Chapter 179. Hematologic Malignancies

1. What are the “classic” clinical and basic laboratory features of each of the common hematologic malignancies? (“How do I prove the diagnosis?”)

2. What is the natural history of each disease entity without therapy?

3. What is the goal of treatment for each disease entity (cure, prolongation of survival, or purely palliation)?

4. Which modalities may be employed for each disease entity (chemotherapy, immunotherapy, radiation, stem cell transplant)?

5. What is the prognosis with therapy? How can the prognosis estimate be refined?

6. What needs to be done to prepare the patient for therapy (to communicate risks and benefits and to reduce toxicity)?

7. How do we assess the response?

8. How do we monitor the patient after completion of therapy, both early on (for relapse) and later (for delayed toxicities of therapy)?

Introduction

Practitioners need to be familiar with the broad classes of hematologic malignancy (acute and chronic leukemias, aggressive and indolent lymphomas, myeloma, myeloproliferative neoplasms, and myelodysplastic syndromes). They should also be familiar with the side effects of therapy, for example, acute and chronic cardiotoxicity from anthracyclines, long-lasting immunosuppression from purine analogs, and the expected timing of neutropenia (Table 179-1). He or she should also be comfortable managing a number of hematologic emergencies, which are described in the following chapter. The specifics of diagnosis and treatment can be both subtle and complex. Subspecialty consultation with a hematologist or oncologist is essential in caring for a patient who is suspected or known to suffer these conditions.

Pathophysiology

In general, each nucleated somatic cell belonging to a given person contains an identical DNA sequence. The exception occurs in normal lymphocyte development, in which the actual DNA sequences encoding immunoglobulin genes (in the case of B cells) or the T cell receptor (in the case of T cells) are altered. Because different cell types do not derive their unique features from differences in the DNA sequence, the regulation of gene expression is crucial to ensure that growth, proliferation, cell-specific functions, and cell death occur at the appropriate times in the life of the cell.

Clonal proliferation is the sine qua non of malignancy. Clonal proliferation refers to the concept that an entire population of malignant cells arises from a single ancestral cell that, due to one or more genetic or epigenetic changes, develops the ability to proliferate autonomously, independent of physiologic growth stimuli. The cancer-initiating cell is often conceptualized as a “cancer stem cell,” but whether the inciting genetic mutations actually occur in a normal stem cell or in a more mature cell that then reactivates primitive or “embryonic” gene expression programs, and so regresses in differentiation, is a matter of active investigation. The hallmark of a stem cell is its ability to “self-renew” an unlimited number of times. Self-renewal may be accomplished through symmetric cell division in which the stem cell gives rise to two identical daughter stem cells, or through asymmetric cell division in which the stem cell divides in a way that yields one copy of itself and one daughter cell that will launch a differentiation program.

Two basic mechanisms of genetic alteration contribute to neoplastic transformation: mutations in the DNA sequence, and chromosomal aberrations. Genomic instability is an important consequence of DNA mutations and chromosomal aberrations. Fusions may corrupt transcription factors that would otherwise activate genes needed for DNA mismatch repair and for repair of double strand breaks. The p53 protein normally pauses the cell cycle long enough for DNA repair to occur or if the damage is extensive, directs the cell toward apoptotic cell death. In hematologic malignancies, as in solid tumors, p53 function is often sabotaged. This allows accumulation of additional defects in tumor suppressor and oncogenic pathways, which leads to continued evolution of the malignant clone and favors the emergence of more aggressive subclones.

Although clonal proliferation is necessary for malignancy, it is not sufficient. Secondary clonal events due to genomic instability must lead to loss of cell cycle control, increased self-renewal, and escape from apoptosis. Dissemination of malignant cells is facilitated by down-regulation of adhesion molecules that anchor cells to their stromal niches, up-regulation of surface molecules that promote interaction with the endothelium, and expression of particular cytokines to promote extravasation. The neoplastic cells must also evolve mechanisms to escape immune surveillance.

Cell of Origin: Myeloid versus Lymphoid

Lymphoid neoplasms Lymphoid neoplasms appear to recapitulate stages of normal B cell or T cell differentiation, so they are largely classified according to the normal counterpart of the neoplastic cell. For example, B cell neoplasms can be related to one of four stages: (1) precursor B cells, (2) pregerminal center B cells, (3) germinal center B cells (centroblasts and centrocytes), and (4) post-germinal center B cells (memory B cells and plasma cells).

Classification of lymphoid neoplasms is not based on any single parameter. Morphology and various surface markers in combination (as detected by immunohistochemistry or flow cytometry) usually suffice to render a diagnosis. The subtleties in refining the diagnosis are complex; morphology can be atypical and no surface marker is 100% sensitive and specific for any particular lymphoid neoplasm. Chromosome translocations, overexpression of particular gene products (like the ALK enzyme or bcl2), rearrangement of the immunoglobulin genes or TCR, and detection of viral components (eg, Epstein-Barr virus, human T cell leukemia/lymphoma virus) are considered when they are appropriate to the pathologic differential diagnosis.

Myeloid neoplasms The acute and chronic myeloid leukemias likewise can be classified according to the normal counterpart that most closely resembles them in morphology and immunophenotype. The analogy is not ideal, as most myeloid leukemias likely arise from a primitive hematopoietic stem cell or progenitor cell, even if the ultimate differentiation block produces a more mature-appearing neoplasm. By contrast, the lymphoid neoplasms might have actually arisen from the presumed normal counterpart. The French-American-British classification first produced in 1976 and updated through 1989 distinguished eight subtypes of acute myeloid leukemia based on morphology and simple immunohistochemical stains. These include M0 (minimally differentiated), M1 (without maturation), M2 (with granulocytic maturation), M3 (promyelocytic), M4 (myelomonocytic), M5a (monoblastic) and M5b (monocytic), M6a (erytholeukemia) and M6b (pure erythroid leukemia, which is extremely rare), and M7 (megakaryocytic). The FAB also identified subtypes of myelodysplastic syndrome (eg, refractory anemia) and myeloproliferative disorders (eg, polycythemia vera). FAB terms are still widely used in common speech, but the current standard classification was issued by the World Health Organization and most recently updated in 2008. The WHO classification of myeloid neoplasms relies upon surface markers, genetic aberrations, clinical presentation and prognosis, and any relation to known inciting factors.

The terms “lymphoma” and “leukemia” are often confusing. In general, “leukemia” means there are cancerous cells of hematopoietic origin in the bone marrow and usually also circulating in the peripheral blood. These cells may be of myeloid or of lymphoid origin. “Lymphoma” means that there are tumors of lymphoid origin causing enlargement of lymph nodes or spleen, or causing masses in organs like the liver or gut.

More precisely, the exact definition of leukemia versus lymphoma depends on the clinical and pathologic features of specific disease entities. For example, in acute lymphoblastic diseases, some treatment protocols use the term “leukemia” if malignant blasts comprise more than 25% of nucleated cells in the bone marrow and the term “lymphoma” if there are fewer than 25% marrow blasts, regardless of whether the patient bears other masses, such as enlarged lymph nodes or tumors in the anterior mediastinum. This 25% cut-off is arbitrary. The current WHO classification advises using the term “lymphoblastic leukemia” when marrow and blood involvement is extensive. In acute myeloid leukemias, the WHO considers 20% marrow involvement to represent the lowest threshold at which to diagnose “leukemia” as opposed to “myelodysplasia” (barring certain genetic aberrations that flip the diagnosis to “leukemia” even at lower proportions of blasts). By contrast, in the WHO classification, there is no “lower threshold” for bone marrow involvement in the diagnosis of acute lymphoblastic leukemia.

As another example, for CLL/SLL, we use the term “chronic lymphocytic leukemia” if there are more than 5 × 109/L circulating malignant B cells with or without lymph node, spleen, or liver enlargement, but we use the term “small lymphocytic lymphoma” if there is lymphadenopathy (or spleen or liver enlargement) with fewer than 5 × 109/L circulating malignant lymphocytes and no cytopenias attributable to marrow infiltration. Finally, if the blood shows fewer than 5 × 109 cells/L malignant lymphocytes and nodal and organ enlargements are absent, we diagnose “monoclonal B lymphocytosis of unknown significance” (MBUS). MBUS can be found in 3–4% of healthy adults over age 40 and occasionally evolves to CLL.

On the other hand, lymphadenopathy and “masses” are not unique to neoplasms of lymphoid origin. Myeloid leukemias do occasionally form masses and do occasionally cause lymph node enlargement. Masses of myeloid blasts infiltrating organs (other than bone marrow) and effacing normal tissue architecture are called “myeloid sarcomas.” (Old terms include “granulocytic sarcoma” and “chloroma.”) Simple enlargement of the spleen due to infiltrating AML or simple infiltration of the skin or gingival without effacement of the normal tissue architecture would not be considered a myeloid sarcoma.

Molecular Diagnostics

In the course of establishing a diagnosis, hematologists increasingly rely on advanced molecular laboratory methods to detect DNA mutations, chromosomal aberrations, and chimeric proteins. For example, polymerase chain reaction (PCR) can be used to detect jak2 harboring the V617F mutation that characterizes most cases of polycythemia vera. Standard G-banded karyotypes often reveal chromosomal aberrations of diagnostic importance. Fluorescence in situ hybridization (FISH) can be used to detect fusion genes such as BCR-ABL in CML or PDGFRβ-FLIPI in chronic myelomonocytic leukemia. Several techniques are available to study the immunoglobulin genes and the T cell receptor in order to prove clonality of suspected lymphoid malignancies. PCR or immunohistochemistry can also be used to detect certain viruses (like Epstein-Barr virus or human T cell leukemia/lymphoma virus) that are associated with particular lymphoid cancers.

The results of such investigations often influence treatment decisions based upon their prognostic properties. For example, certain chromosomal aberrations, such as t(8;21) and inversion of chromosome 16, confer a good prognosis in AML. Consequently, hematologists would not recommend frontline allogeneic stem cell transplants to these patients. If acute promyelocytic leukemia is associated with t(15;17) (q22;q12) fusing PML to RARα, the patient is likely to respond well to all-trans retinoic acid (ATRA). Other chromosomal aberrations, such as loss of part of chromosome 5 or 7, or inversion of chromosome 3, confer a dismal prognosis in AML. Hematologists would routinely offer allogeneic stem cell transplant to young, fit patients with these karyotypes. DNA sequence mutations can also inform prognosis. For example, a particular type of mutation in the Flt3 tyrosine kinase (internal tandem duplication in the DNA sequence encoding the juxtamembrane domain of the molecule) confers a poor prognosis in AML.

Bone Marrow Aspiration

When a clinician performs a bone marrow aspiration in a patient suspected of harboring an undiagnosed hematologic malignancy, three draws should normally be performed: one for histopathology smears (prepared at the bedside or drawn into EDTA for immediate preparation in the lab), one for flow cytometry (sodium heparin or EDTA tube, per institutional guidelines), and one for cytogenetics/molecular testing (sodium heparin tube). For the smears and flow cytometry samples, only 0.5–1 mL should be withdrawn with each pull to avoid diluting the sample with blood. The bone marrow biopsy is useful to assess cellularity, infiltration with carcinoma, and fibrosis. Although not all hospital laboratories can perform the more specialized tests, the samples can normally be sent to reference centers.

Epidemiology

Acute Leukemias

Acute myeloid leukemia (AML) occurs in 3.5 persons per 100,000 per year. It comprises 80–90% of adult acute leukemias. Acute lymphoblastic leukemia (ALL) occurs in 1 person per 100,000 per year. It comprises only 10–20% of adult acute leukemias but accounts for the majority of childhood leukemia.

Chronic Leukemias

Chronic myeloid leukemia (CML) accounts for 15% of all adult leukemias. Its global incidence is 1.6 per 100,000 persons per year. The median age at diagnosis is 53 years and the incidence increases with age, although CML can even occur in childhood. While ionizing radiation is associated with CML and its incidence is increased among survivors of the Hiroshima nuclear bomb, most cases have no known cause. The incidence of chronic lymphocytic leukemia (CLL) in Western countries is 2–6 per 100,000 persons per year. The incidence rises sharply with increasing age; above 75 years, the incidence is 35 to 40/100,000 persons per year. The median age at diagnosis is 72 years. There is a 2:1 male to female predominance. CLL is not associated with radiation exposure.

Myelodysplasia

The median age at diagnosis is around 70 years. While the crude incidence is around 2 per 100,000 persons annually, the age-adjusted incidence is around 20 per 100,000 persons over age 70. Ten percent to 15% of cases are estimated to be related to prior chemotherapy or radiation.

Myeloproliferative Neoplasms

The incidence of each of the major non-CML myeloproliferative neoplasms (MPNs) ranges from 0.2 to 3 cases per 100,000 persons per year. They can occur at any age but are more common in older adults. Essential thrombocythemia (ET) shows a second peak in younger women in the third to fifth decade, and these women usually suffer few complications. Familial predisposition to adult-onset MPNs is also described. Radiation exposure has been linked to polycythemia vera (PV).

Non-Hodgkin Lymphoma

NHL is the fifth most common cancer in adults, with a crude incidence of around 20 per 100,000 persons per year. Its incidence rises with age. For unknown reasons, its incidence in the Western hemisphere and Australia has been rising at a rate of 2–3% per year for the past three decades.

Hodgkin Lymphoma

HL is uncommon with an annual incidence of 2.5 per 100,000 persons. The peak incidence is around age 30, but there is a second, smaller peak in adults older than 65 years.

Monoclonal Gammopathy of Undetermined Significance (MGUS) and Myeloma

Monoclonal gammopathy, detected as an abnormal spike on serum protein electrophoresis, is common. In the absence of cytopenias (anemia), renal insufficiency, hypercalcemia, lytic lesions attributable to plasma cell expansion, or conditions such as cryoglobulinemia or cold agglutinin disease, the presence of an asymptomatic monoclonal component is termed “monoclonal gammopathy of undetermined significance” (MGUS). MGUS was detected in 3% of persons 50 years of age or older, 5% percent of persons 70 years of age or older, and 7.5% of those above age 85 in a predominantly Caucasian cohort. The prevalence is about three-fold higher among African Americans. MGUS evolves to myeloma, related plasma cell dyscrasias, or less frequently to lymphoma at a rate of approximately 1% per year, but the risk can be more precisely quantified for the individual patient by taking into account the immunoglobulin isotype (IgG vs. non-IgG), the size of the monoclonal peak (risk increasing above 15 g/L), and the serum free light chain ratio. It is thought that most myeloma evolves from antecedent MGUS.

The incidence of myeloma is 5.4 per 100,000 persons per year, but it is twice as high among African Americans, who have higher physiologic immunoglobulin levels and a higher prevalence of MGUS. Like MGUS, the incidence of myeloma increases with age.

This section will discuss acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) together, comparing and contrasting them at times, because the salient clinical features are similar in adults. The acute leukemias are very aggressive hematologic cancers, are usually fatal within weeks if not properly treated, and require urgent inpatient management. The goal of care in young, fit patients is to cure the disease with chemotherapy and possibly stem cell transplantation. In elderly patients (above age 60), outcomes are poor, with less than 10% survival in those with unfavorable cytogenetics, even with the most aggressive therapy. In this population, palliation with periodic “gentle” chemotherapy or investigational agents, treatment of infections, and supportive red cell and platelet transfusions may be more appropriate.

Pathogenesis

AML and ALL are due primarily to increased proliferation and failure of differentiation. Most leukemias arise de novo. AML may also result from evolution of myelodysplastic syndromes or progression of myeloproliferative neoplasms. Either AML or ALL may evolve from CML. Prior chemotherapy can initiate DNA damage that, if not repaired, leads to AML. If alkylating agents or radiation is implicated, the usual latency is 5–10 years and loss of chromosomes 5 or 7 is frequent. If topoisomerase II inhibitors are implicated, the usual latency is one to five years and translocations involving 11q23 are frequent. Prior chemotherapy may also lead to ALL, but rarely. Certain chemical exposures, such as benzene, are also leukemogenic. Down syndrome is characteristically associated with acute megakaryocytic leukemia, other AML subtypes, or ALL, as well as a transient myeloproliferative disorder in newborns. Familial predisposition to AML is described. Examples include kindreds with germline RUNX1 (AML1) gene mutations that are sometimes associated with thrombocytopenia and platelet function defects and kindreds with germline CEBPA mutations that are sometimes associated with increased eosinophils. Sporadic aplastic anemia and certain inherited bone marrow failure syndromes predispose to AML. Other syndromes that predispose to development of various solid tumors, such as Li Fraumeni syndrome and Bloom syndrome, also increase the risk of leukemia. In short, a family history of hematologic cancer, bone marrow failure, bleeding diathesis, and solid tumors should be sought.

Diagnosis

The WHO classification, revised in 2008, is widely accepted but the old French-American-British (FAB) classification is still used in common parlance. The FAB classification relies upon microscopy and simple immunohistochemistry, while the WHO classification also incorporates immunophenotyping and molecular investigations.

Per the WHO, the diagnosis generally requires that very immature cells, called “blasts,” comprise at least 20% of circulating peripheral blood white cells or of nucleated bone marrow cells. There are three exceptions to this rule: (1) cases with particular recurrent, balanced translocations or inversions are considered AML even at lesser blast counts; (2) certain AML subtypes when abnormal promyelocytes, promonocytes, monocytes, or proerythroblasts count as “blast equivalents”; and (3) myeloid sarcomas, which may be unaccompanied by circulating leukemia or increased bone marrow blasts, but for all intents and purposes are a form of AML. Normal bone marrow comprises < 5% blasts and normal blood contains none.

It is often impossible to distinguish the lineage of poorly differentiated leukemia under the light microscope. Auer rods are pathognomonic of AML (Figure 179-1). In AML, immunophenotyping by flow cytometry will show typical combinations of myeloid markers (eg, CD33, CD13, CD15, HLA-DR), monocytic markers (eg, CD4, CD14, CD11b, CD11c, CD64, CD36, CD68, CD163, lysozyme), and rarely megakaryocytic or erythroid markers. In ALL, lymphoid markers are expressed (eg, TdT and CD10, as well as B cell markers CD19, cytoplasmic CD79a, cytoplasmic or surface CD22, or T cell markers CD2, CD3, CD5, CD7). Either leukemia may express markers of primitive blasts (eg, CD34, CD117). Biphenotypic and bilineage leukemias are encountered occasionally.

Immunohistochemistry is still useful; myeloperoxidase stains myeloblasts, nonspecific esterase stains monoblasts, and periodic acid Schiff (PAS) stains lymphoblasts. Cytogenetics or molecular analyses (FISH or PCR) may show characteristic translocations, deletions, or fusion genes. These are routine investigations. Sequencing for point mutations and internal tandem duplications of Flt3 and other genes is increasingly performed for risk stratification, and the results may steer some patients toward trials of Flt3 inhibitors or to transplant.

Presentation

Blasts overtake the marrow, preventing normal hematopoiesis. Patients may come to clinical attention because of classic symptoms related to anemia, infection (due to neutropenia), bruising, or abnormal bleeding (usually with platelets < 20 × 109/L). Some patients are leukopenic, even when the marrow is “packed” with blasts, but most have normal to extremely elevated white counts. Blasts are ineffective at fighting infections. Although fever may be disease related, cultures of blood and urine should be done in all cases, and sputum and stool cultures when localizing symptoms are present. Gram-negative sepsis due to translocation of gut organisms is common when the neutrophil count is < 0.5 × 109/L. In the setting of neutropenic fever or suspected infection, broad spectrum antibiotics that cover Pseudomonas aeruginosa and other gut pathogens should be initiated promptly (eg, piperacillin/tazobactam 4.5 gram IV every 6 to 8 hours, ceftazidime 2 gram IV every 8 hours). Bone pain may occur as a result of rapid bone marrow expansion from proliferating blasts. In such cases, narcotic analgesia may be appropriate; nonsteroidal anti-inflammatory drugs and acetaminophen are usually avoided owing to increased bleeding risks (in the setting of thrombocytopenia) and masking of fevers respectively. Despite narcotics, pain relief may be suboptimal until chemotherapy takes effect, often just a few days into the treatment course.

Tissue infiltration is typical of certain AML subtypes, especially monoblastic and monocytic forms (FAB subtype M4/5) and M2 with t(8;21). Rarely, AML cells can form a solid tumor, called a myeloid sarcoma. These may be located anywhere in the body including skin, lymph nodes, gastrointestinal tract, bone, soft tissue, testes, and mediastinum. Lymphadenopathy is rarely seen with AML but is more common with ALL. Splenomegaly may occur with either. Large anterior mediastinal tumors are typical of T cell ALL. When associated with airway obstruction or the superior vena cava syndrome they are medical emergencies that should be handled with the involvement of anesthesia and intensive care teams. Prompt institution of steroids is required and chemotherapy should follow as soon as the diagnosis is confirmed. Mediastinal radiation is indicated only if the patient's condition deteriorates and the mass grows despite these measures. Leukostasis is much more likely to occur in AML with white counts exceeding 200 × 109/L and is rare in ALL. Hyperfibrinolysis and disseminated intravascular coagulation are classically described with acute promyelocytic leukemia (M3) but can occur in other subtypes and should be routinely evaluated in all newly diagnosed patients. Markers of tumor lysis need to be checked in all patients; abnormalities detected prior to initiating chemotherapy (spontaneous tumor lysis) must be promptly treated. Patients with normal tumor lysis markers prior to chemotherapy also require treatment to prevent the development of tumor lysis syndrome, which commonly complicates the management of aggressive hematologic malignancies once chemotherapy is started (see chapter 180 for more details). Hypokalemia sometimes complicates FAB M4 or M5 AML subtypes because monocytic forms release lysozyme that damages renal tubules, causing potassium wasting. It should not be over-vigorously corrected because hyperkalemia may supervene once chemotherapy is initiated.

Central nervous system involvement is more frequent with ALL. Neurologic symptoms are usually due to leptomeningeal disease. Early CNS involvement is very rare in AML. ALL protocols all mandate a diagnostic lumbar puncture at presentation, even in the absence of neurologic symptoms. Patients with CNS disease are treated with intensified intrathecal chemotherapy and, depending on the extent of CNS involvement and the protocol, cranial irradiation. ALL patients without CNS involvement have a sufficiently high risk of future CNS disease that intrathecal chemotherapy, high dose systemic chemotherapy that crosses the blood-brain barrier, and cranial irradiation on a prophylactic schedule are routinely included in treatment protocols.

Treatment Principles and Supportive Care

Induction therapy requires admission to the hospital. Central venous access is essential for multiagent intravenous chemotherapy. Supportive care includes prevention and management of tumor lysis syndrome (see chapter 180), treatment of neutropenic fever and infections, and administration of blood products.

Chemotherapy

Acute Myeloid Leukemia

For AML and ALL, the first day of chemotherapy is considered “Day 1.” A typical AML induction regimen is “3 + 7”, that is, three daily infusions of an anthracycline overlapping with seven days of continuous-infusion cytarabine, although other acceptable regimens exist. Marrow aplasia generally lasts four to six weeks. Some institutions examine the bone marrow around the fourteenth day of induction. If the bone marrow is hypoplastic and contains < 5% blasts, the patient is considered to have responded to chemotherapy. If the marrow is > 20% cellular with > 5% blasts, the response is inadequate and a second round of induction (usually with alternative drugs) may be administered. Intermediate results such as a hypoplastic marrow with > 5% blasts might prompt reexamination of the marrow in a few days' time. Other institutions only examine the marrow once reconstitution of blood counts has occurred. The bone marrow is then examined to confirm histologic remission (ie, a normocellular marrow with < 5% blasts), although cytogenetic and molecular testing may still detect the malignant clone at this point. Patients are generally discharged after peripheral blood counts recover.

Consolidation therapy generally consists of three to four monthly cycles. Again, several acceptable regimens exist. One common regimen employs high-dose cytarabine administered every 12 hours on days 1, 3, and 5. Patients may be hospitalized for the few days of chemotherapy infusion but are usually discharged immediately thereafter. Supportive transfusions are routinely provided through the outpatient hematology-oncology clinics, but it is common for patients to be readmitted to hospital for fever/infection.

For acute promyelocytic leukemia (FAB M3), the differentiating agents ATRA and arsenic are added to induction and consolidation therapy. APL is currently the only type of AML for which maintenance therapy is employed.

Acute Lymphoblastic Leukemia

Regimens for ALL are generally more complicated. They entail four phases: remission induction, intensification (also called consolidation in some protocols), continuation (also called maintenance), and CNS therapy. In adults, four anchor drugs are included in induction: glucocorticoids, vincristine, L-asparaginase, and an anthracycline. Some regimens incorporate other drugs too. The intensification phase lasts many weeks. Intensification employs multiagent chemotherapy. Continuation relies on oral daily 6-mercaptopurine and weekly oral or IV methotrexate with pulses of vincristine and steroids for one to two years or even longer in some protocols. CNS-directed treatment is given throughout all phases with intrathecal methotrexate and/or cytarabine, but an aggressive schedule of CNS prophylaxis with intrathecal drugs and/or cranial irradiation is intercalated into many protocols between segments of intensification therapy. Residual mediastinal masses are generally irradiated. Patients may be offered allogeneic stem cell transplantation in lieu of intensification or continuation therapy depending on their risk stratification. Recent studies suggest that allogeneic transplant offers a substantial survival advantage compared to chemotherapy alone in certain patient subgroups, but also that transplant-related mortality may be considerable in patients older than 35 years.

A coagulopathy related to depletion of specific proteins involved in maintenance of normal hemostasis, particularly fibrinogen and antithrombin III, can develop in patients treated with L-asparaginase. Usually this is subclinical, but bleeding and thrombotic complications occasionally develop. Patients at increased risk for bleeding complications who develop abnormalities in coagulation testing (eg, severe hypofibrinoginemia) should be considered for prophylactic factor replacement. Adults presenting with venous thrombosis should be treated with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our general practice is to use a full-dose UFH or LMWH at platelet counts above 50 × 109/L and to consider reduced doses of UFH or LMWH at platelet counts lower than 50 × 109/L. Patients sometimes receive platelet transfusions to permit adequate anticoagulation, but this approach is not feasible for many because of eventual platelet refractoriness. For those who cannot be safely anticoagulated because of more profound thrombocytopenia or recent bleeding, a temporary inferior vena cava filter is placed. Other reasons to suspend anticoagulation are intramuscular injection of L-asparaginase and planned lumbar punctures.

The Philadelphia chromosome (BCR-ABL p190 variant) occurs in about 30% of adult ALL cases and portends a particularly poor prognosis. Appropriate candidates are offered up-front allogeneic stem cell transplant for Ph+ ALL as soon as they enter complete remission.

CNS Prophylaxis

CNS prophylaxis is established in ALL but is not routinely required in AML. Patients with AML who should be considered for a screening LP include those with monocytic or myelomonocytic subtypes, those with t(8;21), biphenotypic leukemia, or a presenting WBC > 100 × 109/L. Some guidelines also recommend CNS surveillance in APL patients who develop hyperleukocytosis during therapy. If CSF cytology is positive, intrathecal chemotherapy is given twice a week until blasts clear, then weekly for four to six weeks.

Supportive Care

Because several weeks of aplasia are anticipated following induction, and to a lesser extent consolidation chemotherapy, excellent supportive care is integral to patients' survival.

Infections

Neutropenia is the central immune defect induced by antileukemic chemotherapy. Enteric Gram-negative bacteria, due to mucositis, and catheter-related Gram-positive bacteria are the most frequent causes of neutropenic sepsis. With prolonged neutropenia, opportunistic fungal infections become important. These include invasive candidal infections and pulmonary Aspergillosis. In patients with AML, viral infections and Pneumocystis jiroveci are less frequently encountered, as cell-mediated immunity is relatively preserved.

Antibiotics The use of broad-spectrum antibiotics for febrile neutropenia, even in the absence of an isolated pathogen, is imperative. Health care providers must be familiar with guidelines for the management of neutropenic fever and consultation with the infectious disease service is recommended if available/appropriate.

The use of prophylactic antibiotics is controversial. The National Comprehensive Cancer Network (NCCN) and the Infectious Disease Society of America (ISDA) state that prophylactic fluoroquinolone antibiotics may be offered to leukemia patients who are anticipated to be neutropenic (ANC < 1 × 109/L) for longer than seven days. There is evidence from placebo-controlled, randomized trials in leukemia and lymphoma and from large meta-analyses that such antibiotics dramatically decrease the frequency of fever and of documented Gram-negative infections and may decrease overall mortality. Levofloxacin may be superior to other quinolones because of its additional Gram-positive coverage. Prophylactic antibiotics are likely cost effective in high risk patients, but they may increase the frequency of Clostridium difficile infection and of Gram-positive infections like Streptococcus viridans. PCP prophylaxis is recommended for patients with ALL, but is not used in all protocols.

The use of prophylactic antifungals during induction is widely accepted. Fluconazole covers most but not all Candida species while the other antifungals mentioned below cover molds as well as yeast. In a randomized trial, prophylactic posaconazole led to fewer invasive fungal infections and reduced overall mortality compared to fluconazole or itraconazole in neutropenic AML patients receiving induction chemotherapy and the NCCN recommends its use in this setting. Many institutions continue to use fluconazole, which is less expensive and available intravenously. Also, ALL patients should receive fluconazole prophylaxis despite its narrower spectrum of activity because posaconazole, itraconazole, and voriconazole reduce clearance of vinca alkaloids, which might cause neurotoxicity. Patients with chronic severe neutropenia due to aplastic anemia or MDS should also receive prophylactic antifungal therapy. There is insufficient data to advise primary antifungal prophylaxis in consolidation therapy of leukemia.

Prophylactic growth factor support Granulocyte colony stimulating factor (G-CSF, filgrastim) is widely used in neutropenic patients with ALL. Prophylactic G-CSF enables ALL protocols in adults to be intensified, approximating the more successful pediatric protocols. However, the American Society of Clinical Oncology (ASCO) does advise caution in prescribing G-CSF to children with ALL because there is some suggestion that growth factors increase the risk of secondary MDS/AML.

Institutional practice varies with regard to the use of G-CSF in AML. G-CSF shortens the duration of neutropenia following AML induction by two to six days and decreases the incidence of infections. However, most studies do not show a survival benefit for G-CSF in AML. Current ASCO recommendations are to refrain from using G-CSF before or concurrent with chemotherapy because “priming” with G-CSF does not improve survival. The ASCO guidelines note that it is reasonable to use prophylactic G-CSF after induction to decrease the duration of hospitalization and the incidence of severe infections, but study results have been modest and variable. Post-induction growth factor support does not improve complete remission (CR) rates, CR duration, or overall survival (OS). The rare elderly patients who receive aggressive induction therapy might benefit most. ASCO does recommend the use of prophylactic G-CSF after consolidation treatments to avoid hospitalization for infection, despite the lack of impact on CR duration or OS. The long-acting pegylated filgrastim is not recommended for AML patients pending further trials.

Therapeutic growth factor support G-CSF is not routinely given as adjunctive therapy to febrile neutropenic patients. However, it may be considered in patients at high risk of complications. These include those aged > 65 years, those expected to be profoundly neutropenic with ANC < 1 × 109/L for longer than 10 days, those with pneumonia, hypotension, multiorgan dysfunction, invasive fungal infection, uncontrolled primary disease, or who were hospitalized at the time the fever developed.

Transfusion Support

Platelet transfusion Cytopenias result both from the disease and from chemotherapy. Platelet transfusions are generally administered prophylactically at platelet counts below 10,000 to 20,000/uL (10 to 20 × 109/L). One randomized trial showed no difference in the proportion of major bleeding events in patients allocated to a transfusion threshold of 10,000/ul compared with those allocated to a threshold of 20,000/uL despite receiving 21.5% fewer platelet transfusions. Because modern randomized studies have not tested a transfusion threshold below 10,000/uL, and because current ASCO evidence-based guidelines advise the use of the 10,000 to 20,000/uL threshold to trigger prophylactic transfusion, this is the “community standard” and most physicians are reluctant to deviate from it. Higher triggers are necessary in the presence of fever, DIC, splenomegaly, leukostasis, active bleeding, neurologic symptoms, recent ingestion of antiplatelet drugs, or planned invasive procedures.

Fever, splenomegaly, and large body habitus increase platelet transfusion requirements. In the absence of these factors, two consecutive one-hour post-transfusion increments below 15,000/uL (15 × 109/L) should provoke suspicion for platelet refractoriness and may warrant consultation with the Transfusion Medicine service.

Red cell transfusion Packed red cells are generally transfused when the hemoglobin falls below 80 g/L, not only to ameliorate symptoms of anemia, but also to preserve the rheologic properties of the blood so that the platelets flow along the periphery of the vessels, maximizing their hemostatic efficacy. Patients whose marrow is infiltrated with leukemia or whose marrow was recently ablated by chemotherapy do not respond to erythropoietin, so red cell transfusion is the mainstay of anemia management.

Coagulopathy Clinically significant DIC should be investigated and corrected with cryoprecipitate, fresh frozen plasma, and platelets as required, and monitored closely until resolution.

Other considerations Cellular blood products (including platelets) should be from CMV negative donors in patients who may be future allogeneic stem cell transplant candidates. CMV status should be determined serologically in such patients. The use of CMV negative blood products needs only to continue in transplant candidates who are CMV negative. Beware that recent IVIG administration frequently leads to falsely positive CMV serology.

Transplant recipients and patients treated with purine analogue chemotherapy (eg, fludarabine) should receive irradiated blood products to prevent transfusion-associated graft-versus-host disease. Irradiation is not necessary for cryoprecipitate or fresh frozen plasma. Local institutions vary in their policies as to which other groups of patients receive irradiated blood products.

Fertility and contraception Oral contraceptive pills or other hormonal therapy may prevent or ameliorate severe menstrual bleeding during the period of thrombocytopenia. Sperm banking and oocyte collection should be considered, particularly for young ALL patients, because chemotherapy increases the risk of infertility. Unfortunately, the urgency to institute therapy often does not allow for clomiphene stimulation and oocyte harvesting. Cryopreservation of unfertilized oocytes is suboptimal, so treatment is usually reserved for women in stable relationships that allow fertilized eggs to be cryopreserved. Regardless, all patients should be counselled about the fertility risks associated with treatment and offered referral to an appropriate clinic to review options for fertility preservations prior to initiating therapy if possible. Due to teratogenicity of treatment, all patients should be counseled to use appropriate contraception.

Avoiding cardiotoxicity Both AML and ALL induction regimens (in adults) contain anthracyclines. Acute cardiotoxicity is rare, appears unrelated to total dose, manifests as sinus tachycardia, flat T waves, ST segment depression, pericarditis/myocarditis, or left ventricular failure, and usually reverses within months. Early onset progressive and late onset cardiotoxicity often present as resting tachycardia in an asymptomatic patient. Patients may have a nonproductive cough or jugular venous distention and progress to frank congestive heart failure.

The occurrence of late cardiotoxicity is dose dependent. Although there is no cumulative dose that is “definitely safe,” current protocols limit cumulative lifetime doses to 450–550 mg/m2 doxorubicin, 800 mg/m2 daunorubicin, 150 mg/m2 idarubicin, 900 mg/m2 epirubicin, or 160 mg/m2 mitoxantrone. Echocardiography or rest radionucleotide scanning to assess the ejection fraction should be performed prior to anthracycline administration. Anthracyclines are contraindicated when the ejection fraction is below 45%, if the patient suffered an MI in the past three months, and in the presence of severe arrhythmia. Anthracycline-induced congestive heart failure is managed with the same drugs and devices used for nonischemic dilated cardiomyopathy with left ventricular dysfunction from other causes.

Prognosis

Median five-year overall survival for AML and ALL is about 30% in adults. This figure varies widely according to age (with fewer than 15% of adults > age 60 surviving) and the presence or absence of specific cytogenetic and molecular abnormalities.

Cytogenetic abnormalities are the most powerful prognostic factors in AML and ALL. The poor outcomes among older adults are in part due to over-representation of unfavorable cytogenetics in this cohort, in addition to a higher likelihood of therapy-related disease and antecedent hematologic disorders, and to comorbidities that increase treatment-related morbidity. Higher blast counts, delayed time to clearance of blasts from the blood and marrow, expression of multidrug resistance proteins, and mutations in various genes that control cell cycling, proliferation, and propensity to apoptosis are other important prognostic factors.

Molecular Pathogenesis

Peter Nowel and David Hungerford's discovery of a small stump on routine G-banded karyotypes in Philadelphia in 1960 proved for the first time that cancer is attributable to abnormal DNA. In 1973, Janet Rowley recognized that the Philadelphia chromosome (Ph) is due to a reciprocal translocation between chromosomes 9 and 22. In 1982, scientists identified the translocation partners as ABL (chromosome 9q34) and BCR (chromosome 22q11) genes. Later, scientists showed how the BCR-ABL fusion protein can transform cells.

Highly sensitive methods can detect the BCR-ABL fusion gene in about 30% of people. However, these mutations likely arise in and are restricted to the myeloid progenitor cells or their progeny. Their limited self-renewal capacity is thought to explain why frank CML does not develop; the mutation-bearing cells eventually die off. Thus, a final important discovery was that the disease-causing BCR-ABL fusion gene arises in a multipotent hematopoietic stem cell (HSC, Figure 179-2).

Additional mutations eventually accumulate in myeloid progenitors, causing them to acquire unlimited self-renewal (ie, stem cell-like) capacity and paving the way for transformation to myeloid blast crisis. Alternatively, the HSC or lymphoid progenitor compartments may accumulate additional mutations that lead to lymphoid blast crisis.

Clinical Presentation

Roughly 20–40% of cases are discovered by routine blood counts, when patients are still asymptomatic. Other patients may present with fatigue, weight loss, night sweats, or symptomatic anemia. Splenomegaly is common and may cause symptoms such as early satiety, left upper quadrant pain, or pain referred to the shoulder. Hepatomegaly is less frequent and usually asymptomatic, and liver function is almost invariably normal. Rare patients present with leukostasis and require urgent leukapheresis (see Chapter 180, Management of Emergencies in Patients with Hematologic Malignancies). The majority (˜85%) of patients are diagnosed during the chronic phase.

Laboratory Features

The median white count at diagnosis is ˜100–170/mm3 and it will be left-shifted. Myelocytes and metamyelocytes may be seen, but blasts are rare. Absolute basophilia occurs in almost all patients, and eosinophilia occurs in some. Monocytes should not comprise more than 3% of the white cells, even though the absolute monocyte count may be increased. (The exception here is rare cases with the p190 BCR-ABL isoform, which may exhibit sufficient monocytosis to be confused with chronic myelomonocytic leukemia. This emphasizes the need to test for BCR-ABL in any disorder that presents similarly.) Occasional patients present with significant thrombocytosis, and rarely patients may have a marked isolated thrombocytosis. It is important to exclude CML when evaluating a patient with suspected essential thrombocythemia that lacks the jak2 V617F mutation.

Differential Diagnosis

The differential diagnosis of a marked granulocytic, left-shifted leukocytosis (WBC > 50/mm3) includes a leukemoid reaction, as might be seen with infections like Clostridium difficile colitis. In the hospital context, a recently normal neutrophil count essentially excludes CML and the rarer disorder, chronic neutrophilic leukemia (CNL). Unlike CML, a leukemoid reaction will not exhibit basophilia. An outmoded test, the leukocyte alkaline phosphatase (LAP) score, will be high in leukemoid reactions and CNL and low in CML. If serious doubt exists, the peripheral blood should be tested for BCR-ABL by FISH or PCR to exclude CML, and clonality assays could be performed to exclude CNL. A high, markedly left-shifted white count along with evidence of stressed erythropoiesis, such as nucleated red cells and erythroblasts, as well as bizarre red cell shapes including teardrop forms, should raise suspicion for a leukoerythroblastic process (Figure 179-3). In adults, a leukoerythroblastic blood film suggests either bone marrow fibrosis or neoplastic infiltration. In that situation, a bone marrow biopsy should be stained for reticulin, collagen, and epithelial cells (to detect occult carcinoma).

Natural History

Classically, CML exhibits three phases. The chronic phase is characterized by a prolonged period of stable or gradually rising white count and a hypercellular marrow with less than 5% blasts. Untreated, the median duration of the chronic phase is two to three years. The WHO denotes the accelerated phase (AP) by any of the following: increasing WBC, increasing splenomegaly, persistent thrombocytosis (> 1000/mm3) unresponsive to therapy, thrombocytopenia (< 100/mm3) unrelated to therapy, or clonal cytogenetic evolution occurring after the initial diagnostic karyotype. The delineation between phases is not always clear cut. Basophilia exceeding 20% of peripheral blood white cells and an increase in bone marrow or blood myeloblasts to 10–19% may indicate progression from the chronic to accelerated phase, but are more likely to signify imminent progression to blast crisis. Untreated, the median duration of the accelerated phase is less than one year. Finally, the definition of blast crisis (BC) rests on the presence of ≥ 20% blasts in the blood or bone marrow, or extramedullary blast proliferation, which is generally in the skin, lymph nodes, spleen, bone, or central nervous system. In two-thirds of cases, the blast crisis is myeloid. In the other third, it is lymphoid. Normal white cells and platelets are markedly decreased. Blast crisis is difficult to treat and usually fatal. The median survival in myeloid blast crisis is three to six months and in lymphoid blast crisis, nine months.

Treatment

The goal of therapy is to slow excessive granulocytic (and sometimes megakaryocytic) proliferation and to slow or stop disease progression. At present, short of allogeneic stem cell transplantation, the disease is not considered curable, although research programs aimed at devising curative approaches are active.

Treatment of Chronic Phase

The IRIS trial established imatinib, a BCR-ABL tyrosine kinase inhibitor, as the new standard for chronic phase disease. There are no head-to-head trials comparing up-front allogeneic stem cell transplant to imatinib therapy. Historically, transplant in the first chronic phase was associated with 26% mortality at two years. Although surviving transplant patients are generally cured of disease, this compares poorly to the imatinib six-year survival data. First-line transplant may still be considered for young patients (< age 40) with high Sokal risk scores (see below) and matched sibling donors. However, transplant as a first-line strategy has generally fallen out of favor.

Monitoring Response

The main goal of therapy is to achieve a complete cytogenetic response (CCyR), which is the most important predictor of long-term freedom from progression. Even when a patient achieves a complete molecular response (undetectable BCR-ABL), current recommendations are to continue tyrosine kinase inhibitor (TKI) therapy lifelong. TKIs should not be discontinued outside of ongoing clinical studies aimed at characterizing the rates and risk factors for relapse.

Neutropenia and thrombocytopenia are common with all TKIs because in untreated CML, the majority of myelopoiesis is from the malignant clone. Once growth of the CML clone is inhibited, peripheral blood count recovery lags until normal myelopoiesis is replenished.

Treatment of Accelerated Phase and Blast Crisis

Dasatinib and nilotinib are second generation TKIs that improve peripheral blood counts in about half of patients in AP for whom imatinib was ineffective or intolerable, and some AP patients even achieve cytogenetic and molecular responses. Nonetheless, responses may be transient, so appropriate transplant candidates should be HLA typed and potential donors should be identified. The final decision on whether to proceed to transplant may depend on the individual patient's response to the alternative TKI therapy, the presence of other cytogenetic abnormalities, and the patient's preference.

On the other hand, patients in BC fair uniformly poorly. Myeloid BC should be treated with induction chemotherapy as for AML. Lymphoid BC should be treated with induction protocols for ALL. TKI therapy may be added to chemotherapy, at the risk of added toxicity.

Survival of patients transplanted while in AP or BC is poor (47% and 16% at two years, per the European Blood and Marrow Transplant registry). Therefore, a concerted effort should be made to achieve a second chronic phase with chemotherapy and TKIs prior to proceeding with transplant. Nontransplant candidates who do not respond to TKI therapy may be palliated with drugs like busulfan and hydroxyurea.

Prognosis

A number of prognostic scores take into account such factors as age, spleen size, platelet count, and percentages of blasts, eosinophils, and basophils in the blood. The most popular is the Sokal Score (published in 1984). It has been validated in the imatinib era. In the IRIS trial, the overall survival at six years was 76.3%, 86.9%, and 93.9% in the high, intermediate, and low Sokal risk groups, respectively.

Clonal evolution, as evidenced by the acquisition of additional cytogenetic abnormalities in Ph+ cells on G-banded bone marrow karyotypes, is prognostically important. Certain aberrations, such as trisomy 8, duplication of the Ph chromosome (implying amplification of BCR-ABL), isochromosome 17q, and del(der)9, stereotypically herald progression through accelerated phase and into blast crisis. Failure to meet the NCCN milestones for hematologic, cytogenetic, and molecular responses within the specified time frames and loss of a previous cytogenetic or molecular response also signify the likelihood of progression.

Pathogenesis

Chronic lymphocytic leukemia (CLL) is due to the accumulation of monoclonal small lymphocytes that have low proliferative capacity. The etiology of CLL is unknown. The existence of structurally similar B cell receptors across CLL cases suggests that the malignant B cells might recognize similar epitopes. Familial CLL has been described but most cases are sporadic. However, there may be an increased incidence of other hematologic malignancies in first-degree relatives of CLL patients. Also, the rarity of CLL in the Far East persists in emigrant populations, implying that genetic background predisposes to this leukemia.

Clinical Presentation

Most patients are diagnosed while asymptomatic because a blood count is performed for other indications. Others present with fatigue, B symptoms (fever, weight loss, night sweats), lymphadenopathy, or hepatosplenomegaly. Immune dysfunction accounts for infectious, autoimmune cytopenias, and other malignant complications.

Leukostasis is extremely unusual, even at white counts well in excess of 500 × 109/L. The physical examination should identify which nodal areas are involved and detect liver or spleen enlargement.

Infections

Secondary T cell, NK cell, neutrophil, and macrophage impairments are well described. Hypogammaglobulinemia results from the CD95 ligand/CD95 interaction between plasma cells and malignant B cells that inhibits plasma cells from secreting immunoglobulin and induces their apoptosis, and from T cell dysfunction. Zoster and respiratory tract infections due to viruses, Streptococcus pneumoniae or Haemophilus influenzae are frequently encountered as the disease progresses. Two randomized studies and one cross-over study in CLL show that low-dose intravenous immune globulin (IVIG) infusions reduce the incidence of infections, especially at IgG levels below 3 g/L, but there was no improvement in quality of life or survival. This finding was confirmed in a meta-analysis that also included studies in myeloma patients. In addition, IVIG prophylaxis is expensive and generally not considered cost effective. As a result, IVIG (0.4 mg/kg every 3–4 weeks) is usually reserved for selected patients with recurrent serious infections requiring hospitalization.

All patients with CLL should be vaccinated against viral influenza and pneumococcus. Haemophilus influenzae type b and meningococcal vaccines are advised pre-splenectomy and might be given to all patients too. Live vaccines are generally contraindicated.

Autoimmunity

Autoimmune phenomena are generally directed against red cells or platelets. Between 10% and 25% of patients develop autoimmune hemolytic anemia (AIHA) at some point during the course of disease. The direct antiglobulin test (DAT) should be checked at diagnosis and periodically thereafter, even in the absence of ancillary evidence of hemolysis such as elevated bilirubin, LDH, or reduced haptoglobin. ITP occurs in 2–3% of patients, while pure red cell aplasia and autoimmune neutropenia complicate the course of CLL even less frequently (the latter are more commonly associated with T cell large granular leukemia).

By themselves, AIHA and ITP are not indications for chemotherapy, but if more conservative measures such as a course of corticosteroids are ineffective, then treating the underlying CLL may be required. The majority of patients respond to steroids (eg, prednisone 1 mg/kg/day) within one to two weeks. The successful dose should be maintained for two to six weeks and tapered slowly over three months. If there is no response to steroids, then rituximab-containing combination chemotherapy, splenectomy, or other ITP-appropriate immunosuppressive drugs are considered. In urgent situations, high-dose IV methylprednisolone and full-dose IVIG (eg, 1 gram/kg/day for two days) may work rapidly.

Secondary Malignancy

Immune dysregulation is implicated in the increased incidence of solid tumors among patients with CLL. These include an excess of colorectal, lung, and squamous cell skin cancers. Age-appropriate cancer screening, sun protection, and annual dermatologic examination are advised.

Laboratory Features

The National Cancer Institute (NCI)-sponsored International Working Group definition of CLL, endorsed by the WHO, requires the presence of ≥ 5 × 109/L monoclonal B cells with typical CLL immunophenotype circulating in the peripheral blood (kappa or lambda restriction, dim surface IgM or IgD, CD5 positive, CD23 positive, dim CD20) sustained over three months. The blood film will show small, fairly normal-appearing lymphocytes as well as smudge cells, but these are not pathognomonic for CLL. Fewer than 55% of lymphocytes should be prolymphocytes (medium-sized cells with moderately more open chromatin and a single, prominent nucleolus); otherwise, the diagnosis is prolymphocytic leukemia, an entity that behaves quite differently from CLL. When arising de novo, prolymphocytic leukemia is usually CD5 and CD23 negative. Small lymphocytic lymphoma is the nonleukemic counterpart of CLL with identical tissue morphology and immunophenotype, circulating monoclonal B-lymphocytes < 5.0 × 109/L, and no cytopenias related to bone marrow infiltration. Monoclonal B lymphocytosis is a recently described entity in which the relevant circulating cells fall below the concentration threshold for diagnosing CLL (see Natural History, below).

A bone marrow is not necessary at diagnosis but might be useful before aggressive therapy to assess “marrow reserve” or to elucidate the etiology of reticulocytopenic anemia (eg, heavy marrow infiltration with CLL vs. pure red cell aplasia) or thrombocytopenia (eg, ample megakaryocytes imply ITP).

Other investigations should include standard chemistries, quantitative serum immunoglobulins, serum and urine protein electrophoresis (a small monoclonal component is common), LDH, uric acid, and a direct antiglobulin test. Spherocytes may be noticed on the blood film if there is significant extravascular hemolysis. Baseline HIV and hepatitis B and C serological studies should be ordered at diagnosis; this applies to all the diseases discussed in this chapter.

Outside of a clinical trial, no imaging is required. However, a baseline chest X-ray is recommended to aid assessment when suspected pulmonary infections develop and many clinicians do order a computed tomography (CT) of the chest, abdomen, and pelvis before initiating treatment.

Natural History

In general terms, CLL is considered an indolent, albeit incurable, lymphoproliferative disease with progression in most cases over months to years. It is managed primarily in the outpatient setting, especially in the early, asymptomatic phase. The natural history and prognosis are extremely heterogeneous with median survivals ranging from 2 to 20 years within specific subgroups of patients. A number of novel prognostic markers have recently been discovered that provide powerful prognostic information in addition to clinical stage and help to explain some of the observed heterogeneity. These tests are often obtained at diagnosis and/or prior to initiating chemotherapy by sending peripheral blood or bone marrow samples to an appropriate molecular diagnostics laboratory. Examples include assessment of CD38 and ZAP-70 expression on leukemic B-cells as measured by flow cytometry (negativity conferring a favorable prognosis), mutational status of the immunoglobulin heavy chain gene (unmutated IgVH associated with poorer prognosis), interphase FISH cytogenetic evaluation (high risk markers include deletions of 17p and 11q), and beta-2 microglobulin. Testing for ZAP-70 and IgVH sequencing are not available at most centers.

The most frequent cause of death is infection. Death from secondary malignancies and from non-CLL related causes follows in frequency. Richter transformation to an aggressive, treatment-refractory large B cell lymphoma occurs in 1% to 10% of patients. Transformation to prolymphocytic leukemia occurs in up to 10% of patients. Rare patients develop other lymphomas, including Hodgkin disease.

The factors determining whether monoclonal B lymphocytosis evolves into CLL are under active investigation. A recent study found that the rate of progression to symptomatic CLL needing treatment is only 4% per year in the first seven years, and negligible thereafter. Currently, asymptomatic patients with low level CLL-phenotype clones should be considered to have “monoclonal B lymphocytosis of unknown significance (MBUS),” analogous to patients with monoclonal gammopathy of undetermined significance (MGUS), and followed clinically at approximately 6–12 month intervals to monitor for disease progression.

Treatment

Asymptomatic patients do not require chemotherapy and should be placed on clinical observation, often referred to as “watchful waiting.” Data from more than 2000 patients with early-stage disease enrolled in randomized clinical trials of immediate versus delayed alkylator-based chemotherapy have been synthesized in a meta-analysis. These studies showed no survival benefit to immediate therapy. According to the National Cancer Institute, indications for initiating therapy include B-symptoms (fever, drenching night sweats, weight loss), severe fatigue, massive lymphadenopathy (> 10 cm), massive splenomegaly (> 6 cm below the costal margin), anemia, or thrombocytopenia (Rai Stage 3 or 4) that is due to marrow infiltration or autoimmune mediated and not responsive to steroids; or a lymphocyte doubling time < 6 months. Patients with cytopenias due to marrow infiltration usually do not respond to growth factors (G-CSF or erythropoietin); chemotherapy is required. However, growth factors may be useful to support patients through periods of chemotherapy-induced cytopenias.

Symptomatic patients generally require treatment with chemotherapy. There are a number of first-line treatment options, depending on the clinical circumstance. Fit, younger patients are candidates for combination chemo-immunotherapy incorporating a purine analogue and monoclonal antibody. In a recent landmark randomized trial, the addition of rituximab (an anti-CD 20 monoclonal antibody) to fludarabine plus cyclophosphamide (FCR) increased overall survival compared with fludarabine and cyclophosphamide alone without a substantial increase in toxicity. This trial is the only randomized controlled trial to demonstrate a survival benefit for a first-line treatment regimen and FCR is now recommended for this indication. Toxicities associated with FCR include myelosuppression, neutropenic fever, and infections, including the potential for opportunistic infections such as Pneumocystis jiroveci (formerly: Pneumocystis carinii) and reactivation of herpes simplex and varicella zoster viruses; appropriate prophylaxis is required during and after therapy (eg, Septra, acyclovir). If preventative measures are implemented (allopurinol, oral hydration), clinically important tumor lysis syndrome is relatively uncommon.

Very elderly or frail patients with significant comorbidity may not be suitable candidates for aggressive treatment and may fair best with conservative therapy, such as single-agent oral chlorambucil. To date, the results of prognostic marker testing have had little impact on treatment decision making because their predictive properties remain unclear in most cases. Detection of del17p (approximately 5–7% of patients) or del11q (approximately 15–20% of patients) are notable exceptions that may impact initial choice of chemotherapy regimen in selected cases.

Transformation to a large B cell lymphoma is generally refractory to treatment. An attempt is often made to control disease with regimens for aggressive lymphomas that include anthracyclines.

Monitoring Response

In general practice, response is monitored by history, physical exam, CBC, and differential white counts. Follow-up CT scans are increasingly being performed, particularly in clinical trials. Immunophenotyping of blood or marrow lymphocytes is used to confirm suspected complete remission. A marrow aspirate need only be done to investigate cytopenias of unclear cause. For clinical trials, more stringent disease assessment is performed.

Myelodysplasia is a condition in which ineffective hematopoiesis in one or more lineages is accompanied by increased cell turnover in the bone marrow and morphologic dysplasia. Clinically, it manifests as peripheral blood cytopenias affecting one or more lineages, while the bone marrow is classically hypercellular. Patients might die of infections, bleeding, transfusion-related iron overload, or progression to acute leukemia.

Pathogenesis

The myelodysplastic syndromes (MDS) are clonal disorders. The transforming event probably occurs in a myeloid stem cell. Clonal hematopoiesis encompasses the myeloid, erythroid, and megakaryocytic compartments. Immature cells tend to die prematurely by programmed cell death, and those cells that reach terminal differentiation states are defective. For example, mature neutrophils may lack myeloperoxidase and mature platelets might be unable to aggregate effectively. A number of genetic lesions have been described, but the driving defects remain elusive.

Sideroblastic anemia generally exhibits reticulocytopenia and erythroid marrow hyperplasia with iron-laden mitochondria ringing the nucleus, as demonstrated by a Prussian blue stain. Congenital forms present with microcytic anemia, whereas the acquired form is generally normocytic or macrocytic. Reversible acquired sideroblastic anemia may be due to alcohol, drugs (isoniazid, chloramphenicol), copper deficiency/zinc toxicity, or hypothermia; in these instances, the marrow is often hypocellular and other cytopenias may also occur.

Diagnosis

The possibility of MDS is raised when a patient presents with one or more refractory cytopenias. The WHO classification mandates that minimally 10% of bone marrow cells in at least one lineage (erythroid, myeloid, or megakaryocytic) are morphologically dysplastic. In the absence of definitive morphologic dysplasia, the presence of specified unbalanced or balanced chromosomal abnormalities is considered presumptive evidence of MDS. Further subcategorization is based on the number of cytopenias and dysplastic lineages (eg, refractory anemia with unilineage dysplasia vs. refractory anemia with multilineage dysplasia), the presence of ≥ 15% ringed sideroblasts, and the percentage of blasts in the blood and marrow. MDS with isolated del(5q) occupies a unique category. Nutritional deficiencies (including B12 and folate deficiency), medications, toxins (eg, arsenic, alcohol), growth factor therapy, regenerative stress erythropoeisis (eg, following an episode of hemolytic anemia), and systemic infection (eg, tuberculosis) should be excluded before a diagnosis of primary MDS is rendered.

Clinical Presentation

Patients usually present with gradually progressive macrocytic (and sometimes normocytic) anemia. Neutropenia and thrombocytopenia are much less frequent initial manifestations but develop as the condition progresses. Organomegaly is quite uncommon. Rarely, autoimmune complications like vasculitis, monoarticular arthritis, or a syndrome of fever, edema, and pulmonary infiltrates occur.

Laboratory Investigations

Initial investigations should include a CBC, reticulocyte count (which will be inappropriately low), erythropoietin level, and iron studies. Attention should be paid to the blood monocyte count, which should be below 1 × 109/L, otherwise the diagnosis of chronic myelomonocytic leukemia is more likely. Bone marrow aspiration and biopsy with iron stain, cytogenetics, flow cytometry (to assess the blast count), and reticulin stain are crucial. In most instances, the marrow is hypercellular. Hypoplastic MDS may be difficult to distinguish from aplastic anemia. A minimal amount of dysplasia may accompany the latter entity too. Hypocellular MDS is more likely to show a normal or high percentage of CD34+ cells in the marrow (mean 3.5%, range 1–7%). In aplastic anemia, CD34+ stem cells are under immune attack and are often extremely low by flow cytometry or immunohistochemistry (mean 0.13%, range 0.02–0.36%). Apart from those chromosomal abnormalities listed by the WHO, many other cytogenetic aberrations are frequently seen but not specific for MDS and may occur in aplastic anemia too. Therefore, cytogenetic findings cannot always be used to distinguish the two entities. HLA-DR15 is associated with both aplastic anemia and MDS in younger patients and > 40% of these MDS patients may respond to immunosuppressive therapy, but responses drop sharply as age increases. HLA typing is also warranted in younger patients for whom allogeneic transplant may be warranted.

Natural History

Most patients die of progressive marrow failure, either due to infections in the setting of neutropenia or to cardiac failure from transfusion-associated iron overload. Others progress to overt AML. Certain WHO subtypes, including MDS with isolated del(5q) and refractory anemia with ringed sideroblasts confer a better prognosis and rarely transform to AML.

Two prognostic scores, the International Prognostic Scoring System (IPSS) and the WHO-classification based scoring system (WPSS) are commonly used to predict the risk of leukemic evolution and overall survival. Among patients older than 60, survival is shortened further. The WPSS has the advantage of applicability at any time during the disease course.

Treatment

Specific therapies such as hypomethylating agents (azacitidine, decitabine), lenalidomide, growth factor support, and possibly chelation therapy in those with transfusion-associated iron overload are generally administered on an outpatient basis and will not be discussed here. MDS is usually a chronic illness, often not directly related to the reason for hospitalization. Physicians should be sensitized to the cardiac complications resulting from iron overload. When cytopenias are severe or when MDS progresses to AML, the same supportive care as discussed above applies (ie, transfusion of blood products to support hemoglobin and platelets, and prompt management of infection-related complications, especially in neutropenic patients). Younger patients with poor risk disease may be offered allogeneic stem cell transplant.

The classic myeloproliferative neoplasms (MPNs) include CML (already discussed), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). There are also a number of less common (eg, chronic eosinophilic leukemia, systemic mastocytosis) and extremely rare (eg, chronic basophilic leukemia) MPNs. By definition, MPNs feature < 20% blasts in blood and marrow. The goal of treatment is to relieve symptoms and to prevent complications such as thrombosis. MPNs are not curable with available pharmacologic therapies.

Pathogenesis

MPNs likely result from increased sensitivity to growth-promoting cytokines due to activating somatic mutations. Whether the different disease phenotypes are due to different cell types in which the same culprit mutation originates, to other interacting genetic factors, to the “dosage” of heterozygously or homozygously jak-2 mutated cells, or to genetic lesions that precede jak-2 mutation is not clear; evidence exists to support each of these hypotheses.

Diagnosis

The diagnosis of MPNs rests on demonstrating clonal proliferation leading to accumulation of mature circulating blood cells. Clonal proliferation may not be demonstrable in all cases and some instances of essential thrombocythemia are probably truly polyclonal. In such cases, reactive thrombocytosis (eg, due to iron deficiency, infection, or metastatic cancer) should be carefully excluded. Similarly, when considering a diagnosis of PV, it is important to rule out physiologic and nonphysiologic causes of erythrocytosis, such as (1) hypoxia from chronic pulmonary disease, sleep apnea, and right-to-left cardiac shunts; (2) elevated carboxyhemoglobin from smoking or occupational exposure to hydrocarbon fumes; (3) inappropriate renal, hepatic, or paraneoplastic erythropoietin production; and (4) relative polycythemia due to decreased plasma volume (as in dehydration, diuretic use, or alcoholism). An algorithm for evaluating erythrocytosis is presented in Chapter 173 Abnormalities in Red Blood Cells. Myelofibrosis might be secondary to a separate hematologic neoplasm, including antecedent PV or ET, to carcinoma metastatic to the marrow, or to other inflammatory conditions. The WHO classification should be consulted for the specific diagnostic criteria for each entity.

Clinical Presentation

In addition to elevated blood counts, the classic MPNs share many clinical features, including frequent hepatosplenomegaly, hyperuricemia that can lead to gout, a risk of arterial and venous thrombosis, and hypercatabolism leading to fatigue. Symptoms due to hyperviscosity, histamine release, and microvascular vasomotor instability include aquagenic pruritus and erythromelalgia. Facial plethora is often described in patients with PV. Hyperviscosity may lead to epistaxis or gastrointestinal bleeding (often occult), particularly in PV. One-fifth of PV patients and 10–25% of ET patients present with thrombotic complications, including transient ischemic attacks, ischemic stroke, myocardial infarction, deep venous thrombosis, hepatic vein thrombosis (Budd-Chiari syndrome), or splanchnic vein thrombosis. Extreme thrombocytosis, as may occur with ET or PV (platelets > 1000 × 109/L), may paradoxically lead to hemorrhage, including hemorrhagic stroke, because of qualitative platelet dysfunction such as acquired type 2 von Willebrand disorder as the platelet surface binds and cleaves large vWF multimers. About 10% of patients with ET present with a hemorrhagic event. Pulmonary hypertension is a serious complication, which portends poor survival. Extramedullary hematopoeisis is unique to primary and secondary myelofibrosis. It results from neoplastic hematopoietic cells migrating to the spleen and liver, not resumption of fetal hematopoiesis.

Laboratory Features and Investigations

PV is considered when the hemoglobin is above 185 g/L in men or 165 g/L in women, when the hematocrit is above the ninety-ninth percentile for age, sex, and altitude, or when there is other evidence of elizabeth increased red cell mass. The patient is usually overtly iron deficient, but iron supplementation should not be prescribed because it can precipitate a rapid, dangerous rise in the red cell count. The white count and platelet count are frequently elevated too. The oxygen saturation should be normal and if carboxyhemoglobinemia is possible, then an arterial blood gas should be obtained. Nocturnal monitoring to exclude sleep apnea may be needed. If the erythropoietin level is inappropriately normal or elevated, abdominal imaging should be performed to rule out renal and liver tumors, and rarely uterine, ovarian, and adrenal tumors. Cerebellar hemangiomas, parotid neoplasms, and lymphomas are occasionally implicated in ectopic erythropoietin production.

ET is considered when the platelet count is persistently above 450 × 109/L in the absence of underlying reactive etiologies and once alternative myeloproliferative neoplasms have been excluded. Myelofibrosis often comes to attention because of a leukoerythroblastic peripheral blood smear featuring teardrop red cell forms, nucleated red blood cells, and left-shifted granulocyte series.

Bone marrow aspiration and biopsy are not mandatory in straightforward instances of PV or ET, in which jak2 or c-mpl mutations in the peripheral blood granulocytes are detected in the setting of a classic clinical picture, but this procedure might still be useful to prove clonality with karyotypes in jak-2 negative cases and to evaluate the degree of fibrosis.

Natural History

Untreated, 40–50% of PV patients will suffer thrombosis, 20–40% will die of thrombosis, 15% will develop significant bleeding, and 5–10% will die of bleeding. In PV, two-thirds of thrombotic events in the ECLAP study were arterial and one-third venous. In ET, arterial thrombosis is about three times as frequent as venous thrombosis and the incidence of bleeding is lower than in PV. PV and ET may evolve from a proliferative phase to a “spent” phase with progressive marrow fibrosis and poor median survival of < 3 years. The risk of developing myelofibrosis increases with duration of PV or ET. Because of overlapping features, some of the ET patients who are “early” progressors might actually have had primary myelofibrosis (PMF) all along. PMF characteristically also evolves from a proliferative, prefibrotic phase to a fibrotic stage. All three conditions can transform to AML. PV transforms to AML at a rate of 0.3–1% per year and although it has been difficult to demonstrate, this risk probably increases with duration of disease. In ET, transformation to AML is rare in the first decade after diagnosis and increases thereafter. The risk of transformation is increased by alkylating agents (eg, chlorambucil, busulfan) and radioactive phosphate (P32). Whether or not hydroxyurea is associated with increased risk of leukemic transformation remains controversial based upon currently available data; however, definitive evidence to support claims of increased risk is lacking in our opinion. Nonetheless, the risks and benefits need to be carefully considered prior to recommending lifelong cytoreductive treatment.

Treatment

Traditional cardiovascular risk factors, including smoking, diabetes, age > 60–65 years, and a history of prior venous or arterial thrombosis are associated with increased risk of thrombotic events in PV and ET. Based on the ECLAP study, low-dose aspirin is recommended for all PV patients and extrapolated to ET patients as well. Weekly or twice weekly phlebotomy to achieve a target hematocrit below 45% in men, 42% in women, and 37% in pregnant women is advised for all patients with PV. Once iron-limited hematopoiesis develops, the frequency of phlebotomy can usually be decreased to two to four times per year to maintain the target hematocrit. PV and ET patients who have suffered a prior thrombotic event should be treated with cytoreductive therapy to reduce their risk of recurrent, potentially fatal thrombosis. Patients older than age 60 and those with extreme thrombocytosis (> 1500–2000 × 109/L) in the absence of prior thrombosis have an intermediate risk of thrombotic complications and bleeding, and should also be considered for hydroxyurea therapy, although the evidence for pharmacologic cytoreduction in these populations derives largely from observational data and expert opinion. Hydroxyurea is titrated to achieve a normal platelet count (150–400 × 109/L) while maintaining adequate counts in other cell lines. All modifiable cardiac risk factors should be aggressively managed according to current guidelines. Jak-2 inhibitors are now entering clinical trials with early promising results.

Finally, it is crucial to delay elective surgery in the face of uncontrolled blood counts. Up to 80% of uncontrolled PV patients will suffer postoperative thrombotic or hemorrhagic events, but only 5–10% will develop such complications if hemoglobin and platelet counts are normalized for several weeks preoperatively. Perioperative DVT prophylaxis should be prescribed.

Erythromelalgia responds to aspirin. Refractory vasomotor symptoms may respond to hydroxyurea or anagrelide. Pruritus may respond to antihistamines, SSRIs, cholestyramine, or psoralen/ultraviolet light (PUVA). Allopurinol should be used prophylactically until cell counts and hyperuricemia are controlled. Symptomatic splenomegaly refractory to cytoreductive drugs may be treated with splenectomy or splenic irradiation. Splenectomy carries risks of portal vein thrombosis propagating from the ligated splenic vein, operative mortality around 10%, post-splenectomy thrombocytosis, and late massive hepatomegaly. Splenic irradiation carries the risk of prolonged, profound cytopenias. Radiation is also used to treat extramedullary hematopoietic tumors that threaten the spinal cord. Growth factors (including erythropoietin) or androgens may be helpful in patients with advanced fibrosis. Extreme thrombocytosis should be treated with pharmacologic cytoreduction but in the setting of severe or life-threatening bleeding, plateletpheresis is recommended together with the initiation of cytoreductive therapy. Iron chelation may be appropriate for transfusion-dependent patients with PMF, ferritin > 1000 ug/L, and good life expectancy. Transformation to AML is associated with a very poor prognosis (median survival < six months). Management may include induction chemotherapy followed by allogeneic stem cell transplantation if the patient is young and fit; otherwise, experimental or palliative therapy is more appropriate.

Acute thrombotic events are managed with the same methods applied to non-MPN patients, including cardiac catheterization, thrombolysis, heparinization, and warfarin. These treatments need to be instituted judiciously as the risk of bleeding might be high, particularly with extreme thrombocytosis or hyperviscosity. The hemoglobin should be controlled with phlebotomy. Whether the platelet count should be controlled with plateletpheresis or with cytoreductive agents in the setting of acute thrombosis and the optimal target platelet count are controversial. Concurrent with introducing hydroxyurea in all such cases, we generally recommend plateletpheresis in instances of life-threatening thrombosis (or bleeding) with platelets above 1500 × 109/L, to achieve a target platelet count below 600 × 109/L. DDAVP, Humate P (vWF/FVIII concentrate), or cryoprecipitate may be helpful to control hemorrhage in patients with acquired type 2 vWD. Antiplatelet and anticoagulant drugs should be discontinued in the face of bleeding.

Older patients with PV can expect a normal life expectancy if they adhere to treatment. Young adults can expect long-term survival, but their life expectancy is still reduced compared to age-matched healthy populations. The survival with ET is likewise long, but reduced after the first decade of disease. The prognosis with PMF is generally poorer and may be estimated using the International Working Group for Myelofibrosis Research and Treatment score, or for adults < 56 years old, the Cervantes scoring system; they take into account factors such as anemia, constitutional symptoms, low or high white count, and blast percentage in the blood. Cytogenetic aberrations do not predict progression to AML, progression to fibrosis, or survival in PV and ET, but they are predictive in PMF.

Non-Hodgkin lymphomas are clinically and pathologically heterogeneous and their presenting signs and symptoms protean. Some are indolent diseases which, untreated, progress over years. Others are aggressive neoplasms that can take the patient's life in a matter of weeks. The propensity for extranodal and secondary CNS dissemination depends on the histologic subtype and the patient's underlying immune status (eg, concurrent HIV infection, post transplant immunosuppression, congenital immunodeficiency syndromes). The importance of obtaining appropriate biopsy material to facilitate a timely and accurate histologic diagnosis cannot be overstated.

Pathogenesis

For most patients diagnosed with non-Hodgkin lymphoma, known risk factors are absent and the underlying etiology remains elusive. Well-established risk factors for the development of non-Hodgkin lymphomas include prior exposure to ionizing radiation, congenital and acquired immunodeficiency states (eg, post-transplant lymphoproliferative disorders [PTLD], HIV-associated lymphoma), and a variety of infectious agents. Examples of the latter include the association of (1) Epstein-Barr virus (EBV) with nasal T/NK cell lymphoma, endemic Burkitt lymphoma, HIV-associated lymphoma, and PTLD among others; (2) hepatitis C with splenic marginal zone lymphoma; (3) human herpes virus 8 (HHV-8) with Castleman disease and primary effusion lymphoma; (4) human T cell lymphotropic virus 1 (HTLV-1) with adult T cell leukemia/lymphoma; and (5) bacterial infections such as Helicobacter pylori, Chlamydia, and Borrelia burgdorferi with marginal zone lymphomas in the gastrointestinal tract, eye, and skin respectively. Pesticide and herbicide exposure has been linked to the higher incidence of NHL in agricultural workers and rural populations.

Many lymphomas are marked by characteristic and even diagnostic chromosome translocations. Typically, the promoters belonging to the immunoglobulin heavy chain gene (IgH) on chromosome 14q32, the kappa light chain gene on 2p12, or the lambda light chain gene on 22p11 are translocated to a partner chromosome where they upregulate transcription of a known or putative oncogene. Common examples include follicular lymphoma t(14;18), mantle cell lymphoma t(11;14), and Burkitt lymphoma t(8;14) that involve the genes for bcl-2, bcl-1, and c-myc respectively.

Classification and Staging

Non-Hodgkin lymphomas (NHL) are classified according to the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. NHL is broadly classified into B cell neoplasms that comprise approximately 85–90% of cases, and T cell/NK cell neoplasms that account for the remaining 10–15%. More than 50 different lymphoma subtypes are now recognized, exclusive of Hodgkin lymphoma and plasma cell neoplasms; however more than 60% of cases are due to the two most common varieties: diffuse large B cell lymphoma (an aggressive subtype) and follicular lymphoma (an indolent B cell neoplasm). It is essential that sufficient tissue be obtained from an adequate biopsy to allow accurate diagnosis of the specific lymphoma subtype; not infrequently, more than one attempt at biopsy is needed. Once an accurate histologic diagnosis of NHL is made, staging investigations, including at a minimum CT scanning of the chest, abdomen, and pelvis and unilateral bone marrow aspirate and biopsy, are generally performed. NHL is staged according to the Cotswolds Modification of the Ann Arbor System (Figure 179-4).

Clinical Prognostic Scores

Relapse-free and overall survival for patients diagnosed with NHL can be estimated using one of several clinical prognostic scores. In general, these prognostic models are developed and validated by retrospectively analyzing large patient data sets to determine pretreatment clinical factors that correlate with clinical outcomes. The original International Prognostic Index (IPI) evaluated patients with aggressive histology lymphoma treated with anthracycline-containing chemotherapy. Ultimately, five equally weighted factors were independently associated with poor patient outcomes and included in the IPI score. One point is assigned for each of the following: age greater than 60, ECOG performance status 2 or greater, LDH above the upper limit of normal, stage III or IV disease, and two or more extranodal sites. Patients are assigned to one of four risk groups based upon the number of factors present at diagnosis as follows: low (zero or one factor present), low-intermediate (two factors), high-intermediate (three factors), and high risk (four or five factors). The IPI provides substantially more prognostic information than disease stage alone and has subsequently been applied to other patient and histologic subgroups. Examples that illustrate the application of the IPI are shown in Table 179-2.

Recently, a number of disease-specific prognostic scores have been developed that have improved prognostic discrimination compared with the IPI. The most commonly used in clinical practice is the follicular lymphoma IPI (FLIPI), which assigns 1 point for the number of involved nodal areas (≤ 4 vs. ≥ 5), elevated LDH, age ≥ 60 years, stage III or IV disease, and hemoglobin < 120 g/L.

For aggressive diseases, progression free survival and overall survival times are similar because second and third-line “salvage” treatment is often unsuccessful. By contrast, for indolent diseases, overall survival far exceeds progression free survival because although incurable, the lymphoma can usually be controlled with subsequent lines of treatment and patients might experience long survivals despite persistent disease.

Essential Investigations

The evaluation of a patient with suspected or confirmed lymphoma begins with a thorough history, focused on presenting and associated symptoms (eg, B symptoms), risk factors, and performance status, and a complete physical exam with attention to node-bearing areas (including Waldeyer ring), liver, and spleen size, CNS, and testicular exam. Routine laboratory tests should include CBC with differential white count and examination of a peripheral blood smear, chemistry including electrolytes, renal function and liver profile, LDH, calcium, albumin, phosphate, uric acid, serum protein electrophoresis, beta-2 microglobulin, hepatitis B, hepatitis C, and HIV testing, and exclusion of pregnancy in women of child-bearing age. An echocardiogram or resting radionucleotide scan should confirm an adequate ejection fraction prior to instituting anthracycline chemotherapy. CT of the chest, abdomen, and pelvis with contrast is appropriate for most types of lymphoma. Imaging of the head and neck with CT or MRI are appropriate in selected cases as dictated by the clinical presentation. Diagnostic lumbar puncture is recommended for symptoms referable to the CNS (following CT head to exclude increased intracranial pressure), and for patients with specific histologic subtypes or presenting features associated with increased risk for CNS involvement (eg, Burkitt lymphoma, lymphoblastic lymphoma, aggressive histology lymphomas with paranasal/sinus, testicular, or diffuse marrow involvement). Endoscopic evaluation of the GI tract should be considered for patients with mantle cell lymphomas and for patients with involvement of Waldeyer ring because of a high incidence of simultaneous involvement at distant gastrointestinal sites.

An abnormal lymph node should be excised or involved tissue (liver, lung) should be biopsied. Although fine needle aspiration biopsy (FNAB) may be able to distinguish lymphoma from carcinoma if there is suspicion of the latter, it has no role in the investigation of suspected lymphoma because the material obtained through this approach is invariably insufficient to provide accurate histologic classification. We recommend proceeding directly to excision of a palpably enlarged lymph node when suspicion of lymphoma exceeds that of metastatic carcinoma or other neoplasm. In cases in which palpable nodes are absent and a more invasive surgical procedure would be required to obtain an excisional biopsy (eg, laparotomy/mediastinoscopy), image-guided percutaneous large bore core biopsies are often attempted first. However, because the histologic pattern of disease relative to the architecture of a normal lymph node is often crucial for accurate diagnosis and because sampling errors may occur, core biopsy is more likely to lead to nondiagnostic sampling compared with an excisional node biopsy. To allow for determination of immunophenotype by flow cytometry, a portion of the biopsy sample should be sent directly to the pathology lab without being placed in formaldehyde.

Treatment

Indolent Lymphomas

The treatment of indolent NHL is dictated primarily by histologic subtype, disease stage, and patient factors such as presence or absence of symptoms and comorbid illnesses. This group of diseases includes follicular lymphoma, mantle cell lymphoma, marginal zone lymphomas, small lymphocytic lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and hairy cell leukemia, among others. A detailed discussion of specific treatment approaches and chemotherapy regimens for each subtype is beyond the scope of this chapter; however it is useful to review guiding principles in the management of such patients. Patients with localized disease (ie, stage I or II) are generally offered involved field radiation therapy with the potential for long-term disease-free survival and possibly cure. Advanced stage disease (stage III/IV) is generally considered incurable with available chemotherapeutic options and the goal of treatment is primarily to alleviate symptoms. Asymptomatic patients are managed with clinical observation and deferral of chemotherapy until symptomatic disease progression because randomized controlled trials have not demonstrated improvement in survival or quality of life with immediate treatment. In the setting of symptomatic disease, (for example, the development of symptomatic lymph node or spleen enlargement, presence of B symptoms), or progressive cytopenias, chemotherapy is indicated. In most cases, response rates are excellent and the clinical course characterized by prolonged disease-free and overall survival (ie, years). Mantle cell lymphoma is a notable exception that is characterized by a clinically aggressive course with relatively brief response duration, early development of chemo-resistance, and median overall survival that is significantly shorter than related indolent histologies (approximately 3–4 years vs. 8–10 years respectively). A major recent advance in the management of indolent B-cell lymphomas including mantle cell lymphoma has been achieved with the incorporation of rituximab, a monoclonal anti-CD20 antibody, into first-line treatment regimens (chemo-immunotherapy) and as maintenance therapy in responding patients. This approach has improved response rates, response duration, and survival across the spectrum of B-cell lymphomas and is now considered standard. Unfortunately, patients with advanced stage indolent lymphoma invariably relapse following therapy and require sequential chemo-immunotherapeutic protocols associated with successively shorter treatment-free intervals before the development of chemo-resistance or large cell transformation. The role of autologous stem cell transplantation in selected patients as part of first-line treatment (mantle cell lymphoma) or as treatment for relapsed disease (follicular lymphoma) is evolving rapidly. Allogeneic stem cell transplant is associated with a strong “graft-versus-lymphoma” effect in indolent subtypes; however, it is associated with substantial toxicity related to infections and graft-versus-host disease and is therefore reserved for a highly selected population of younger, fit patients with relapsed/refractory disease.

Aggressive Lymphomas

Treatment decisions for aggressive lymphomas are based on whether the disease is limited or advanced, in addition to the histologic subtype. Patients with adequate cardiac function are treated using cyclically administered anthracycline-based combination chemotherapy with curative intent. Radiation therapy is incorporated in specific instances. NCCN-endorsed strategies used to treat diffuse large B cell lymphoma (DLBCL) serve as a useful example (Table 179-3). Patients diagnosed with DLBCL have the potential to recur in the CNS. Patients at particularly high risk may benefit from additional therapy directed toward the CNS because most chemotherapeutic drugs commonly used to treat lymphoma do not cross the blood brain barrier sufficiently to protect against subsequent CNS disease. The optimal treatment regimens and specific subgroups that warrant prophylaxis remain controversial owing to a paucity of prospective and randomized clinical trials. The most commonly employed strategies include repeated doses of intrathecal and/or high dose systemic methotrexate; however, other agents are used and schedules vary widely. Whole brain radiation is not favored because of more frequent and long-term neurotoxicity. Specific instances in which CNS prophylaxis is considered include (1) testicular lymphoma, (2) paranasal, sinus, or orbital involvement, (3) diffuse bone marrow involvement, and (4) high IPI and multiple extranodal sites.

Burkitt lymphoma is a highly aggressive subtype that warrants special consideration. Classically associated with a t(8;14) translocation involving the c-myc gene, Burkitt lymphoma proliferates faster than any other mature B-cell neoplasm. The importance of CNS prophylaxis is universally accepted in the case of Burkitt lymphoma when the risk of CNS involvement or recurrence is so high that treatment directed to the CNS is routinely included in regimens used to treat this particular subtype. Patients with limited, low risk disease may receive an abbreviated course of intensive chemotherapy (eg, CODOX-M), and approximately 80% of younger such patients will be cured. By contrast, those with high risk disease receive a longer course of intensive treatment (eg, CODOX-M/IVAC) with long-term remission and cure achieved in approximately 60% of those younger than 60 years. Patients with Burkitt lymphoma have a particularly high risk of severe tumor lysis syndrome and require careful management to prevent this complication; rasburicase is useful in this instance.

Unique approaches and treatment protocols also apply to the management of cutaneous lymphomas and primary CNS lymphoma among others. The specifics are beyond the scope of this chapter. Aggressive histology T cell lymphomas are managed with similar principles as their B-cell counterparts. However, in many instances they are associated with an inferior prognosis.

The management of relapsed or refractory aggressive histology lymphoma remains challenging. Younger, fit patients who respond to second-line chemotherapy are treated with high dose chemotherapy followed by autologous stem cell transplant; approximately 40–50% will achieve long-term remission and cure. Patients not eligible for transplant and those not responsive to second-line chemotherapy have a poor prognosis and are generally treated with palliative measures emphasizing gentler chemotherapeutic regimens and radiation therapy. Allogeneic transplants for relapsed transformed or aggressive lymphoma are still considered experimental and outcomes have been poor.

Response Assessment

The reader is referred to internationally agreed-upon criteria for response assessment (Cheson, Journal of Clinical Oncology, 2007;25:579–586). Response is usually assessed with imaging studies midway through a planned course of therapy (eg, after three cycles of R-CHOP for DLBCL) and sometimes after only a single cycle of therapy (eg, for Burkitt lymphoma) to guide the decision of whether to continue with the planned treatment (in the case of a good response), to extend the planned treatment (eg, from six to eight cycles, in the case of a slow or partial response), or to switch to a salvage regimen (in the case of progressive or chemo-refractory disease).

Often, residual masses are visible on CT at the end of therapy. These masses may signify fibrosis or persistent lymphoma. While tissue biopsy remains the gold standard, positron emission tomography (CT/PET) scanning is increasingly popular for end-of-treatment evaluation of DLBCL and Hodgkin lymphoma (HL). Pretreatment PET is recommended for these two entities to serve as a basis for comparison. For now, interim PET scanning should be limited to clinical trials. To be designated in complete remission, complete disappearance of lymphoma-related symptoms, biochemical abnormalities (eg, increased LDH), and clinically and radiographically detectable disease is required. (In certain situations, PET-negative residual masses are compatible with CR.)

Post-Treatment Monitoring

Each type of NHL has a characteristic interval in which relapses tend to occur. For example, most DLBCL relapses occur within two to three years of achieving remission. Burkitt lymphoma tends to relapse within two years. The median time to progressive or relapsed follicular lymphoma after modern rituximab-containing therapy is approximately four to five years. Patients are generally monitored with a clinical exam and routine laboratory investigations every three months for two years, then every six months for three years. Outside a clinical trial, there is no role for routine surveillance CT or PET scanning. Beyond five years the risk of recurrence is likely sufficiently low that patients are deemed cured and follow-up may revert to the primary care physician for ongoing monitoring of treatment-related late effects. Regular, lifelong monitoring of the CBC is required to detect early myelodysplasic syndrome. The risk of secondary MDS/AML varies, depending on the specific treatment regimen. Patients who received radiation therapy as part of their treatment are at increased risk of early atherosclerotic vascular disease and second malignancies within exposed tissues. As a result, aggressive management of cardiovascular risk factors and strict adherence to cancer screening guidelines are essential.

Hodgkin lymphoma is characterized by contiguous disease progression from one lymph node region to adjacent regions. This distinguishes it from NHL, which frequently involves distant, noncontiguous sites. Pathologic and epidemiologic features also distinguish the two major groups. While therapeutic approaches are similar, different drug combinations are required.

Pathogenesis

Hodgkin lymphoma (HL) is distinguished from NHL by the Reed-Sternberg cell, a large binucleated or multinucleated germinal-center derived B cell with a characteristic immunophenotype (CD15 and CD30 positive). Reed-Sternberg cells are clonal and neoplastic. However, they tend to be scantily distributed in the abnormal lymph node. The surrounding inflammatory reaction is the more prominent feature. The WHO classifies classic HL into four subtypes according to the inflammatory response. The evidence for a microbiologic trigger includes expression of EBV proteins in 30–50% of Western HL patients and virtually all HIV-associated HL, an association with antecedent infectious mononucleosis, and a high incidence among HIV positive patients that is unaffected by HAART. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs from classic HL in important clinical and phenotypic ways. NLPHL will not be addressed here.

Clinical Presentation

Typical presentations include an asymptomatic neck or supraclavicular mass, B symptoms, or alcohol-induced pruritis or pain. A mediastinal mass should raise suspicion for HL, but the pathologist must be careful to differentiate it from primary mediastinal large B-cell lymphoma, T-cell lymphomas, and overlap lymphomas.

Diagnostic Workup

An adequate lymph node or tissue biopsy is essential. Pretreatment CT and gallium or PET scans are required for accurate staging and to evaluate response. A bone marrow aspiration and biopsy is routinely performed for staging purposes, although marrow involvement is rare in the absence of advanced stage, B symptoms, cytopenias, or HIV positivity. Bone scans are indicated if the patient endorses bone pain. Lumbar puncture is not required. The erythrocyte sedimentation rate (ESR) should be measured as part of risk assessment; an elevated ESR is a poor prognostic marker. In anticipation of anthracycline and bleomycin-containing chemotherapy, baseline evaluation of left ventricular function and pulmonary function studies are recommended. The remaining investigations are as outlined for NHL. Staging is performed according to the Ann Arbor system with Cotswolds modifications (Figure 179-4).

Natural History

At diagnosis, HL is usually a slow-growing malignancy. It is not uncommon for a lymph node involved by HL to wax and wane in size over time. However, the disease eventually spreads through contiguous nodal regions. This is in contradistinction to NHL, which can seemingly “skip” to distant nodal or extranodal sites. Modern treatment regimens are associated with high cure rates and aim to minimize late morbidity and mortality due to the late effects of treatment, particularly cardiovascular disease and second cancers associated with radiation therapy. Relapsed disease often behaves aggressively and is frequently difficult to treat, thus disease control remains a priority in initial treatment decisions.

Treatment

Accurate staging is key to selecting the optimal therapeutic approach. Criteria for “limited stage” include stage I or II disease without any bulky disease or B symptoms. Bulky stage I/II, stage III or IV, or B symptoms assign patients to the “advanced disease” group. European criteria for “favorable early stage” disease include stage I or II disease, age < 50 years, absence of B symptoms, absence of bulky mediastinal disease, normal ESR, and fewer than four involved sites. The remaining patients with stage I or II disease are considered to have “unfavorable early stage disease.”

Current management of limited stage and advanced disease has evolved through a series of well-conducted trials. Patients with limited stage disease are usually treated with combined modality therapy consisting of three to four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) plus involved field radiation. Ongoing studies aim at defining algorithms for risk-adapted therapy (based on CT/PET evaluation after two cycles of ABVD) and at testing reduced radiation doses, narrower radiation fields, and the potential to eliminate radiation entirely in selected favorable risk subgroups. Treatment of advanced disease usually consists of six to eight cycles of ABVD chemotherapy. More aggressive chemotherapeutic regimens may improve disease-free survival at the expense of increased toxicity, including secondary acute leukemia.

Younger (eg, < age 65), fit patients with chemo-sensitive systemic relapse are candidates for potentially curative high dose chemotherapy and autologous stem cell transplant. For transplant ineligible patients, options included radiation, palliative chemotherapy, and/or clinical trials. Experience with allogeneic stem cell transplant is limited and outcomes have been poor.

Bleomycin Toxicity

The potential for patients to develop life-threatening pulmonary toxicity is a major limitation of bleomycin therapy. Bleomycin is inactivated in vivo by bleomycin hydrolase, an enzyme that is poorly expressed in lung and skin tissues and a fact that may be responsible for the organ specific drug toxicity. The clinical presentation varies, depending on the type of lung injury; bleomycin-induced interstitial lung disease typically presents subacutely one to six months post therapy, while hypersensitivity pneumonitis may develop and progress more rapidly. Patients presenting with dyspnea, nonproductive cough, chest discomfort, unexplained fever or a large A-a gradient should be evaluated with a chest X-ray and PFTs if they have received bleomycin. Bilateral reticular or nodular opacification without pleural effusions is the most frequent CXR finding, but alveolar infiltrates or a normal CXR do not exclude the diagnosis. The first PFT abnormality is reduced DLCO, which may progress to a restrictive pattern. Prednisone 1 mg/kg or IV equivalent should be instituted immediately. Hypersensitivity pneumonitis is more responsive to steroids than interstitial pulmonary fibrosis. In cases of suspected toxicity, further bleomycin is contraindicated.

Prognosis

For early stage disease, long-term progression or event-free survival is achieved in 81% to 97% of patients across studies and overall survival exceeds 90%. In advanced stage disease, anticipated survival varies widely and is best predicted using the Hasenclever score. Between 10% and 30% of patients relapse, depending on initial disease stage, bulk, and therapy.

Monitoring Post Therapy

After completing treatment, patients are clinically monitored for relapse every two to four months for one year, then every three to six months for three to five years. Importantly, the risk of death from other causes surpasses the risk of death from HL at 15 years. Secondary breast and thyroid carcinomas are common after radiation to the mediastinum and neck respectively. Hypothyroidism occurs in half of patients treated with neck radiation. They should be given sufficient doses of thyroxine to suppress the TSH to low-normal to minimize the risk of stimulating thyroid cancer. Breast self-exam and serial MRI or mammography are indicated within 8 to 10 years of radiation therapy or when a woman turns 40 (whichever comes first). In patients who were younger than 30 at the time of radiation, the incidence of breast cancer exceeds 30% by age 40. Lung cancer may be detected by surveillance CXRs. Smoking should be avoided. The lifelong incidence of other solid tumors is likewise increased. Coronary artery disease, pericardial disease, and myocardial damage are late manifestations of radiation and/or anthracycline chemotherapy. Secondary AML is less common with ABVD than with previous alkylator-based regimens. Radiation also contributes to the risk of AML. Dental follow-up is required for patients who received high neck radiation. Vaccinations against encapsulated bacteria in those who received splenic irradiation and annual influenza vaccination, especially in patients who received bleomycin, is important. Finally, patients with HL have a higher incidence of subsequent NHL. Any suspected recurrence of HL should be confirmed with a tissue diagnosis.

Plasma cell dyscrasias include monoclonal gammopathies of undetermined significance (MGUS), multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of bone, primary amyloidosis and the heavy and light chain deposition diseases, as well as very rare conditions like heavy chain diseases and POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome. This section focuses on multiple myeloma.

Pathogenesis

Exposure to fertilizers, pesticides, asbestos, aromatic hydrocarbons, other occupational toxins, and ionizing radiation has been linked to development of both MGUS and myeloma. Like other B-cell malignancies so far discussed, myeloma exhibits recurrent translocations involving the immunoglobulin heavy chain locus fused to one of several potential partner genes. Beyond the aberrations detected in the neoplastic plasma cell clones, the development of myeloma is promoted by the bone marrow microenvironment, including IL-6-secreting stromal cells and neoangiogenic endothelial cells. Finally, myeloma cells secrete RANK ligand (RANKL) and induce stromal cells to do the same. RANKL binds RANK (Receptor Activator for Nuclear Factor κ B) on osteoclast precursors and osteoclasts, triggering osteoclast differentiation and activation. Myeloma cells also produce Dickkopf homolog 1 (DKK1) that inhibits osteoblasts. Osteopenia, osteoporosis, and osteolytic bone lesions result.

Clinical Presentation

Clinical features are related to skeletal destruction (bone pain, fractures, hypercalcemia), marrow infiltration (anemia), extramedullary plasmacytomas (mass effects, airway compromise), and abnormally low levels of uninvolved immunoglobulins (recurrent infections). Rarely, symptomatic hyperviscosity occurs. This complication is more often seen with IgA myeloma and high IgM levels in Waldenstöm macroglobulinemia (an indolent B-cell lymphoproliferative disease associated with a lymphoplasmacytic marrow infiltrate and a monoclonal IgM paraprotein).

Renal insufficiency most frequently results from light chain casts damaging renal tubules. This condition is called “myeloma kidney” and is detected by finding mainly light chain proteinuria in the urine collection. “Light chain deposition disease” can occur with or without concurrent multiple myeloma. LCDD is due to light chain deposits damaging the glomeruli. It is detected by finding mainly albumin in the urine collection, sometimes in the nephrotic range. Light chain (AL) amyloidosis can be considered a form of LCDD in which the light chains form insoluble beta-pleated sheets that aggregate into fibrils and stain with Congo red histologically to produce apple green birefringence under polarized light. LCDD generally predominates in the kidneys, although heart and liver may be affected. AL amyloidosis may present with nephrotic syndrome (with or without renal insufficiency), restrictive cardiomyopathy with characteristic interventricular septal thickening, gastrointestinal infiltration with recurrent hematochezia, hepatomegaly and transaminitis, macroglossia, or purpura. Periorbital purpura (“raccoon eyes”) precipitated by a valsalva maneuver are rare but characteristic of AL amyloidosis. About 10% of patients with AL amyloidosis have coexisting myeloma, while even fewer have Waldenström macroglobulinemia. Hypercalcemia, dehydration, hyperuricemia, and nonsteroidal anti-inflammatory drugs used for bone pain also contribute to renal dysfunction. Rarely, patients acquire type 2 renal tubular acidosis, a normal anion gap acidosis with bicarbonate wasting above the reabsorptive threshold such that plasma HCO3– usually stabilizes between 12 and 20 mmol/L, sometimes associated with hypophosphatemia, hypouricemia, and glucosuria due to proximal tubule wasting.

Diagnosis

Multiple myeloma will usually yield abnormally elevated IgG (55%) or IgA (25%) in association with kappa or lambda light chains. Light chain-only myeloma occurs in about 15% of patients. IgM myeloma is extremely rare; elevated IgM is more likely due to lymphoplasmacytic lymphoma (called “Waldenström macroglobulinemia” if the level exceeds 30 g/L) or other NHL. Monoclonality must be confirmed with serum or urine protein electropheresis and the heavy and light chain isotype must be confirmed with immunofixation. Approximately 15% of patients will manifest light chain proteinuria without concurrent abnormalities on serum protein electrophoresis, so it is important to order urine free light chains when considering the diagnosis. Polyclonal immunoglobulin elevations may be due to underlying infection, connective tissue disease, or cirrhosis. Serum free light chains (kappa or lambda chains not associated with a heavy chain) are a new, very sensitive test for plasma cell dyscrasias. Approximately 70% of previously-designated nonsecretory myeloma actually does secrete excess monoclonal kappa or lambda light chain and can be detected by this assay. True nonsecretory myeloma is rare. Similarly, if the serum protein electrophoresis indicates a monoclonal peak in the gamma region but the standard immunofixation is negative for heavy chains, the immunology laboratory should perform immunofixation with antibodies to IgD and IgE heavy chains to exclude the unusual instance of IgD or IgE secreting myeloma (< 1%). Biclonal gammopathies (eg, monoclonal IgG-kappa and IgG-lambda or IgG and IgA) occur in approximately 1% of patients. The monoclonal component should be quantitated at diagnosis and a 24-hour urine collection should measure light chain excretion, realizing that it may be less reliable than the serum free light chain level in patients with significant renal impairment. Nonetheless, the two tests are complementary.

Evaluation should minimally include a CBC, assessment of renal function (including a measured creatinine clearance if the serum creatinine is elevated), determination of the presence and extent of proteinuria (light chains are not detected by urine dip stick, but the presence of albumin and other filtered proteins may point to light chain deposition disease or amyloidosis), a skeletal survey (plain radiographs of the skull, ribs, spine, pelvis, bilateral humeri, and femurs), and a bone marrow aspirate and biopsy. MRI of the head, spine, and pelvis is advisable in patients suspected of harboring a solitary plasmacytoma, to exclude multiple plasmacytomas.

If these tests are normal, the diagnosis of MGUS is more likely but semiannual or annual follow-up should be arranged. A bone marrow examination does not necessarily need to be performed in cases in which MGUS is very likely, but if the monoclonal component exceeds 10 to 15 g/L or the serum kappa or lambda free light chain is markedly elevated, it is recommended. Cytogenetic abnormalities are common in MGUS and cannot distinguish MGUS from myeloma. When myeloma is diagnosed, the albumin and beta-2 microglobulin levels are important for estimating prognosis.

The WHO defines symptomatic plasma cell myeloma as the presence of monoclonal immunoglobulin in the serum and/or urine (generally > 30 g/L for IgG and > 25 g/L for IgA, but no lower limit is specified), clonal plasma cell expansion in the marrow (generally representing > 10% of nucleated cells) or a plasmacytoma, and related organ damage (hypercalcemia, renal insufficiency attributed to myeloma, anemia, lytic bone lesions or osteoporosis with compression fractures, symptomatic hyperviscosity, amyloidosis or recurrent bacterial infections). Asymptomatic (also called smoldering) myeloma is defined by the serum monoclonal protein exceeding 30 g/L or bone marrow clonal plasma cells exceeding 10% in the absence of related organ damage.

Staging and Prognosis

The International Staging System (ISS) is simple and robust. Based on a β2-microglobulin cut-off below 3.5 mg/L or above 5.5 mg/L and serum albumin above or below 3.5 g/dL, patients are stratified into three stages. Median survival is 62, 44, and 29 months for stage I, II, and III disease, respectively.

Patients with IgA myeloma generally experience a more rapid and deeper response to induction therapy, but are also more likely to relapse early and their overall survival is inferior to that of patients with IgG myeloma.

Patients with renal impairment fare worse than those with normal renal function. Plasmablastic morphology confers a worse prognosis compared to finding mature-appearing plasma cell expansion in the marrow. A plasma cell labeling index ≥ 3% indicates a high proliferation rate and more aggressive disease. Elderly patients are more likely to have indolent disease, while younger patients more frequently exhibit high-risk cytogenetics. Patients with plasma cell leukemia (≥ 2 × 109/L circulating plasma cells or ≥ 20% of the white cell differential) face a dismal prognosis; survival is only a few months. Plasma cell leukemia may present de novo or evolve from late stage, longstanding myeloma.

Treatment

Prevention of Renal and Musculoskeletal Complications

Aminoglycosides and intravenous radiographic contrast dye should be avoided even in myeloma patients with normal renal function. Renal function in myeloma patients is often exquisitely sensitive to even low doses of NSAIDs, which should be avoided.

Bisphosphonates infused intravenously each month sharply reduce skeletal events in patients with lytic bone lesions. Osteonecrosis of the jaw is an infrequent complication of bisphosphonate therapy. The risk should be minimized by performing any required dental work prior to initiating therapy and by discontinuing infusions after approximately two years. Patients should also be monitored for reversible albuminuria and for the rare occurrence of irreversible renal impairment.

Common Medical Complications

Patients presenting in renal failure should be aggressively hydrated. They should receive hemodialysis for the usual indications. Plasmapheresis is no longer considered standard care for myeloma-attributed renal failure. Ultrasound of the kidneys, ureters, and bladder is recommended to exclude obstructive uropathy, which may rarely be due to an extramedullary plasmacytoma. NSAIDs and other nephrotoxins should be discontinued. Pyelonephritis should be excluded with urinalysis and culture. Antimyeloma treatment with agents that are safe in renal failure (eg, dexamethasone) should be instituted as expeditiously as possible. Uric acid levels should be monitored and allopurinol, in doses adjusted for the renal impairment, is appropriate, particularly in patients not requiring dialysis.

Patients with multiple myeloma commonly experience acute bone pain, which may respond to steroids and radiation in addition to liberal use of narcotic analgesia. Drugs like pregabalin, carbamazepine, and amitriptyline may ameliorate neuropathic pain but local nerve blocks and epidural anesthesia are sometimes required. Two invasive options are available to patients with vertebral compression fractures. Percutaneous vertebroplasty may be used for vertebral stabilization or for pain relief. The procedure, usually performed by an interventional radiologist, involves injection of polymethylmethyl acrylate (PMMA, a component of bone cement) into the vertebral body. Kyphoplasty is a variation of vertebroplasty in which inflatable bone tamps are placed in the vertebral body. Bone cement is then injected into the bone tamp. The goal is to reexpand the collapsed vertebral body to its original height. No randomized controlled trials of vertebroplasty or kyphoplasty in the myeloma population exist, although large case series are encouraging, so it is not possible to know whether the pain relief and increased mobility often observed within one to two days after injection is due to a placebo effect, local anesthetic injected for the procedure, or the bone cement itself. Although leakage of PMMA is common and usually asymptomatic, serious complications occasionally result, including mobility restriction, pain or radiculopathy, and rarely spinal cord compression.

Anemia may be due to marrow infiltration and to renal impairment. It usually improves with therapy directed at the underlying myeloma, but some patients require recombinant erythropoietin or red cell transfusions. The risks of recombinant erythropoietin in cancer patients are discussed in the chapter on red cell disorders.

Reduced levels of normal immunoglobulins predispose to infection. Periodic IVIG infusions are usually reserved for the occasional patient with severe recurrent infections, as reviewed above for CLL.

Treatment of the Myeloma Itself

Multiple myeloma is currently considered incurable. The goal of treatment is to prevent complications such as fractures and renal impairment, improve cytopenias, eliminate symptoms like bone pain, and prolong life. Median survival has improved recently due to the development of effective novel agents that have been successfully incorporated into treatment algorithms and include immunomodulatory drugs (thalidomide and lenalidomide), and proteasome inhibitors (bortezomib, tradename Velcade).

Patients are divided into those who are candidates for autologous stem cell transplantation and those who, due to advanced age or comorbidities, are not. Transplant eligible patients are first treated with four to six cycles of induction therapy that ideally includes one or more novel agents often in combination with dexamethasone. Treatment with stem cell toxic medications (eg, melphalan) must be avoided. Responding patients undergo stem cell mobilization into the peripheral blood using drugs such as cyclophosphamide and G-CSF with or without plerixafor (a CXCR4 inhibitor). Stem cells are subsequently harvested by apheresis and cryopreserved for later use. After induction and harvesting are complete, myeloablative “conditioning” chemotherapy (typically melphalan 200 mg/m2) is administered followed by rescue with autologous stem cell infusion. Patients who achieve only partial remission or stable disease post transplant may be offered a second (“tandem”) transplant, while those who achieve a complete or very good partial response (VGPR, defined as ≥ 90% reduction in serum monoclonal protein and < 100 mg/24 hr monoclonal protein in the urine) are unlikely to benefit from a planned tandem transplant. Several trials have evaluated the role of maintenance therapy post transplant and have demonstrated improved progression free survival compared with observation. Options include thalidomide, lenalidomide, prednisone, other novel agents or combinations, and interferon alpha. Despite improved PFS, steroid and thalidomide-based regimens have not been proven to improve overall survival and drug-induced toxicity can significantly impair quality of life. Better-tolerated novel agents such as lenalidomide and bortezomib are currently being evaluated as maintenance regimens. Patients who achieve less than a VGPR post transplant are most likely to benefit from maintenance therapy. Allogeneic transplant is still experimental; studies have yielded conflicting results.

Historically, transplant ineligible patients were treated with melphalan and prednisone (MP), a well tolerated oral regimen associated with median overall survival of approximately three years. The incorporation of novel agents to MP has led to improved overall survival in recent randomized controlled trials and is now considered standard. Examples include MP plus thalidomide (MPT) and MP plus Velcade (MPV); alternative, perhaps more effective combination therapy is rapidly evolving through sequential and parallel clinical trials.

Immunomodulatory drugs carry an increased risk of deep vein thrombosis. Optimal prophylaxis (aspirin, warfarin, or low-molecular-weight heparin) has not been definitively established. However, patients at lower risk for thrombosis are generally candidates for aspirin while higher risk individuals (eg, prior history of venous thrombosis) are usually prophylaxed with anticoagulation (ie, low-molecular-weight heparin [LMWH] or vitamin K antagonists such as warfarin). Thalidomide causes fatigue, sedation, and constipation. Thalidomide and bortezomib both cause peripheral neuropathy that may be painful. The neuropathy is more likely to be irreversible when caused by thalidomide. Toxic epidermal necrolysis is a rare but recognized potentially fatal complication of thalidomide. Lenalidomide can cause significant myelosuppression. Because it is renally excreted, the dose must be reduced for patients with renal impairment and is generally contraindicated in those with renal failure. Bortezomib is also associated with suppressed myelopoiesis, particularly predictable/reversible thrombocytopenia, and may cause acute or delayed gastrointestinal upset.

Judging the survival impact of any therapy is difficult because life may be prolonged by any of various available salvage treatments. Strategies to treat relapsed myeloma are beyond the scope of this text.

A detailed discussion of special populations will not be embarked upon here. However, the clinician should always bear in mind the uniqueness of individual patients. Populations that merit specific thought include pregnant women, the elderly, those with congenital or acquired immunodeficiency (HIV/AIDS), those with chromosomal fragility syndromes, and those with chronic infections such as hepatitis B that can reactivate during chemotherapy.

A hospitalist may be the first physician to investigate an abnormal CBC, a severe metabolic abnormality, an enlarged lymph node, an acute fracture, or a mediastinal mass, and hence to diagnose a hematologic malignancy. Hospitalists are increasingly called upon to manage complications that develop during treatment. This chapter aims to provide a basic knowledge of the different disease entities, drugs employed, and expected disease course, but consultation with a hematologist or oncologist is always advisable, especially if chemotherapy or radiation is to be prescribed.