevated platelet count is the hallmark of this disorder, and may be over 2,000,000/mcL (2000 × 10⁹/L) (Table 13–14). The white blood cell count is often mildly elevated, usually not above 30,000/mcL (30 × 10⁹/L), but with some immature myeloid forms. The hematocrit is normal. The peripheral blood smear reveals large platelets, but giant degranulated forms seen in myelofibrosis are not observed. Red blood cell morphology is normal.

The bone marrow shows increased numbers of megakaryocytes but no other morphologic abnormalities. The peripheral blood should be tested for the bcr/abl fusion gene (Philadelphia chromosome) since it can differentiate CML, where it is present, from essential thrombocytosis, where it is absent.

DIFFERENTIAL DIAGNOSIS

Essential thrombocytosis must be distinguished from secondary causes of an elevated platelet count. In reactive thrombocytosis, the platelet count seldom exceeds 1,000,000/mcL (1000 × 10⁹/L). Inflammatory disorders such as rheumatoid arthritis and ulcerative colitis cause significant elevations of the platelet count, as may chronic infection. The thrombocytosis of iron deficiency is observed only when anemia is significant. The platelet count is temporarily elevated after a splenectomy. JAK2 mutations are found in over 50% of cases. MPL and CALR mutations frequently occur in patients with JAK2-negative essential thrombocytosis.

Regarding other myeloproliferative disorders, the lack of erythrocytosis distinguishes it from polycythemia vera. Unlike myelofibrosis, red blood cell morphology is normal, nucleated red blood cells are absent, and giant degranulated platelets are not seen. In CML, the Philadelphia chromosome (or bcr/abl by molecular testing) establishes the diagnosis.

TREATMENT

Patients are considered at high risk for thrombosis if they are older than 60 years, have a leukocyte count of 11,000/mcL (11 × 10⁹/L) or higher, or have a previous history of thrombosis. They also have a higher risk for bleeding. The risk of thrombosis can be reduced by control of the platelet count, which should be kept under 500,000/mcL (500 × 10⁹/L). The treatment of choice is oral hydroxyurea in a dose of 500–1000 mg/day. In rare cases in which hydroxyurea is not well tolerated because of anemia, low doses of anagrelide, 1–2 mg/day orally, may be added. Higher doses of anagrelide can be complicated by headache, peripheral edema, and heart failure. Pegylated interferon alfa-2 can induce significant hematologic responses and can potentially target the malignant clone in CALR-mutant cases. Strict control of coexistent cardiovascular risk factors is mandatory for all patients.

Vasomotor symptoms such as erythromelalgia and paresthesias respond rapidly to aspirin. Historically, low-dose aspirin (81 mg/day orally) has been used to reduce the risk of thrombotic complications in low-risk patients, but a recent study found that once daily dosing is not as effective as an every 12-hour regimen. In the unusual event of severe bleeding, the platelet count can be lowered rapidly with plateletpheresis. In cases of marked thrombocytosis (greater than or equal to 1,000,000/mcL [1000 × 10⁹/L]) or of any evidence of bleeding, acquired von Willebrand syndrome must be excluded before starting low-dose aspirin.

COURSE & PROGNOSIS

Essential thrombocytosis is an indolent disorder that allows long-term survival. Average survival is longer than 15 years from diagnosis, and the survival of patients younger than age 50 years does not appear different from matched controls. The major source of morbidity—thrombosis—can be reduced by appropriate platelet control. Late in the disease course, the bone marrow may become fibrotic, and massive splenomegaly may occur, sometimes with splenic infarction. There is a 10–15% risk of progression to myelofibrosis after 15 years, and a 1–5% risk of transformation to acute leukemia over 20 years.

WHEN TO REFER

Patients with essential thrombocytosis should be referred to a hematologist.

GENERAL CONSIDERATIONS

Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR, or MPL mutations; bone marrow fibrosis; anemia; splenomegaly; and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis. Myelofibrosis can also occur as a secondary process following the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). It is believed that fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines. In response to bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes. In these sites, mesenchymal cells responsible for fetal hematopoiesis can be reactivated. According to the 2016 WHO classification, “prefibrotic” primary myelofibrosis is distinguished from “overtly fibrotic” primary myelofibrosis; the former might mimic essential thrombocytosis in its presentation and it is prognostically relevant to distinguish the two.

CLINICAL FINDINGS

A. Symptoms and Signs

Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.

Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early satiety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space.

B. Laboratory Findings

Patients are almost invariably anemic at presentation. The white blood count is variable—either low, normal, or elevated—and may be increased to 50,000/mcL (50 × 10⁹/L). The platelet count is variable. The peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line (eFigure 13–21). Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts. Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen. The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis.

The bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease, biopsy shows it to be hypercellular, with a marked increase in megakaryocytes. Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers. Later, biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen (eFigure 13–22). There is no characteristic chromosomal abnormality. JAK2 is mutated in ~65% of cases, and MPL and CALR are mutated in the majority of the remaining cases; 10% of cases are “triple-negative.”

DIFFERENTIAL DIAGNOSIS

A leukoerythroblastic blood picture from other causes may be seen in response to severe infection, inflammation, or infiltrative bone marrow processes. However, teardrop poikilocytosis and giant abnormal platelet forms will not be present. Bone marrow fibrosis may be seen in metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia. These disorders are diagnosed by characteristic morphology of involved tissues.

Of the other myeloproliferative disorders, CML is diagnosed when there is marked leukocytosis, normal red blood cell morphology, and the presence of the bcr/abl fusion gene. Polycythemia vera is characterized by an elevated hematocrit. Essential thrombocytosis shows predominant platelet count elevations.

TREATMENT

Observation with supportive care is a reasonable treatment strategy for asymptomatic patients with low risk or an intermediate risk—an intermediate-1 score on the Dynamic International Prognostic Scoring system (DIPSS-plus), especially in the absence of high-risk mutations. Anemic patients are supported with transfusion. Anemia can also be controlled with androgens, prednisone, thalidomide, or lenalidomide. First-line therapy for myelofibrosis-associated splenomegaly is hydroxyurea 500–1000 mg/day orally, which is effective in reducing spleen size by half in approximately 40% of patients. Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients. Splenectomy is not routinely performed but is indicated for medication-refractory splenic enlargement causing recurrent painful episodes, severe thrombocytopenia, or an unacceptable transfusion requirement. Perioperative complications can occur in 28% of patients and include infections, abdominal vein thrombosis, and bleeding. Radiation therapy has a role for painful sites of extramedullary hematopoiesis, pulmonary hypertension, or severe bone pain. Transjugular intrahepatic portosystemic shunt might also be considered to alleviate symptoms of portal hypertension.

Patients with high-risk or intermediate-2–risk disease on the DIPSS-plus, or those patients harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for allogeneic stem cell transplant, which is currently the only potentially curative treatment modality in this disease. Nontransplant candidates may be treated with JAK2 inhibitors or immunomodulatory agents for symptom control. Ruxolitinib, the first JAK2 inhibitor to be FDA approved, results in reduction of spleen size and improvement of constitutional symptoms but does not induce complete clinical or cytogenetic remissions or significantly affect the JAK2/CALR/MPL mutant allele burden. Moreover, ruxolitinib can exacerbate cytopenias. The newer selective JAK2 inhibitor fedratinib, FDA approved in 2019, can lead to sustained reduction in spleen size and improvement in disease-associated symptoms for patients with advanced- stage myelofibrosis. However, it carries a significant risk of serious and fatal encephalopathy, including Wernicke encephalopathy, and providers should regularly assess thiamine levels in all patients. The immunomodulatory medications lenalidomide and pomalidomide result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size.

COURSE & PROGNOSIS

The median survival from time of diagnosis is approximately 5 years. Therapies with biologic agents and the application of reduced-intensity allogeneic stem cell transplantation appear to offer the possibility of improving the outcome for many patients. End-stage myelofibrosis is characterized by generalized asthenia, liver failure, and bleeding from thrombocytopenia, with some cases terminating in AML. The DIPSS-plus incorporates clinical and genetic risk variables and is associated with overall survival. These variables are (1) age older than 65 years, (2) hemoglobin less than 10 g/dL, (3) leukocytes greater than 25 × 10⁹ /L, (4) circulating blasts greater than or equal to 1%, (5) constitutional symptoms, (6) red cell transfusion dependency, (7) platelet count less than 100 × 10⁹ /L, and (8) unfavorable karyotype (ie, complex karyotype or sole or two abnormalities that include +8, –7/7q–, i(17q), inv(3), 5/5q–, 12p–, or 11q23 rearrangement). The presence of 0, 1, 2 or 3 and 4 or more adverse factors defines low, intermediate-1, intermediate-2 and high-risk disease with median survivals of 15.4, 6.5, 2.9 and 1.3 years, respectively. Most recently, DIPSS-plus-independent adverse prognostic relevance has been demonstrated for certain mutations including ASXL1 and SRSF2. By contrast, patients with type 1/like CALR mutations, compared to their counterparts with other driver mutations, displayed significantly better survival.

WHEN TO REFER

Patients in whom myelofibrosis is suspected should be referred to a hematologist.

WHEN TO ADMIT

Admission is not usually necessary.

GENERAL CONSIDERATIONS

CML is a myeloproliferative disorder characterized by overproduction of myeloid cells. These myeloid cells continue to differentiate and circulate in increased numbers in the peripheral blood.

CML is characterized by a specific chromosomal abnormality and a specific molecular abnormality. The Philadelphia chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22. The portion of 9q that is translocated contains abl, a protooncogene that is received at a specific site on 22q, the break point cluster (bcr). The fusion gene bcr/abl produces a novel protein that possesses tyrosine kinase activity. This disorder is the first recognized example of tyrosine kinase “addiction” by cancer cells.

Early CML (“chronic phase”) does not behave like a malignant disease. Normal bone marrow function is retained, white blood cells differentiate, and despite some qualitative abnormalities, the neutrophils combat infection normally. However, untreated CML is inherently unstable, and without treatment, the disease progresses to an “accelerated” phase and then an “acute blast” phase, which is morphologically indistinguishable from acute leukemia.

CLINICAL FINDINGS

A. Symptoms and Signs

CML is a disorder of middle age (median age at presentation is 55 years). Patients usually complain of fatigue, night sweats, and low-grade fevers related to the hypermetabolic state caused by overproduction of white blood cells. Patients may also complain of abdominal fullness related to splenomegaly. In some cases, an elevated white blood count is discovered incidentally. Rarely, the patient will present with a clinical syndrome related to leukostasis with blurred vision, respiratory distress, or priapism. The white blood count in these cases is usually greater than 100,000/mcL (100 × 10⁹/L) but less than 500,000/mcL (500 × 10⁹/L). On examination, the spleen is enlarged (often markedly so), and sternal tenderness may be present as a sign of marrow overexpansion. In cases discovered during routine laboratory monitoring, these findings are often absent. Acceleration of the disease is often associated with fever (in the absence of infection), bone pain, and splenomegaly.

B. Laboratory Findings

CML is characterized by an elevated white blood cell count; the median white blood count at diagnosis is 150,000/mcL (150 × 10⁹/L), although in some cases the white blood cell count is only modestly increased (Table 13–14). The peripheral blood is characteristic (eFigure 13–23). The myeloid series is left shifted, with mature forms dominating and with cells usually present in proportion to their degree of maturation. Blasts are usually less than 5%. Basophilia and eosinophilia may be present. At presentation, the patient is usually not anemic. Red blood cell morphology is normal, and nucleated red blood cells are rarely seen. The platelet count may be normal or elevated (sometimes to strikingly high levels). A bone marrow biopsy is essential to ensure sufficient material for a complete karyotype and for morphologic evaluation to confirm the phase of disease. The bone marrow is hypercellular, with left-shifted myelopoiesis (eFigure 13–24). Myeloblasts compose less than 5% of marrow cells. The hallmark of the disease is the bcr/abl gene that is detected by the polymerase chain reaction (PCR) test in the peripheral blood and bone marrow.

With progression to the accelerated and blast phases, progressive anemia and thrombocytopenia occur, and the percentage of blasts in the blood and bone marrow increases (eFigure 13–25). Blast-phase CML is diagnosed when blasts comprise more than 20% of bone marrow cells.

DIFFERENTIAL DIAGNOSIS

Early CML must be differentiated from the reactive leukocytosis associated with infection. In such cases, the white blood count is usually less than 50,000/mcL (50 × 10⁹/L), splenomegaly is absent, and the bcr/abl gene is not present.

CML must be distinguished from other myeloproliferative disease (Table 13–14). The hematocrit should not be elevated, the red blood cell morphology is normal, and nucleated red blood cells are rare or absent. Definitive diagnosis is made by finding the bcr/abl gene.

TREATMENT

Treatment is usually not emergent even with white blood counts over 200,000/mcL (200 × 10⁹/L), since the majority of circulating cells are mature myeloid cells that are smaller and more deformable than primitive leukemic blasts. In the rare instances in which symptoms result from extreme hyperleukocytosis (priapism, respiratory distress, visual blurring, altered mental status), emergent leukapheresis is performed in conjunction with myelosuppressive therapy.

In chronic-phase CML, the goal of therapy is normalization of the hematologic abnormalities and suppression of the malignant bcr/abl-expressing clone. The treatment of choice consists of a tyrosine kinase inhibitor (eg, imatinib, nilotinib, dasatinib) targeting the aberrantly active abl kinase. It is expected that a hematologic complete remission, with normalization of blood counts and splenomegaly will occur within 3 months of treatment initiation. Second, a reduction of bcr/abl transcripts to less than 10% on the international scale should be achieved, ideally within 3 months but certainly within 6 months. Finally, a major molecular response (less than or equal to 0.1% transcripts) is desired within 12 months. Patients who achieve this level of molecular response have an excellent prognosis, with overall survival approaching 100% since disease progression is uncommon. On the other hand, patients have a worse prognosis if these targets are not achieved, molecular response is subsequently lost, or new mutations or cytogenetic abnormalities develop.

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved and it results in nearly universal (98%) hematologic control of chronic-phase disease at a dose of 400 mg/day. The rate of a major molecular response with imatinib in chronic-phase disease is ~30% at 1 year. The second-generation tyrosine kinase inhibitors, nilotinib and dasatinib, are also used as front-line therapy and can significantly increase the rate of a major molecular response compared to imatinib (71% for nilotinib at 300–400 mg twice daily by 2 years, 64% for dasatinib at 100 mg/day by 2 years) and result in a lower rate of progression to advanced-stage disease. However, these agents are associated with additional toxicity. Since they can still salvage 90% of patients who do not respond to treatment with imatinib, they may be reserved for use in that situation. A dual bcr/abl tyrosine kinase inhibitor, bosutinib, is used for patients who are resistant or intolerant to the other tyrosine kinase inhibitors. The complete cytogenetic response rate to bosutinib is 25%, but it is not active against the T315I mutation.

Patients taking tyrosine kinase inhibitors should be monitored with a quantitative PCR assay. Those with a consistent increase in bcr/abl transcript or those with a suboptimal molecular response as defined above should undergo abl mutation testing and then be switched to an alternative tyrosine kinase inhibitor. The T315I mutation in abl is specifically resistant to therapy with imatinib, dasatinib, nilotinib, and bosutinib but appears to be sensitive to the third-generation agent ponatinib. However, ponatinib is associated with a high rate of vascular thrombotic complications. For patients with the T315I mutation as well as patients who have not responded to multiple tyrosine kinase inhibitors, including ponatinib, the novel allosteric inhibitor asciminib can be tried. It has shown a 54% complete hematologic response rate and a 48% sustained major molecular response in heavily pretreated patients. Dose-limiting toxic effects include asymptomatic elevations in the lipase level and clinical pancreatitis. Lastly, omacetaxine—a non–tyrosine kinase inhibitor therapy approved for patients with CML who are resistant to at least two tyrosine kinase inhibitors—can produce major cytogenetic responses in 18% of patients. Patients in whom a good molecular response to any of these agents cannot be achieved or in whom disease progresses despite therapy should be considered for allogeneic stem cell transplantation.

Patients with advanced-stage disease (accelerated phase or myeloid/lymphoid blast crisis) should be treated with a tyrosine kinase inhibitor alone or in combination with myelosuppressive chemotherapy. The doses of tyrosine kinase inhibitors in that setting are usually higher than those appropriate for chronic-phase disease. Since the duration of response to tyrosine kinase inhibitors in this setting is limited, patients who have accelerated or blast- phase disease should ultimately be considered for allogeneic stem cell transplantation.

COURSE & PROGNOSIS

The Sokal score is a prognostic tool based on simple clinical and hematologic data that can estimate overall survival at diagnosis. Since most patients now die of causes other than CML while still in remission, the EUTOS Long Term Survival (ELTS) score has been developed to predict the probability of dying from CML. Patients with good molecular responses to tyrosine kinase inhibitor therapy have an excellent prognosis, with essentially 100% survival at last follow up. Studies suggest that tyrosine kinase inhibitor therapy may be safely discontinued after 2 years in patients who achieve a sustained major molecular response, with ~50% of patients remaining in molecular remission at least 1 year posttreatment. Of importance, more than 80% of recurrences occur within the first 6–8 months after stopping therapy, and loss of major molecular response is uncommon after 1 year. About 90–95% of patients who experience molecular recurrence regain their initial molecular level after restarting tyrosine kinase inhibitor therapy.

WHEN TO REFER

All patients with CML should be referred to a hematologist.

WHEN TO ADMIT

Hospitalization is rarely necessary and should be reserved for symptoms of leukostasis at diagnosis or for transformation to acute leukemia.

GENERAL CONSIDERATIONS

The MDS are a group of acquired clonal disorders of the hematopoietic stem cell. They are characterized by the constellation of cytopenias, a usually hypercellular marrow, morphologic dysplasia, and genetic abnormalities. The disorders are usually idiopathic but may be caused by prior exposure to cytotoxic chemotherapy, radiation or both. In addition to cytogenetics, sequencing can detect genetic mutations in 80–90% of MDS patients. Importantly, acquired clonal mutations identical to those seen in MDS can occur in the hematopoietic cells of ~10% of apparently healthy older individuals, defining the disorder of clonal hematopoiesis of indeterminate potential (CHIP).

Myelodysplasia encompasses several heterogeneous syndromes. A key distinction is whether there is an increase in bone marrow blasts (greater than 5% of marrow elements). The category of MDS with excess blasts represents a more aggressive form of the disease, often leading to AML. Those without excess blasts are characterized by the degree of dysplasia, eg, MDS with single lineage dysplasia and MDS with multilineage dysplasia. The morphologic finding of ringed sideroblasts is used to define a subcategory of the lower-risk MDS syndromes. Patients with isolated 5q loss, which is characterized by the cytogenetic finding of loss of part of the long arm of chromosome 5, comprise an important subgroup of patients with a different natural history. Lastly, a proliferative syndrome including sustained peripheral blood monocytosis more than 1000/mcL (1.0 × 10⁹/L) is termed chronic myelomonocytic leukemia (CMML), a disorder that shares features of myelodysplastic and myeloproliferative disorders. An International Prognostic Scoring System (IPSS) classifies patients by risk status based on the percentage of bone marrow blasts, cytogenetics, and severity of cytopenias. The IPSS is associated with the rate of progression to AML and with overall survival, which can range from a median of 6 years for the low-risk group to 5 months for the high-risk patients.

CLINICAL FINDINGS

A. Symptoms and Signs

Patients are usually over age 60 years. Many patients are asymptomatic when the diagnosis is made because of the finding of abnormal blood counts. Fatigue, infection, or bleeding related to bone marrow failure are usually the presenting symptoms and signs. The course may be indolent, and the disease may present as a wasting illness with fever, weight loss, and general debility. On examination, splenomegaly may be present in combination with pallor, bleeding, and various signs of infection. MDS can also be accompanied by a variety of paraneoplastic syndromes prior to or following this diagnosis.

B. Laboratory Findings

Anemia may be marked with the MCV normal or increased, and transfusion support may be required. On the peripheral blood smear, macro-ovalocytes may be seen. The white blood cell count is usually normal or reduced, and neutropenia is common. The neutrophils may exhibit morphologic abnormalities, including deficient numbers of granules or deficient segmentation of the nucleus, even a bilobed nucleus (the so-called Pelger-Huët abnormality) (eFigure 13–26). The myeloid series may be left shifted, and small numbers of promyelocytes or blasts may be seen. The platelet count is normal or reduced, and hypogranular platelets may be present.

The bone marrow is characteristically hypercellular but occasionally may be hypocellular. Erythroid hyperplasia is common, and signs of abnormal erythropoiesis include megaloblastic features, nuclear budding, or multinucleated erythroid precursors (eFigure 13–27). The Prussian blue stain may demonstrate ringed sideroblasts. In the marrow, too, the myeloid series is often left shifted, with variable increases in blasts. Deficient or abnormal granules may be seen. A characteristic abnormality is the presence of dwarf megakaryocytes with a unilobed nucleus. Genetic abnormalities define MDS; there are frequent cytogenetic abnormalities involving chromosomes 5 and 7. Some patients with an indolent form have an isolated partial deletion of chromosome 5 (MDS with isolated del[5q]). Aside from cytogenetic abnormalities, the most commonly mutated genes are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2.

DIFFERENTIAL DIAGNOSIS

MDS should be distinguished from megaloblastic anemia, aplastic anemia, myelofibrosis, HIV-associated cytopenias, and acute or chronic drug effect. In subtle cases, cytogenetic evaluation of the bone marrow may help distinguish this clonal disorder from other causes of cytopenias. As the number of blasts increases in the bone marrow, myelodysplasia is arbitrarily separated from AML by the presence of less than 20% blasts.

TREATMENT

Myelodysplasia is a heterogeneous disease, and the appropriate treatment depends on a number of factors. For patients with anemia who have a low serum erythropoietin level (500 units/L or less), erythropoiesis-stimulating agents may raise the hematocrit and reduce the red cell transfusion requirement in 40%. Addition of intermittent granulocyte colony-stimulating factor (G-CSF) therapy may augment the erythroid response to epoetin. Unfortunately, the patients with the highest transfusion requirements and those with erythropoietin levels above 200 units/L are the least likely to respond. Patients who remain dependent on red blood cell transfusion and who can tolerate it should receive iron chelation in order to prevent serious iron overload; the dose of oral agent deferasirox is 20 mg/kg/day in divided dosing. Patients affected primarily with severe neutropenia may benefit from the use of myeloid growth factors such as filgrastim. Oral thrombopoietin analogs, such as romiplostim and eltrombopag, have shown effectiveness in raising the platelet count in myelodysplasia. Finally, occasional patients can benefit from immunosuppressive therapy including ATG. Predictors of response to ATG include age younger than 60 years, absence of 5q–, and presence of HLA DR15.

For patients who do not respond to these interventions, there are several therapeutic options available. Lenalidomide is the treatment of choice in patients with MDS with isolated del(5q) with significant responses in 70% of patients, and responses typically lasting longer than 2 years. In addition, nearly half of these patients enter a cytogenetic remission with clearing of the abnormal 5q– clone. The recommended initial dose is 10 mg/day orally. The most common side effects are neutropenia and thrombocytopenia, but venous thrombosis occurs and warrants prophylaxis with aspirin, 325 mg/day orally. A novel agent, luspatercept, has been developed to target signaling via the SMAD2–SMAD3 pathway, which is constitutively increased in the bone marrow cells of patients with MDS and ineffective erythropoiesis. In a randomized study, luspatercept induced transfusion independence in 38% of lower-risk MDS patients who had not responded to growth factor therapy compared to 13% in the placebo arm. The most common adverse events included fatigue, diarrhea, asthenia, nausea, and dizziness.

For patients with high-risk MDS, hypomethylating agents are the treatment of choice. Azacitidine can improve both symptoms and blood counts and prolong overall survival and time to conversion to acute leukemia. It is used at a dose of 75 mg/m² daily for 5–7 days every 28 days and up to six cycles of therapy may be required to achieve a response. Decitabine, a related hypomethylating agent, given at 20 mg/m² daily for 5 days every 28 days can produce similar hematologic responses but has not demonstrated a benefit in overall survival compared to supportive care alone. Unfortunately, the progress that has been made over the past decade in understanding the complex molecular mechanisms underlying MDS has not yet translated into new therapeutic options.

Allogeneic stem cell transplantation is the only curative therapy for myelodysplasia, but its role is limited by the advanced age of many patients and the variably indolent course of the disease.

COURSE & PROGNOSIS

Myelodysplasia is an ultimately fatal disease, and allogeneic transplantation is the only curative therapy, with cure rates of 30–60% depending primarily on the risk status of the disease. Patients most commonly die of infections or bleeding. Patients with MDS with isolated del(5q) have a favorable prognosis, with 5-year survival over 90%. Other patients with low-risk disease (with absence of both excess blasts and adverse cytogenetics) may also do well, with similar survival. Those with excess blasts or CMML have a higher (30–50%) risk of developing acute leukemia, and short survival (less than 2 years) without allogeneic transplantation.

WHEN TO REFER

All patients with myelodysplasia should be referred to a hematologist.

WHEN TO ADMIT

Hospitalization is needed only for specific complications, such as severe infection.

GENERAL CONSIDERATIONS

Acute leukemia is a malignancy of the hematopoietic progenitor cell. Malignant immature cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. Most cases arise with no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition, a number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in chromosomes 5 and 7. Those related to etoposide or anthracyclines may have abnormalities in chromosome 11q23 (MLL locus).

Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cells. Less common manifestations result from organ infiltration (skin, gastrointestinal tract, meninges). Acute leukemia is potentially curable with combination chemotherapy.

The myeloblastic subtype, AML, is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced age. Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17), which produces the fusion gene PML-RAR-alpha, leading to a block in differentiation that can be overcome with pharmacologic doses of retinoic acid. The lymphoblastic subtype of acute leukemia, ALL, comprises 80% of the acute leukemias of childhood. The peak incidence is between 3 and 7 years of age. It is also seen in adults, causing approximately 20% of adult acute leukemias.

CLASSIFICATION OF THE LEUKEMIAS

A. Acute Myeloid Leukemia (AML)

AML is primarily categorized based on recurrent structural chromosomal and molecular abnormalities. The cytogenetic abnormalities can be identified on traditional karyotyping or metaphase fluorescence in situ hybridization (FISH) and the molecular abnormalities are identified by either targeted or genome-wide sequencing of tumor DNA. Favorable cytogenetics such as t(8;21) producing a chimeric RUNX1/RUNX1T1 protein and inv(16)(p13;q22) are seen in 15% of cases and are termed the “core-binding factor” leukemias. These patients have a higher chance of achieving both short- and long-term disease control. Unfavorable cytogenetics confer a very poor prognosis. These consist of chromosomal translocations [t(6;9), t(3;3) or inv (3), t(v;11q23)], isolated monosomy 5 or 7, the presence of two or more other monosomies, or three or more separate cytogenetic abnormalities and account for 25% of the cases. The majority of cases of AML are of intermediate risk by traditional cytogenetics and have either a normal karyotype or chromosomal abnormalities that do not confer strong prognostic significance. However, there are several recurrent gene mutations with prognostic significance in this subgroup. On the one hand, internal tandem duplication in the gene FLT3 occurs in ~30% of AML and is conditionally associated with a very poor prognosis in the setting of wild type NPM1. Other mutations conferring a poor prognosis occur in RUNX1, ASXL1, and TP53. On the other hand, a relatively favorable group of patients has been identified that lacks FLT3-ITD mutations and includes mutations of nucleophosmin 1 (NPM1) or carries CEBPA biallelic mutations.

B. Acute Promyelocytic Leukemia (APL)

In considering the various types of AML, APL is discussed separately because of its unique biologic features and response to non-chemotherapy treatments. APL is characterized by the cytogenetic finding of t(15;17) and the fusion gene PML-RAR-alpha. It is a highly curable form of leukemia (over 90%) with integration of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) in induction, consolidation, and maintenance regimens.

C. Acute Lymphoblastic Leukemia (ALL)

ALL is most usefully classified by immunologic phenotype as follows: common, early B lineage, and T cell. Hyperdiploidy (with more than 50 chromosomes), especially of chromosomes 4, 10, and 17, and translocation t(12;21) (TEL-AML1), is associated with a better prognosis. Unfavorable cytogenetics are hypodiploidy (less than 44 chromosomes), the Philadelphia chromosome t(9;22), the t(4;11) translocation (which has fusion genes involving the MLL gene at 11q23), and a complex karyotype with more than five chromosomal abnormalities.

D. Mixed Phenotype Acute Leukemias

These leukemias consist of blasts that lack differentiation along the lymphoid or myeloid lineage or blasts that express both myeloid and lymphoid lineage-specific antigens. This group is considered very high risk and has a poor prognosis. The limited available data suggest that an “acute lymphoblastic leukemia–like” regimen followed by allogeneic stem cell transplant may be advisable; addition of a tyrosine kinase inhibitor in patients with t(9;22) translocation is recommended.

CLINICAL FINDINGS

A. Symptoms and Signs

Most patients have been ill only for days or weeks. Bleeding (usually due to thrombocytopenia) occurs in the skin and mucosal surfaces, with gingival bleeding, epistaxis, or menorrhagia. Less commonly, widespread bleeding is seen in patients with disseminated intravascular coagulation (DIC) (in APL and monocytic leukemia). Infection is due to neutropenia, with the risk of infection rising as the neutrophil count falls below 500/mcL (0.5 × 10⁹/L). Common presentations include cellulitis, pneumonia, and perirectal infections; death within a few hours may occur if treatment with appropriate antibiotics is delayed. Fungal infections are also commonly seen.

Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. The most dramatic presentation is hyperleukocytosis, in which a markedly elevated circulating blast count (total white blood count greater than 100,000/mcL [100 × 10⁹/L]) leads to impaired circulation, presenting as headache, confusion, and dyspnea. Such patients require emergent chemotherapy with adjunctive leukapheresis since mortality approaches 40% in the first 48 hours.

On examination, patients appear pale and have purpura and petechiae; signs of infection may not be present. Stomatitis and gum hypertrophy may be seen in patients with monocytic leukemia, as may rectal fissures. There is variable enlargement of the liver, spleen, and lymph nodes. Bone tenderness may be present, particularly in the sternum, tibia, and femur.

B. Laboratory Findings

The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts (eFigure 13–28). However, blasts may be absent from the peripheral smear in as many as 10% of cases (“aleukemic leukemia”). The bone marrow is usually hypercellular and dominated by blasts (greater than 20%).

Hyperuricemia may be seen. If DIC is present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin degradation products or fibrin D-dimers present. Patients with ALL (especially T cell) may have a mediastinal mass visible on chest radiograph. Meningeal leukemia will have blasts present in the spinal fluid, seen in approximately 5% of cases at diagnosis; it is more common in monocytic types of AML and can be seen with ALL.

The Auer rod, an eosinophilic needle-like inclusion in the cytoplasm, is a characteristic of AML (though sometimes seen in APL, high-grade MDS, and myeloproliferative disorders) (see an example of an Auer rod in eFigure 13–29). The phenotype of leukemia cells is usually demonstrated by flow cytometry or immunohistochemistry. AML cells usually express myeloid antigens such as CD13 or CD33 and myeloperoxidase. ALL cells of B lineage will express CD19, and most cases will express CD10, formerly known as the “common ALL antigen.” ALL cells of T lineage will usually not express mature T-cell markers, such as CD3, CD4, or CD8, but will express some combination of CD2, CD5, and CD7 and will not express surface immunoglobulin. Almost all cells express terminal deoxynucleotidyl transferase (TdT).

DIFFERENTIAL DIAGNOSIS

AML must be distinguished from other myeloproliferative disorders, CML, and MDS. Acute leukemia may also resemble a left-shifted bone marrow recovering from a previous toxic insult. If the diagnosis is in doubt, a bone marrow study should be repeated in several days to see if maturation has taken place. ALL must be separated from other lymphoproliferative disease such as CLL, lymphomas, and hairy cell leukemia. It may also be confused with the atypical lymphocytosis of mononucleosis and pertussis.

TREATMENT

Acute leukemia is considered a curable disease, especially among younger patients without significant comorbidities. The first step in treatment is to obtain complete remission, defined as normal peripheral blood with resolution of cytopenias, normal bone marrow with no excess blasts, and normal clinical status. The type of initial chemotherapy depends on the subtype of leukemia.

1. AML

Most patients with AML who are treated with a curative intent receive a combination of an anthracycline (daunorubicin or idarubicin) plus cytarabine, either alone or in combination with other agents (eg, gemtuzumab ozogamicin). This therapy will produce complete remissions in 80–90% of patients under age 60 years and in 50–60% of older patients (see Table 39–2). Patients with secondary AML (evolved from prior myelodysplastic or myeloproliferative disorders) or treatment-associated AML should receive the drug Vyxeos (a liposomal formulation of daunorubicin and cytarabine). Patients with a FLT3 mutation benefit from the addition of the FLT3 kinase inhibitor midostaurin to their regimen. Post-remission therapy options include additional chemotherapy and allogeneic stem cell transplantation. Patients with a favorable genetic profile can be treated with chemotherapy alone or with autologous transplant with cure rates of 60–80%. For intermediate-risk patients with AML, cure rates are 35–40% with chemotherapy and 40–60% with allogeneic transplantation. Patients who do not enter remission (primary induction failure) or those with high-risk genetics have cure rates of less than 10% with chemotherapy alone and are referred for allogeneic stem cell transplantation.

Patients who are not treated with initial curative intent (those older than 75 years or with significant comorbidities) can derive benefit from newer targeted agents, including the bcl2 inhibitor venetoclax added to a hypomethylating agent or low-dose cytarabine, enasidenib (targeting IDH2 mutations), ivosidenib (targeting IDH2 mutations), or glasdegib. Some of these patients can still benefit from a reduced-intensity allogeneic transplant if they achieve good disease control.

Once leukemia has recurred after initial chemotherapy, the prognosis is poor. For patients in second remission, allogeneic transplantation offers a 20–30% chance of cure. Targeted therapies described above are useful for selected patients and can offer long-term disease control.

2. ALL

Adults with ALL are treated with combination chemotherapy, including daunorubicin, vincristine, prednisone, and asparaginase. This treatment produces complete remissions in 90% of patients. Those patients with Philadelphia chromosome-positive ALL (or bcr-abl-positive ALL) should receive a tyrosine kinase inhibitor, such as dasatinib or ponatinib, added to their initial chemotherapy. Remission induction therapy for ALL is less myelosuppressive than treatment for AML and does not necessarily produce prolonged marrow aplasia. Patients should also receive central nervous system prophylaxis so that meningeal sequestration of leukemic cells does not develop.

After achieving complete remission, patients may be treated with either additional cycles of chemotherapy or high-dose chemotherapy and stem cell transplantation. Treatment decisions are made based on patient age and disease risk factors. Adults younger than 39 years have uniformly better outcomes when treated under pediatric protocols. For older patients, minimal residual disease testing early on can identify high-risk patients who will not be cured with chemotherapy alone and who will do better with allogeneic transplantation. For patients with relapsed disease, the bispecific antibody blinatumomab targeting CD19 and the antibody-drug conjugate inotuzumab ozogamicin targeting CD22 have shown remarkable activity and are considered superior to traditional chemotherapy options. Tisagenlecleucel is a therapy utilizing autologous T cells engineered to express an anti-CD-19 antigen receptor (CART-19) and is FDA-approved for the treatment of children and young adults with relapsed/refractory B-ALL.

PROGNOSIS

Approximately 70–80% of adults with AML under age 60 years achieve complete remission and ~50% are cured using risk-adapted post-remission therapy. Older adults with AML achieve complete remission in up to 50% of instances. The cure rates for older patients with AML have been very low (approximately 10–20%) even if they achieve remission and are able to receive post-remission chemotherapy.

Patients younger than 39 years with ALL have excellent outcomes after undergoing chemotherapy followed by risk-adapted intensification and transplantation (cure rates of 60–80%). Patients with adverse cytogenetics, poor response to chemotherapy, or older age have a much lower chance of cure (cure rates of 20–40%).

WHEN TO REFER

All patients should be referred to a hematologist.

WHEN TO ADMIT

Most patients with acute leukemia will be admitted for treatment.

GENERAL CONSIDERATIONS

CLL is a clonal malignancy of B lymphocytes. The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes. These cells are immune-incompetent and respond poorly to antigenic stimulation.

CLL is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. With advanced disease, CLL may cause damage by direct tissue infiltration.

CLL usually pursues an indolent course, but some subtypes behave more aggressively; a variant, prolymphocytic leukemia, is more aggressive. The morphology of the latter is different, characterized by larger and more immature cells. In 5–10% of cases, CLL may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node transforms into an aggressive large-cell lymphoma (Richter syndrome).

Information about CLL is evolving rapidly, with new findings in biology and new treatment options; outcomes are improving significantly.

CLINICAL FINDINGS

A. Symptoms and Signs

CLL is a disease of older patients, with 90% of cases occurring after age 50 years and a median age at presentation of 70 years. Many patients will be incidentally discovered to have lymphocytosis. Others present with fatigue or lymphadenopathy. On examination, 80% of patients will have diffuse lymphadenopathy and 50% will have enlargement of the liver or spleen.

The long-standing Rai classification system remains prognostically useful: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly (spleen, liver); stage III, anemia; stage IV, thrombocytopenia. These stages can be collapsed into low risk (stages 0–I), intermediate risk (stage II), and high risk (stages III–IV).

B. Laboratory Findings

The hallmark of CLL is isolated lymphocytosis. The white blood cell count is usually greater than 20,000/mcL (20 × 10⁹/L) and may be markedly elevated to several hundred thousand. Usually 75–98% of the circulating cells are lymphocytes. Lymphocytes appear small and mature, with condensed nuclear chromatin, and are morphologically indistinguishable from normal small lymphocytes, but smaller numbers of larger and activated lymphocytes may be seen. The hematocrit and platelet count are usually normal at presentation. The bone marrow is variably infiltrated with small lymphocytes (eFigures 13–30 and 13–31). The immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5; this finding is commonly observed only in CLL and mantle cell lymphoma. CLL is distinguished from mantle cell lymphoma by the expression of CD23, CD200, and LEF-1, low expression of surface immunoglobulin and CD20, and the absence of a translocation or overexpression of cyclin D1. Patients whose CLL cells have mutated forms of the immunoglobulin gene (IgVH somatic mutation) have a more indolent form of disease; these cells typically express low levels of the surface antigen CD38 and do not express the zeta-associated protein (ZAP-70). Conversely, patients whose cells have unmutated IgVH genes and high levels of ZAP-70 expression do less well and require treatment sooner. The assessment of genomic changes by FISH provides important prognostic information. The finding of deletion of chromosome 17p (TP53) confers the worst prognosis, while deletion of 11q (ATM) confers an inferior prognosis to the average genotype, and isolated deletion of 13q has a more favorable outcome.

Hypogammaglobulinemia is present in 50% of patients and becomes more common with advanced disease. In some, a small amount of IgM paraprotein is present in the serum.

DIFFERENTIAL DIAGNOSIS

Few syndromes can be confused with CLL. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings; however, fever may occur in CLL from concomitant bacterial infection. Pertussis may cause a particularly high total lymphocyte count. Other lymphoproliferative diseases such as Waldenström macroglobulinemia, hairy cell leukemia, or lymphoma (especially mantle cell) in the leukemic phase are distinguished on the basis of the morphology and immunophenotype of circulating lymphocytes and bone marrow. Monoclonal B-cell lymphocytosis is a disorder characterized by fewer than 5000/mcL (5.0 × 10⁹/L) B cells and is considered a precursor to B-CLL.

TREATMENT

The treatment of CLL is evolving as several active targeted agents have emerged. Most cases of early indolent CLL require no specific therapy, and the standard of care for early-stage disease has been observation. Indications for treatment include progressive fatigue, symptomatic lymphadenopathy, anemia, or thrombocytopenia. These patients have either symptomatic and progressive Rai stage II disease or stage III/IV disease. Initial treatment for patients with CLL consists of targeted biologic therapy in most cases. Options include ibrutinib (a Bruton tyrosine kinase inhibitor targeting B-cell receptor signaling) or venetoclax (a bcl2 inhibitor resulting in apoptosis) in combination with anti-CD20 antibody therapy. Choice between these agents is based on toxicity as well as preference. Ibrutinib is a well-tolerated, oral agent given at 420 mg daily; it can be associated with hypertension, cardiac arrhythmias, rash, and increased infections. Caution should be exercised when this agent is used in conjunction with CYP3A inhibitors or inducers. In addition, there is a potential for serious bleeding when it is used in patients taking warfarin. Venetoclax (slowly titrated up to 400 mg daily) is usually given for a shorter course of therapy and is associated with tumor lysis syndrome and neutropenia; some patients may require hospitalization for initial therapy. Venetoclax has to be combined with a monoclonal CD20 antibody, usually obinutuzumab, which can result in infusion reactions. Traditional combination chemotherapy is used only in selected cases (see Table 39–3). For older patients, chlorambucil, 0.6–1 mg/kg orally every 4 weeks, in combination with obinutuzumab is another therapy option.

For patients with relapsed or refractory disease, both venetoclax and ibrutinib or another BTK inhibitor, acalabrutinib, demonstrate significant activity, even for patients with high-risk genetics. Other options include idelalisib and duvelisib (inhibitors of PI3 kinase delta), which are associated with higher toxicity. The dosage for idelalisib is 150 mg orally twice a day, and the dosage for duvelisib is 25 mg orally twice a day. There are risks for colitis, liver injury, and fatal infectious complications in patients treated with PI3k inhibitors. Patients should be given antimicrobial prophylaxis and monitored closely while taking these agents.

Of note, BTK and PI3k inhibitors can be initially associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. This results in a significant early reduction in lymphadenopathy but a potentially misleading, more delayed clearance of lymphocytes from peripheral blood and bone marrow.

Associated autoimmune hemolytic anemia or immune thrombocytopenia may require treatment with rituximab, prednisone, or splenectomy. Fludarabine should be avoided in patients with autoimmune hemolytic anemia since it may exacerbate it. Rituximab should be used with anti-HBV agent prophylaxis in patients with past HBV infection. Patients with recurrent bacterial infections and hypogammaglobulinemia benefit from prophylactic infusions of gamma globulin (0.4 g/kg/month), but this treatment is cumbersome and expensive, justified only when these infections are severe. Patients undergoing therapy with a nucleoside analog (fludarabine, pentostatin) should receive anti-infective prophylaxis for Pneumocystis jirovecii pneumonia, herpes viruses, and invasive fungal infections until there is evidence of T-cell recovery.

Allogeneic transplantation offers potentially curative treatment for patients with CLL, but it should be used only in patients whose disease cannot be controlled by the available therapies. Nonmyeloablative allogeneic transplant can result in over 40% long-term disease control in CLL but with risk of moderate toxicity.

PROGNOSIS

Therapies have changed the prognosis of CLL. Patients with stage 0 or stage I disease have a median survival of 10–15 years, and these patients may be reassured that they can live a normal life. Patients with stage III or stage IV disease had a median survival of less than 2 years in the past, but with current therapies, 5-year survival is more than 70% and the long-term outlook appears to be substantially changed. For patients with high-risk and resistant forms of CLL, there is evidence that allogeneic transplantation can overcome risk factors and lead to long-term disease control.

WHEN TO REFER

All patients with CLL should be referred to a hematologist.

WHEN TO ADMIT

Hospitalization is rarely needed.

GENERAL CONSIDERATIONS

Hairy cell leukemia is a rare malignancy of hematopoietic stem cells differentiated as mature B lymphocytes with hairy cytoplasmic projections. The V600E mutation in the BRAF gene is recognized as the causal genetic event of hairy cell leukemia, since it is detectable in almost all cases at diagnosis and is present at relapse.

CLINICAL FINDINGS

A. Symptoms and Signs

The disease characteristically presents in middle-aged men. The median age at presentation is 55 years, and there is a striking 5:1 male predominance. Most patients present with gradual onset of fatigue, others complain of symptoms related to markedly enlarged spleen, and some come to attention because of infection.

Splenomegaly is almost invariably present and may be massive. The liver is enlarged in 50% of cases; lymphadenopathy is uncommon.

Hairy cell leukemia is usually an indolent disorder whose course is dominated by pancytopenia and recurrent infections, including mycobacterial infections.

B. Laboratory Findings