Leukopenia may occur with a broad array of medical problems. Leukopenia can range from a mild suppression of the WBC to clinically significant neutropenia (Table 103-3). Most intrinsic (hereditary/familial) disorders and syndromes are detected during infancy or childhood. Leukopenia in older adults is generally the result of acquired or secondary disorders, either reactive (drugs, nutritional, infections, immune) or malignant. Table 103-4 presents key components in the clinical workup of neutropenia.
Table 103-3 Neutropenia ||Download (.pdf)
Table 103-3 Neutropenia
Slight ↑ risk
Table 103-4 Key Components in the Evaluation of Neutropenia ||Download (.pdf)
Table 103-4 Key Components in the Evaluation of Neutropenia
1. Clinical history
Duration (acute vs. chronic)
History of infection
History of bleeding/bruising/fatigue
Presence of comorbidities (rheumatologic disease, cirrhosis, malabsorption)
Evaluate for signs of infection including careful skin and mucosal examination
Evidence of bleeding/bruising
3. Complete blood count
Severity of neutropenia
Presence of anemia or thrombocytopenia
Immature granulocytes on differential
4. Peripheral smear
Toxic granulation/vacuolation of neutrophils
Presence of dysplastic features
Nucleated red cells
Megaloblastic changes (hypersegmentation of neutrophils)
5. Bone marrow biopsy
Indicated for severe neutropenia, pancytopenia, evidence of dysplasia or granulocytic immaturity on peripheral smear
Elderly patients commonly consume many prescribed and over-the-counter medications and are at higher risk for developing drug-related neutropenia or pancytopenia. The bone marrow is one of the more rapidly proliferating organs of the body; therefore, it is not surprising that exposure to noxious agents may temporarily or permanently inhibit production of one or more elements of the blood. The list of possible offenders is extensive and constantly evolving with new drug development. Table 103-5 lists some of the more commonly reported offenders. In a situation of neutropenia, leukopenia, or pancytopenia, the physician should thoroughly review the patient's medications and the duration of the medication exposure. In the absence of alternative explanations, medications administered within 4 weeks of onset of neutropenia should be evaluated. Short duration of exposure does not remove the possibility of a drug-induced cytopenia; it could be an idiosyncratic reaction. Diagnosis involves identification of a possible offending agent and exclusion of alternative etiologies for the leukopenia. A bone marrow biopsy is often indicated as part of the workup if the leukopenia is severe.
Table 103-5 Drugs Associated with Agranulocytosis/Neutropenia
Drug effects on the bone marrow range from mild neutropenias (more common) to agranulocytosis; lymphocytopenia occurs less frequently. The RBC and platelets may or may not be affected. Drug-induced reduction of the granulocytic series may be a direct toxic effect, as with many cancer chemotherapeutic drugs or may be the result of an immunologic phenomenon wherein a drug–antibody complex reacts with mature neutrophils and/or their precursors in the peripheral blood or bone marrow. Treatment usually consists of supportive care, with administration of antibiotics for febrile patients. Upon withdrawal of the offending agent, there may be a relatively brisk marrow recovery within 14 to 21 days. A bone marrow examination during this recovery period may reveal an increased number of immature elements, which can be confused with a malignant process such as an acute leukemia or myelodysplasia. If this is a possibility, close follow-up for an additional 2 to 3 weeks will usually provide the answer. The recovering marrow will go on to differentiate, but the malignant marrow will either stay the same or worsen. Other marrow toxins include a variety of household and industrial chemicals, especially organic solvents, naphthalenes, insecticides, and herbicides. Inquiries about chemical exposure from hobbies or occupations must therefore be part of history taking. While the hematologic effects of drug and chemical exposure are frequently reversible, some may result in myelodysplastic syndromes (MDS) or aplastic anemia which, in turn, may evolve into acute myelogenous leukemia (AML).
Mild neutropenia may be associated with nutritional anemias secondary to folate or B-12 deficiency. Older individuals, especially those living alone, may not be attentive to their diet for various socioeconomic, psychological, or medical reasons. The main sources of folates are fresh green vegetables, many fruits, and beans. Cooking and canning destroys folates. The body's folate stores can be depleted after 4 to 5 months of poor dietary intake. Thus, a dietary history may provide an important clue to the diagnosis of the hematologic problem. Dietary folate deficiency may be aggravated by alcoholism and chronic hemolysis. Additional hematologic findings of folate deficiency include macrocytic anemia and hypersegmented neutrophils. Potential folate deficiency is best evaluated by measuring RBC folate.
In contrast, body stores of vitamin B-12 are not readily depleted by poor dietary habits alone. It takes 3 to 5 years to deplete the body stores of vitamin B-12. However, gastric atrophy is more common with increasing age, and this may lead to failure of gastric secretion of intrinsic factor, which binds to dietary cobalamin—a necessary step in the absorption of vitamin B-12 in the ileum. Other conditions that cause a B-12 deficiency include gastrectomy or subtotal small-bowel (ileal) resection. It should be noted that neurologic signs and symptoms of B-12 deficiency may be confused with other neurologic problems in the elderly patient. These include peripheral paresthesias (peripheral neuritis), loss of balance (posterior column damage), spasticity (lateral column damage), and impaired cognitive function. Any of these neurological signs and symptoms may be mistakenly attributed to “old age,” but if caused by B-12 deficiency may be corrected with vitamin B-12 replacement therapy. Low serum cobalamin levels (<200 ng/L) are diagnostic of deficiency and will be found in the majority of patients who are symptomatic. Subclinical cobalamin deficiency can be detected by measuring serum methylmalonic acid. Subclinical cobalamin deficiency is characterized by low normal serum cobalamin level (200–350 ng/L) and an elevated methylmalonic acid level. It should be noted that homocysteine will be elevated in both folate and cobalamin deficiency.
Copper deficiency is a more recently reported but uncommon cause of neutropenia. Neutropenia is typically associated with anemia and may be confused with early MDS, particularly in an older adult. Copper deficiency is most commonly associated with malabsorption, malnutrition, use of total parenteral nutrition, or excess oral zinc supplementation. The diagnosis is suggested by the appropriate clinical setting and a low serum copper level. Hematological changes are potentially reversible with oral copper supplementation.
A number of infections can be associated with neutropenia and/or leukopenia in older adults. These infections include viral (e.g., influenza, varicella, hepatitis A, B, or C, cytomegalovirus, human immunodeficiency virus, parvovirus B19), and bacterial (e.g., Staphylococcus aureus, brucellosis, tularemia, rickettsia, and tuberculosis). Neutropenia associated with most viral illnesses is self-limited and of minimal clinical consequence. A few viruses (hepatitis B, Epstein–Barr, and human immunodeficiency virus) can cause protracted, clinically significant neutropenia. Bacterial septicemia, particularly with Gram-negative organisms, is a serious cause of acquired neutropenia and confers a poor prognosis. The mechanism of leukopenia is usually bone marrow suppression, but in the case of overwhelming bacterial sepsis, can result from exhaustion of bone marrow reserves. Treatment focuses on supportive care including use of antibiotics for infection; the role of myeloid growth factors in this setting is unproven.
Severe and prolonged bone marrow failure may occur in association with drugs, toxins, or infections, but is frequently idiopathic. Aplastic anemia is characterized by severe pancytopenia and bone marrow hypoplasia. Clinical signs and symptoms reflect the cytopenias: infection, bleeding, and/or the signs/symptoms of anemia. Pure white cell aplasia occurs rarely. Treatments for this life-threatening disease include supportive care (transfusion, antibiotics), immunosuppression (antithymocyte globulin, cyclosporine, steroids), and stem cell transplant (limited application in the elderly population).
Immune neutropenia may be associated with various rheumatologic conditions such as systemic lupus erythematosus, rheumatoid arthritis, polyserositis, and lymphoproliferative malignancies. In these situations, neutropenia is caused by the elimination of immunoglobulin-coated granulocytes by the reticuloendothelial system. Immune-mediated neutropenia is often clinically significant with absolute neutrophil count (ANC) <500 cells/mm3, predisposing to increased infection risk. In general, the bone marrow is hypercellular or normocellular and lacking in mature neutrophils. Neutropenia of Felty's syndrome (rheumatoid arthritis, splenomegaly, and neutropenia) has a complex etiology that includes immune destruction and suppression as well as splenic sequestration. These neutropenias frequently respond to granulocyte colony-stimulating factors (G-CSF) or granulocyte-macrophage colony-stimulating factors (GM-CSF).
Any condition causing splenomegaly (e.g., hepatic cirrhosis) may lead to sequestration of sufficient neutrophils to cause mild-to-moderate neutropenia as a component of the pancytopenia of hypersplenism. The mild-to-moderate neutropenia usually does not predispose to increased infections and often occurs in association with anemia and/or thrombocytopenia.
Neoplastic Causes of Decreased WBC
Malignancies (hematological and nonhematological) can present with neutropenia and need to be considered in the evaluation of this finding. Details of the presentation and workup of many of these disorders will be presented later in this chapter.
Hematologic malignancies, although most frequently characterized by elevated WBC, can be associated with low, normal, or high WBC. The WBC differential, as well as the red cell and platelet counts, are usually abnormal.
Malignant diseases of the WBCs include the four major subtypes of leukemia—AML, acute lymphocytic leukemia (ALL), CML, and chronic lymphocytic leukemia (CLL); as well as the MDS (preleukemias); the myeloproliferative disorders other than CML; hairy cell leukemia; large granular lymphocytic leukemia; metastatic cancers to the bone marrow; and circulating non-Hodgkin's lymphoma cells. Older adults make up a large proportion of incident and prevalent cases of these diseases. In fact, the age-specific incidence rates of all leukemias increase in the elderly population (Figure 103-1). As the population ages, the burden of these diseases is nearly certain to rise, with the elderly population being most affected.
The effectiveness of treatments has improved substantially over recent decades for most hematologic malignancies. Unfortunately, the response rates and cure rates in elderly patients have lagged behind for a number of reasons, including the more common occurrence of chronic leukemias, MDS, and myeloproliferative disease in the elderly person, limited ability of the elderly person to tolerate the more aggressive curative approaches for acute leukemia, underrepresentation of older adults in clinical trials, and the more common occurrence of multiple poor prognostic factors in elderly patients. With the increased focus on elderly specific clinical trials and the ongoing development of less toxic, targeted therapies, opportunities for effective treatment of older adults with malignant WBC disorders should improve.
Myelodysplastic (Preleukemia) Syndromes
The myelodysplastic syndromes, frequently referred to as preleukemia, encompass a heterogenous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and hypercellularity of the bone marrow. In these diseases, cells of the affected lineage are unable to undergo maturation and differentiation, resulting in cytopenias. The major clinical significance of these disorders is the morbidity associated with profound cytopenias and the potential to evolve into AML.
The true incidence of myelodysplastic syndromes is not known, but currently estimated at 15,000 to 20,000 new cases per year in the United States. About two thirds of patients with MDS are elderly males. MDS are clearly diseases of aging patients, with a median age at diagnosis of 65 to 70 years. The nomenclature associated with myelodysplastic syndromes is confusing. Terms found in the literature include odoleukemia (threshold of leukemia), subacute myeloid leukemia, smoldering leukemia, dysmyelopoietic syndrome, and preleukemia.
Diagnosis of MDS relies mainly on peripheral blood and bone marrow findings. The diagnosis should be suspected in individuals presenting with cytopenia. In clinical studies, the majority of patients have a hemoglobin of less than 11, platelet count <100,000, and an ANC <1000 at the time of diagnosis. However, careful attention should be paid to consistent decreases in blood counts over time in an older adult, which may signify early developing MDS. Many patients are asymptomatic at the time of diagnosis. However, careful history taking should include questions regarding recurrent infections, bruising, and bleeding. The differential diagnosis for suspected MDS includes AML, aplastic anemia, megaloblastic anemia (B-12 and folate deficiency), copper deficiency, viral infections (HIV), large granular lymphocytic leukemia, and heavy metal poisoning.
The initial serologic workup includes a complete blood count (CBC) with differential, reticulocyte count, RBC folate, serum B-12, iron studies, and review of the peripheral smear. Classic peripheral blood findings associated with MDS include macrocytosis and hypogranular, hypolobated (dysplastic) neutrophils. A bone marrow biopsy with cytogenetic analysis is required to confirm the diagnosis. The bone marrow is typically hypercellular and demonstrates evidence of dysplasia. Cytogenetic abnormalities play a critical role in the diagnosis and natural history of MDS. Common cytogenetic abnormalities involve chromosomes 5, 7, 8, 17, or 20.
The classification of MDS has evolved over the past 10 years. In 1982, the French-American-British (FAB) Cooperative Group established a classification system with five diagnostic categories based on peripheral blood and bone marrow characteristics. These include refractory anemia (RA), RA with ring sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEBT), and chronic myelomonocytic leukemia (CMML). Details of this classification system are presented in Table 103-6.
Table 103-6 Characteristics and Prognosis of Myelodysplastic Syndromes ||Download (.pdf)
Table 103-6 Characteristics and Prognosis of Myelodysplastic Syndromes
PERIPHERAL BLOOD BLASTS (%)
BONE MARROW BLASTS (%)
PROGRESSION TO AML (%)
MEDIAN SURVIVAL (MONTHS)
Refractory anemia with ring sideroblasts
Chronic myelomonocytic leukemia
Refractory anemia with excess blasts
Refractory anemia with excess blasts in transformation
A more recent classification scheme was proposed by the World Health Organization (WHO), which incorporates evolving knowledge of the biology of disease including the significance of cytogenetic abnormalities. This classification scheme is presented in Table 103-7 and better reflects the heterogeneity of MDS. There are several important differences between the FAB and WHO classifications. The WHO classification defines ≥20% blasts (RAEBT) as AML; defines CMML as a myelodysplastic/myeloproliferative disease; and adds new categories of MDS such as the 5q-syndrome.
Table 103-7 WHO Classification of Peripheral Blood and Bone Marrow Findings in Myelodysplastic Syndromes ||Download (.pdf)
Table 103-7 WHO Classification of Peripheral Blood and Bone Marrow Findings in Myelodysplastic Syndromes
BONE MARROW FINDINGS
No or rare blasts
Erythroid dysplasia only
<15% ringed sideroblasts
Refractory anemia with ringed sideroblasts
≥15% ringed sideroblasts
Erythroid dysplasia only
Refractory cytopenia with multilineage dysplasia (RCMD)
Cytopenias (bicytopenia or pancytopenia)
No or rare blasts
No Auer rods
<1 × 109/L monocytes
Dysplasia in ≥10% of the cells of two or more myeloid cell lines
<5% blasts in marrow
No Auer rods
<15% ringed sideroblasts
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
Cytopenias (bicytopenia or pancytopenia)
No or rare blasts
No Auer rods
<1 × 109/L monocytes
Dysplasia in ≥10% of the cells in two or more myeloid cell lines
≥15% ringed sideroblasts
No Auer rods
Refractory anemia with excess blasts-1 (RAEB-1)
No Auer rods
<1 × 109/L monocytes
Unilineage or multilineage dysplasia
No Auer rods
Refractory anemia with excess blasts-2 (RAEB-2)
Auer rods ±
<1 × 109/L monocytes
Unilineage or multilineage dysplasia
Auer rods ±
Myelodysplastic syndrome-unclassified (MDS-U)
No or rare blasts
No Auer rods
Unilineage dysplasia: one myeloid cell line
No Auer rods
MDS associated with isolated del (5q)
Usually normal or increased platelet count
Normal to increased megakaryocytes with hypolobated nuclei
Isolated del(5q) cytogenetic abnormality
No Auer rods
The natural history of patients with MDS syndromes is quite variable and can range from a chronic relatively indolent disease to an acute fulminant and progressive process. It is well established that mutagen-induced MDS is associated with a poor prognosis and that increased age is also a negative prognostic factor. However, the heterogeneity of this disease has complicated accurate prognostication in de novo MDS. The International Prognostic Scoring System (IPSS) (Table 103-8) was developed to risk stratify patients at the time of diagnosis based on cytogenetic, morphologic, and clinical data. The IPSS for MDS was developed based on an analysis of 816 patients, which demonstrated that specific cytogenetic abnormalities, the percentage of marrow blasts in the bone marrow, and the number of hematopoietic lineages involved in the cytopenia were the most important variables in disease outcome. Risk scores are determined based on these variables, and a categorization of low risk, intermediate-1, intermediate-2, and high risk is assigned (Table 103-9). The IPSS has demonstrated improved prognostic discrimination over earlier classification schemes and has been incorporated into clinical practice and subsequent trial design.
Table 103-8 International Prognostic Scoring System (IPSS) for MDS ||Download (.pdf)
Table 103-8 International Prognostic Scoring System (IPSS) for MDS
Bone marrow blasts (%)
Table 103-9 Median Survival by IPSS Score Category for MDS ||Download (.pdf)
Table 103-9 Median Survival by IPSS Score Category for MDS
IPSS RISK CATEGORY
MEDIAN SURVIVAL (yr)
There are few effective therapies for MDS. However, treatment strategies have been evolving in recent years to target higher risk MDS and subgroups defined by specific cytogenetic abnormalities. Current treatment recommendations involve a risk-adapted therapeutic approach. In general, the National Comprehensive Cancer Center guidelines recommend classifying patients into relatively low risk (IPSS Low or Intermediate-1 categories) and higher risk (IPSS Intermediate-2 and High categories). Supportive care aimed at controlling symptoms related to cytopenias is the mainstay of treatment for lower risk patients. Supportive care with red cell and platelet transfusions and antibiotics for infection has long been considered standard therapy for most patients with MDS. Hematopoietic growth factors such as erythropoietin are used to try to minimize transfusion requirements in responding patients. Over time, most patients become transfusion-dependent, increasing the risk of iron overload. Iron chelation therapy should be initiated after 20 to 30 units of red cells have been transfused or the serum ferritin is >2500 mcg/L. Supportive care is also recommended for adults with higher risk disease who have poor performance status and are more likely to suffer complications from aggressive therapies.
Patients in the higher risk IPSS categories are more likely to experience morbidity related to cytopenias and to progress to acute leukemia in a shorter time interval from diagnosis. Publications by Silverman and Kornblith described improvements in survival, quality of life, and a longer time to progression to acute leukemia, in patients with MDS who received 5-azacytidine (vs. observation) in a randomized trial of the national cooperative group Cancer and Leukemia Group B (CALGB). The strongly positive results of this large randomized study support 5-azacytidine as a standard of care for treatment of MDS. The FDA also recently approved decitabine, a second pyrimidine nucleoside analog of cytidine, which inhibits DNA methylation for the treatment of higher risk MDS. While these medications are associated with toxicity, they represent the mainstay of treatment for good performance status older adults with higher risk MDS. Higher intensity therapy such as allogeneic transplantation, to date the only curative therapy for MDS, is restricted to younger adults with acceptable donors because of the high morbidity and mortality associated with the therapy itself.
Treatment options have expanded for patients with the 5q-syndrome. This subset of MDS is defined by a deletion of the long arm of chromosome 5 as the sole abnormality. The 5q-syndrome typically manifests as refractory anemia and is considered a more favorable MDS subset because a large percentage of patients do not progress to acute leukemia. In a recent clinical study, lenalidomide, an oral immunomodulatory drug, significantly decreased transfusion requirements and demonstrated reversal of cytogenetic abnormalities in patients with 5q-syndrome. This drug has become the standard of care for treatment of transfusion-dependent, lower risk patients with 5q-syndrome and reinforces the clinical and therapeutic importance of cytogenetic evaluation in MDS.
Acute Myelogenous Leukemia
AML refers to a group of clonal hematopoietic disorders that are characterized by proliferation of immature myeloid cells in the bone marrow. Accumulation of leukemic cells impairs the normal hematopoietic function of the bone marrow, resulting in cytopenias with or without leukocytosis.
AML is a disease of older adults, with a median age at diagnosis of 67 years. The American Cancer Society estimated that 11 930 patients would be diagnosed with AML in 2006 with an anticipated 9040 dying of disease. The incidence increases with age (see Figure 103-1). According to the Surveillance Epidemiologic and End Results (SEER) statistics from 2000 to 2003, over 55% of incident cases of AML were diagnosed in adults aged 65 years and older.
Risk factors for the development of AML include a history of preceding MDS, exposure to certain chemotherapy drugs (alkylating agents, topoisomerase 2 inhibitors, and nitrosoureas), radiation or benzene exposure, and a history of Down's syndrome. The majority of diagnosed cases of AML, however, are not linked to any known risk factor.
The clinical signs and symptoms of AML can be varied and nonspecific. Patients usually present with evidence of bone marrow failure: anemia, thrombocytopenia, granulocytopenia. Fatigue, dyspnea, bleeding, fever, and infection are common upon presentation. Leukemic infiltration of tissues outside the bone marrow such as liver, spleen, skin, lymph nodes, and central nervous system (CNS) can produce a variety of other symptoms specific to the site of involvement. Some patients present with severe leukocytosis, which can produce symptoms of leukostasis as a result of a large blast fraction in the peripheral blood. Peripheral blood findings range from pancytopenia with or without circulating blasts cells to severe leukocytosis with circulating blasts typically with anemia and thrombocytopenia.
The diagnosis of AML depends primarily upon detection of leukemic blasts of myeloid lineage (≥20%) in the bone marrow. Morphologic evaluation can be aided by immunohistochemical and flow cytometry techniques to confirm myeloid versus lymphoid origin. The traditional international classification system (FAB) details subtypes of AML (M1 through M7) based on morphology, histochemical characteristics, and immunophenotyping. The more recently proposed WHO classification of AML (Table 103-10) incorporates morphologic, immunophenotypic, genetic, and clinical features. There are four major categories, each with two or more subtypes described by Brunning et al. The WHO classification highlights the importance of a cytogenetic classification for prognosis and treatment. In recent years, subsets of AML defined by specific cytogenetic abnormalities have been shown to be associated with improved prognosis such as the core binding factor leukemias (inv 16, t(8;21), t(16;16)), and acute promyelocytic leukemia (t(15;17)). Risk-adapted treatment strategies have been developed to maximize clinical outcomes and minimize toxicity based upon cytogenetic classification.
Table 103-10 Classification of Acute Myeloid Leukemia ||Download (.pdf)
Table 103-10 Classification of Acute Myeloid Leukemia
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); (AML1/ETO)
Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22); (CBFβ/MYH11)
Acute promyelocytic leukemia (AML with t[15;17][q22;q12] [PML/RARα] and variants)
Acute myeloid leukemia with 11q23 (MLL) abnormalities
Acute myeloid leukemia with multilineage dysplasia
Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder
Without antecedent myelodysplastic syndrome
Acute myeloid leukemia and myelodysplastic syndromes, therapy-related
Topoisomerase type II inhibitor-related (some may be lymphoid)
Acute myeloid leukemia not otherwise categorized
Acute myeloid leukemia minimally differentiated
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
If untreated or unresponsive to chemotherapy, AML may be rapidly fatal (median survival < 2 months). The major causes of death are overwhelming infection and hemorrhage related to the disease-associated cytopenias.
Standard induction therapy for AML is combination chemotherapy that includes cytosine arabinoside (ara-C) and an anthracycline such as daunorubicin. These drugs yield complete remissions (CRs) in 50% to 80% of patients, depending upon various prognostic factors. Increased age is an important negative prognostic factor. The poorer prognosis associated with increased age is related to both a higher frequency of fatal infections and hemorrhage during the period of disease and treatment-related marrow hypoplasia (induction deaths) and to chemotherapy failure (residual or resistant leukemia). While CR rates have usually been 60% to 80% in younger patients with AML, the CR rate in patients aged 60 years and older has generally been ≤50% (with induction death rates of 20% to 40%).
Tumor biology contributes to worse prognosis in older adults with AML. As a group, older patients with AML have a higher percentage of unfavorable cytogenetic abnormalities and a lower percentage of favorable cytogenetic abnormalities compared to younger patients. Unfavorable cytogenetic abnormalities are associated with decreased rates of remission and shortened overall survival. Expression of MDR1, which confers resistance to chemotherapeutic agents, is more common in older AML patients. Older patients are more likely to have a secondary AML arising from underlying myelodysplastic syndrome, which is less responsive to standard therapy. Clinical characteristics including increased comorbidity, age-associated physiologic changes, polypharmacy, and functional and cognitive impairment complicate therapy in older adults and likely also contribute to outcome disparities.
To date, the optimal treatment strategy for older adults remains controversial with recommendations ranging from supportive care alone to standard aggressive therapies. A landmark randomized study by Lowenberg et al. demonstrated improved survival in selected patients aged 65 years and older treated with induction chemotherapy versus supportive care alone. This study demonstrated a potential benefit to aggressive treatment for selected older adults. However, outcomes remain suboptimal in this population. Attempts to improve response rates in older patients with AML have included attenuated doses of standard therapy; these treatments have resulted in decreased induction death rates but without improved CR rates. The roles of gemtuzumab ozogamicin (Mylotarg), a monoclonal antibody directed at CD33, and other directed therapies are yet to be determined. Patients in the subgroup with acute promyelocyte leukemia (APL; AML-M3) are now treated very effectively with oral all-trans-retinoic acid (ATRA) plus chemotherapy; AML-M3, however, occurs uncommonly in older patients. The role of more aggressive therapies, including stem cell transplantation (high-dose therapy with stem cell rescue), has been limited in elderly patients by the high rates of complications and prohibitive toxicity. However, improvements in supportive care have allowed for increased investigation of dose-intensive therapies in older patients.
The median duration of CR is approximately 1 year, and a small percentage (≤15%) of older (60 years of age and older) patients will be cured of their leukemia. Patients who achieve CRs should be considered for therapy after remission in an attempt to prevent or delay relapse. However, the exact role and optimal type of such postremission therapy in older patients remain poorly defined.
Treatment decisions for older adults with AML should be individualized. Decisions should include risk stratification based on tumor biology (cytogenetic risk groups) and an estimate of physiologic reserve based on clinical characteristics such as comorbidity and functional status. Older adults with favorable cytogenetics and good functional status should be considered for aggressive curative treatment. Poor-risk patients based on tumor biology or clinical characteristics could be considered for novel treatments on clinical trials or supportive care in an effort to maximize quality of life.
Acute Lymphoblastic Leukemia
ALL is primarily a disease of children, but in adults, age-adjusted incidence increases in the elderly. There are approximately 3900 new cases of adult ALL in the United States annually, with a slight male predominance (1.2:1). With available therapy today, childhood ALL is curable in the majority of patients. ALL in adults is not the same as the childhood disease. First, the frequency of complete response is lower—70% to 75% in adults as opposed to more than 90% in children. Second, the remission duration and curability using the same therapy is considerably less. Important prognostic features for outcome in the treatment of ALL include age, cytogenetics, and immunophenotype. Poor prognosis is especially associated with the presence of chromosomal translocations such as Philadelphia (Ph) chromosome t(9;22), t(4,11), t(8;14), t(2;8), or t(8;22), and with a phenotype indicating mixed lymphoid–myeloid leukemia (also called biphenotypic leukemia).
The initial goal of therapy for adult ALL is to correct problems secondary to bone marrow failure; that is, to treat anemia with blood transfusions, treat documented or suspected infection, and control bleeding. Specific antileukemia treatment is then directed toward the achievement of a CR. Induction chemotherapy therapy for ALL, very different from that for AML, usually includes the use of prednisone, vincristine, daunorubicin, and asparaginase. While these drugs are well-tolerated in children, increasing age is associated with poorer drug tolerance. Mortality, usually from infection and/or bleeding during the induction process, may occur in 10% to 20% of elderly patients.
In contrast to the treatment of AML, it is widely accepted that patients with ALL require therapy after CR. These phases of treatment once the patient is in CR have been referred to as intensification therapy and maintenance therapy. The optimal therapy after remission and the duration of such therapy in older patients are not clearly defined. Most programs use multiple drugs administered in a cyclic fashion over a 2-year period; the more intensive therapy is given over about 6 months after CR is achieved (intensification or consolidation), followed by a less-intensive outpatient maintenance regimen for approximately 18 months.
Directed treatment to the craniospinal axis (CNS prophylaxis) is standard practice in the treatment of childhood ALL. While the incidence of CNS leukemia is lower in adults than in children, treatment to the CNS is also part of ALL therapy in adults. This usually consists of intrathecal methotrexate in conjunction with high-dose systemic therapy such as high-dose methotrexate and ara-C, or cranial radiation.
With the above intensive treatment plan, the median duration of remission is approximately 2 years, with 35% to 45% of adult patients disease-free at 5 years; however, prognosis is poorer for older adults. One contributing feature to this poorer response duration in adults as opposed to children is the inability to deliver optimal chemotherapy at maximal doses caused by comorbid diseases and increased susceptibility to toxicity.
Chronic Lymphocytic Leukemia
CLL is the most common leukemia in the western hemisphere and may be commonly encountered in a geriatric practice. CLL is a disorder of clonal proliferation of mature lymphoid cells in the peripheral blood, bone marrow, and lymphoid organs. CLL occurs predominantly in older adults, with median age at diagnosis of approximately 70 years. The reported incidence of 3.8 per 100,000 population in western countries (about 10,000 new cases per year in the United States) may be an underestimate because many patients are asymptomatic for years; incidence in persons older than age 60 years is about 20 per 100,000 population. There is no racial difference in the United States between blacks and whites, but there are very few cases in the Far East and among persons of Oriental descent; the male:female ratio is approximately 2:1. Current diagnostic studies, especially immunophenotyping, allow for differentiation of the chronic lymphoid malignancies: B-cell CLL, T-cell CLL, prolymphocytic, circulating non-Hodgkin's lymphomas, and hairy cell leukemia.
B-cell CLL accounts for over 95% of all CLL. Twenty-five percent of such patients are identified with asymptomatic lymphocytosis during evaluation for other medical problems. Symptomatic patients may present with weight loss, fatigue, recurrent infections, fevers, or pain associated with hepatosplenomegaly or bulky lymphadenopathy. In most patients, the disease has a gradual progression spanning several years and the extent of the lymphoid burden at diagnosis correlates well with length of preexisting disease. In some patients, the disease has a more aggressive course and progression to advanced clinical stages may occur within a few months of diagnosis. Identification of molecular and protein markers are beginning to explain the heterogenous natural history observed in this disease.
The diagnosis of CLL is based on peripheral blood lymphocytosis >10,000 lymphocytes/μL and a specific immunophenotyping pattern (coexpression of CD5 and CD20/23 with weak expression of surface immunoglobulin) showing a clonal proliferation of lymphocytes. Diagnosis and staging of CLL can usually be established by history, physical examination (careful evaluation for lymphadenopathy and splenomegaly), CBC with review of the blood smear, and immunophenotyping of the peripheral blood using flow cytometry. Classic findings on the peripheral smear include increased mature appearing lymphocytes and smudge cells (peripheral smear artifact reflecting the fragility of the B-CLL cells to mechanical manipulation). Bone marrow studies are usually not needed for diagnosis.
The differential diagnosis for B-CLL includes other mature B-lymphoproliferative disorders such as mantle cell lymphoma, prolymphocytic leukemia, hairy cell leukemia, and splenic lymphoma with villous lymphocytes. The clinical course and treatments differ widely for these disorders, particularly mantle cell lymphoma. Evaluation of clinical presentation, morphology, and immunophenotype are necessary to arrive at the correct diagnosis (Table 103-11).
Table 103-11 Immunophenotype of Mature B-Cell Neoplasms ||Download (.pdf)
Table 103-11 Immunophenotype of Mature B-Cell Neoplasms
Mantle cell lymphoma
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma
The original Rai classification (Table 103-12) implied an orderly progression from lymphocytosis alone to the successive development of adenopathy, organomegaly, and, eventually, anemia and thrombocytopenia. The prognostic importance of these variables has been confirmed. Specific cytogenetic abnormalities correlate with prognosis. A 13q deletion is associated with a better prognosis, compared to deletions of 11q and 17p, which confer a worse prognosis. Additional molecular markers of prognostic significance include presence of CD38 and ZAP-70.
Table 103-12 CLL Rai Clinical Classification ||Download (.pdf)
Table 103-12 CLL Rai Clinical Classification
↑ Lymphs plus ↑ nodes
↑ Lymphs plus ↑ spleen and/or liver
± ↑ Nodes
↑ Lymphs plus ↓ Hgb (<11 g/dl)
± ↑ Nodes, ↑ liver, ↑ spleen
↑ Lymphs plus ↓ platelets (<100, 000/ul)
± ↑ Nodes, ↑ liver, ↑ spleen, ↓ Hgb
Therapy for B-cell CLL has been considered palliative and therefore has been reserved for patients who are symptomatic or who progress to develop cytopenias (Rai stages 3 or 4). The mainstay of therapy has been oral alkylating agents (chlorambucil or cyclophosphamide) for control of lymphoid proliferation and steroids for autoimmune complications. Leukocytosis alone (stage 0) does not require therapy, because the prognosis of these patients is excellent in the absence of the other poor prognostic factors. The rate of increase of leukocytosis is a better indicator of disease activity than the absolute count. Leukostasis associated with high circulating blast counts in acute leukemias does not generally occur in this condition because most of the lymphocytes are mature, small cells.
Treatment with chemotherapy or local radiation can be used to control symptoms in patients with stage I or II disease; however, symptomatic improvement does not appear to prolong survival. In contrast, when treated with combination chemotherapy, patients with stage III or IV CLL have an improved median survival, which ranges from 1.5 years to more than 4 years. The development of more effective initial therapies for CLL such as nucleoside analogs (e.g., fludarabine) have resulted in an increased number of patients achieving CR. It is not yet clear that these remissions result in prolonged survival, although data from recent clinical trials are encouraging. These promising results have encouraged many hematologists and oncologists to institute therapy at an earlier stage. A monoclonal antibody against CD-52, altuzemab, has been approved as second line therapy for patients previously treated with alkylating agents and fludarabine. The best way to integrate newer agents such as fludarabine and monoclonal antibodies (e.g., rituximab and alemtuzumab) with each other and/or with more traditional therapies (alkylators and steroids) are not yet well-defined. There are multiple clinical trials currently evaluating different combinations of these medications (concurrent or sequential). Unfortunately, each of these agents has been associated with increased risk of opportunistic infections, particularly in the older adult.
Autoimmune manifestations of CLL are common and include development of antibodies to platelets and red cells (IgG and C3 on direct antiglobulin test) and to erythroid precursors, resulting in red cell aplasia. For anemic patients, reticulocyte counts and direct Coomb's testing should be obtained to help differentiate hemolysis from decreased bone marrow production. All of the autoimmune complications are indications for therapy with steroids or intravenous gamma globulin for refractory cases of red cell aplasia.
Recurrent infections are the most common complications leading to death in CLL. Patients with stage 0 CLL have minimal increased risk of infection. In anticipation of gradual deterioration in immune response, however, pneumococcal vaccine and boosters should be administered while the potential for response is still intact. All other patients have higher risks for infection. As the disease advances clinically, immune function becomes progressively compromised, with increased susceptibility to viral, bacterial, and fungal infection. Patients should avoid direct contact with the body fluids of children who have received live-virus vaccines (oral polio, measles-mumps-rubella) for the duration of viral shedding. The subset of patients presenting with recurrent bacterial infections may benefit from administration of intravenous gamma globulin.
B-Cell Prolymphocytic Leukemia
This rare subtype of lymphoid leukemia is characterized by marked lymphocytosis (often >100,000 lymphocytes/μL), extensive bone marrow infiltration, massive splenomegaly, and minimal to absent adenopathy. Prolymphocytes comprise the majority of circulating WBC (>55%; often >90%). The prolymphocyte is about twice the size of a normal lymphocyte, with a characteristic dense border outlining a prominent nucleolus. B-cell prolymphocytic leukemia (B-PLL) cells usually express CD19, CD20, CD22, CD79a, FMC7, and strong surface IgM; CD23 is usually negative.
Most patients with B-PLL have advanced clinical disease at presentation, with a prognosis similar to that of patients with stage III and IV B-cell CLL. Therapy for these patients has included multiagent chemotherapy to control the splenomegaly and leukocytosis, and radiation therapy to palliate splenic engorgement. Patients become increasingly refractory to therapy, with an expected survival of 1.5 years and death caused by uncontrolled disease. Recent data suggest that more aggressive newer agents such as alemtuzumab (CAMPATH-1H) are more effective than previous therapies for PLL, with improved response rates and survival.
T-cell PLL/CLL is a rare subtype that accounts for 2% to 3% of all small lymphocytic leukemia (“CLL”) cases. Clinical manifestations include lymphocytosis, hepatosplenomegaly, generalized lymphadenopathy, skin infiltration (20%), and bone marrow involvement. Immunophenotyping in the peripheral blood shows a clonal proliferation of the malignant T cells—CD2, CD3, CD7 positive with weak CD3; in approximately 60% of patients, the cells are CD4+/CD8–, 25% are CD4+/CD8+, and 15% are CD4–/CD8+. Prognosis is generally poor, with limited responsiveness to therapy though newer agents (e.g., alemtuzumab) appear to be active.
Hairy cell leukemia is rare and almost exclusively seen in men older than age 60 years. The clinical features include massive splenomegaly, absence of adenopathy, and peripheral pancytopenia. The diagnosis is made by the morphologic characteristics of the circulating lymphocytes, which are small and have cytoplasmic projections (“hairs”). Diagnosis, previously made histochemically with the tartrate-resistant acid phosphatase (TRAP) stain, is now made with immunophenotyping that shows positive sIgM, CD19, CD20, CD22, CD79a, CD11c, CD25, and CD103; negative CD5, CD10, and CD23. Bone marrow aspiration usually yields little material (dry tap) and bone marrow biopsy shows increased cellularity with diffuse infiltration by the hairy cells. The spleen is infiltrated with the same clone of cells. Infections with Gram-negative and staphylococcal species is the predominant complication.
Splenectomy was the treatment of choice in the past with improvement of neutropenia in about 50% of patients for 8 to 10 years. Interferon (IFN)-α produced partial and CRs in more than 50% of patients, sparing many patients a surgical procedure and the effects of the splenectomy on the immune system. Interferon has now been replaced by the nucleoside analogs, especially cladribine (2-CdA), which is very well tolerated. This 5-day treatment yields high remission rates, frequently after only one course of therapy.
T-Cell Large Granular Lymphocytic Leukemia
T-cell large granular lymphocytic (T-LGL) leukemia is a rare clonal disorder of cytotoxic T lymphocytes, which typically presents with chronic neutropenia. T-LGL leukemia represents approximately 4% of lymphoproliferative disorders. Patients tend to be older, with a median age of 60 years. Many patients are asymptomatic and will have chronic neutropenia, mild lymphocytosis with or without anemia. Symptoms are typically related to recurrent infections particularly of the skin, oropharynx, and perirectal regions. Splenomegaly is common but lymphadenopathy is uncharacteristic. The peripheral blood demonstrates a proliferation of large granular lymphocytes. These can also be seen in reactive disorders such as viral infections. The diagnosis depends upon establishing a clonal T-cell receptor gene rearrangement within the population of large granular lymphocytes using polymerase chain reaction (PCR) or flow cytometry techniques on the peripheral blood. The diagnosis is supported by the characteristic immunophenotype of CD3+, CD8+, CD16+, and CD57+. T-LGL leukemia is a relatively indolent disease with median survival >10 years. Indications for treatment include severe neutropenia (ANC < 500), recurrent infections, and transfusion-dependent anemia. Treatment involves immunosuppression with agents such as methotrexate, cyclosporine, or steroids.
Chronic Myelogenous Leukemia
CML is a myeloproliferative disorder characterized by excess production of mature granulocytes that eventually progresses to a clinical picture similar to acute leukemia with an overgrowth of immature cells (blast crisis). It accounts for 15% to 20% of all leukemias, with an age-adjusted incidence rate of 1.5 per 100,000 population without geographic, sex, or racial differences. The incidence increases with age and the median age at diagnosis is 67 years.
Diagnosis is suspected by the demonstration of granulocytosis in the peripheral blood with a predominance of segmented neutrophils and myelocytes, increased basophils and eosinophils, increased bone marrow cellularity, a low LAP score. The presence of the Philadelphia chromosome t(9;22) and or its products (BCR/ABL fusion mRNA, Bcr/Abl protein) are required to confirm the diagnosis. Diagnosis can be made on peripheral blood using PCR or fluorescence in-situ hybridization (FISH) techniques. Bone marrow biopsy is still required for complete cytogenetic evaluation.
The disease characteristically proceeds through three phases: chronic, accelerated, and terminal (blastic) phase (Table 103-13). The length of the chronic phase is highly variable, from 1.5 years to 14 years (median duration of 3 years). In the chronic phase, the disease is easily controlled without aggressive therapy. The accelerated phase begins with gradual increases in white cells, platelets, and spleen size. Initially good maturation persists, but eventually more blasts are seen in the peripheral blood, and higher doses of medication are required to maintain control. This phase generally lasts a few months but may extend over 1 year. The terminal phase of the disease is indistinguishable from acute leukemia. The blasts have myeloid surface markers in 85% of the patients and lymphoid markers in the remaining 15%.
Table 103-13 CML Classification ||Download (.pdf)
Table 103-13 CML Classification
Any of the following:
Any of the following:
Peripheral basophilia >20%
Appearance of additional cytogenetic abnormality
Increasing spleen size or WBC on therapy
Treatment for CML has changed dramatically in recent years, altering the natural history of this disease. IFN-α was the first drug to change the natural history of CML, decreasing the percentage of cells exhibiting the Ph chromosome and prolonging the chronic phase by 1 to 2 years. Imatinib mesylate (Gleevec; STI-571), a targeted tyrosine kinase inhibitor designed specifically for the treatment of CML (in oral formulation), proved to have significant activity in the blast phase and accelerated phase of CML. In chronic phase CML, imatinib mesylate yielded marked improvements in clinical and cytogenetic responses, rates of disease progression, and treatment related toxicity compared to IFN-α plus low-dose ara-C in a randomized clinical trial. Based on these results, imatinib mesylate has replaced interferon regimens as the standard of care for patients with chronic phase CML. Imatinib is very well tolerated, which is particularly relevant for the elderly population. Many patients who would not have been good candidates for cytotoxic therapy or interferon can be effectively treated with imatinib. It is too early to determine the duration of remissions for elderly patients treated with this medication. However, second line therapy with newer tyrosine kinase inhibitors (dasatinib, nilotinib) have demonstrated activity in patients who have progressed on imatinib providing additional treatment options for older adults.
Allogeneic stem cell transplantation in the chronic phase, a promising intervention in younger patients, has limited benefit in the elderly patient because of the morbidity and mortality of this treatment. Imatinib mesylate should be the initial treatment for both the accelerated and blastic phases of CML if not already used during the chronic phase of the disease. Treatment of the blastic transformation (after imatinib) depends on the cell origin of the blasts. Myeloid blastic states respond poorly to standard AML therapies, and no standard therapy is available. Lymphoid blastic states can be controlled for 6 to 12 months, with standard combination regimens as used for de novo ALL.
Myeloproliferative diseases include CML (described above), polycythemia vera, myelofibrosis, and essential thrombocytosis. Both polycythemia vera and myelofibrosis can be associated with increased WBC. Polycythemia vera is usually associated with mild increases in white count with a relatively normal differential, while myelofibrosis is frequently associated with immature WBCs in addition to nucleated RBCs. The leukocytosis associated with polycythemia vera is usually of little consequence and treatment is directed towards the control of the increased red cells. Myelofibrosis can be associated with variable abnormalities in WBC numbers, either increased WBC with circulating immature precursors or decreased WBCs, especially in the present of massive splenomegaly.
Cancers Metastatic to Bone Marrow
Many of the common malignancies have a propensity for metastasis to the bone and bone marrow. These include carcinomas of the breast, lung, prostate, and the lymphomas. Space-occupying lesions in the bone marrow, which crowd out normal hematopoietic elements, are termed myelophthisis. Manifestations of myelophthisis in the peripheral blood include pancytopenia and leukoerythroblastosis. Pancytopenias may be aggravated by nutritional deficiencies, especially folate deficiency.