Bethesda Handbook of Clinical Oncology, 2nd Edition

Hematologic Malignancies


Chronic Leukemias

Muzaffar H. Qazilbash

Michael J. Keating

M.D. Anderson Cancer Center, University of Texas, Houston, Texas

Chronic lymphocytic leukemia (CLL) accounts for more than one third of all leukemias, and because of its prevalence in hematologic practice, it is the focus of this chapter. Additional chronic leukemias discussed in this chapter include prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL) (see Tables 24.1 and 24.2).

TABLE 24.1. Chronic Lymphocytic Leukemia



CLL, chronic lymphocytic leukemia.


B-cell malignancy (>95%)


10,000 cases annually in the United States

Median age

55 yr




No known causes; slight increased risk of CLL and B-cell malignancies in family members


Accumulation of clonal lymphocytes, possibly a result of overexpression of bcl-2, which can interfere with apoptosis

Cytogenetic abnormalities

Trisomy 12; abnormalities in chromosomes 11 and 17; Deletion of 13q14

TABLE 24.2. Clinical and Laboratory Features



Fatigue, weight loss, fever in the absence of active infection, night sweats, unusually severe local reactions to insect bites, increased frequency of bacterial and viral infections

Physical examination

Lymphadenopathy and splenomegaly

Laboratory features

Lymphocytosis (5–500 × 103/µL), appear as normal lymphocytes by light microscopy with presence of scant cytoplasm; presence of smudge cells (artifact of blood smear preparation); absolute neutrophil count can be low, normal, or increased; anemia or thrombocytopenia may be present

Bone marrow

Demonstrates nodular or diffuse infiltration of small- to medium-sized lymphocytes with mature features and normal myeloid components

Lymph nodes

Infiltrates of small- to medium-sized lymphocytes with condensed mature-appearing chromatin and an occasional nucleolus; larger lymphocytes with more prominent nucleoli are usually present and are termed prolymphocytes, can be clustered as pseudofollicles

Immunologic features

The hallmark is the coexpression of CD5, CD19, CD20, and CD23 surface antigens that are detected by flow cytometry


Various diagnostic criteria have been proposed for CLL; two of the most commonly used criteria are the guidelines of the National Cancer Institute–sponsored working group (NCI-WG) and of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL). The NCI-WG guidelines require (a) an absolute lymphocytosis (≥5 × 103 per µL), with cells having a morphologically mature appearance sustained for 4 weeks; (b) a normocellular or hypercellular bone marrow with lymphocyte count ≥30%; and (c) monoclonal B-cell phenotype expressing CD5, with a low-level surface immunoglobulin (Ig) expression. The IWCLL recommends similar criteria but requires a lymphocyte count of ≥10 × 103 per µL if facilities for obtaining phenotyping are not available.


There are several staging methods for CLL. The three most commonly used staging methods are the Rai, modified Rai (see Table 24.3), and the Binet staging systems. Prognosis based on Rai staging system is outlined in Table 24.4.

TABLE 24.3. Staging


Modified Rai


Hb, hemoglobin.


Low risk

Lymphocytosis only (≥15 × 103/µL in peripheral blood)


Intermediate risk

Lymphocytosis with enlarged nodes


Intermediate risk

Lymphocytosis with increased splenic or hepatic size


High risk

Lymphocytosis with anemia (Hb ≤11 g/dL)


High risk

Lymphocytosis with thrombocytopenia (≤100 × 103/µL)

TABLE 24.4. Prognosis

Modified Rai stage

Median survival (yr)

Low risk


Intermediate risk


High risk



A number of newly identified prognostic factors predict an inferior outcome. These factors include an elevated serum β-2-microglobulin level, high-soluble CD23 level, naive B cells that lack Ig gene hypermutation, and elevated CD38 level.


CLL is clearly an indolent hematologic malignancy often not requiring treatment at diagnosis. In general, treatment is initiated after the occurrence of one of the following complications:


(a) significant and persistent fatigue; (b) weight loss; (c) fever without infection; (d) night sweats; (e) significant anemia (hemoglobin level <10 g per dL); (f) thrombocytopenia (platelet count <50 × 103 µL); and (g) disfiguring or bulky lymphadenopathy and/or significant splenomegaly. Usually, the level of lymphocytosis is not an absolute indication for treatment. However, treatment is usually initiated for a lymphocytosis >200 × 103 per µL.

Historically, the most common initial systemic therapies used are chlorambucil and fludarabine. Although none of the regimens have so far demonstrated a survival advantage, the overall survival in the management of CLL has improved over a number of years. Now that purine analogs and alkylating agent combinations have been demonstrated to be active, with suggestions of superior responses, new opportunities continue to appear. The role of monoclonal antibodies (MoAbs) and their integration into overall therapeutic plans is actively being explored.Table 24.5 describes several treatment options available for CLL and comments on each of these therapies.

TABLE 24.5. Therapy



CVP, cyclophosphamide–vincristine–prednisolone; CLL, chronic lymphocytic leukemia.


Well tolerated, can be administered daily (4–8 mg/d), or pulse intermittent schedule of 40–80 mg PO over 1–3 d q2–4wk; myelosuppression is the main toxicity


Not evaluated extensively as a single agent but used predominantly in combinations like CVP


25 mg/m2 i.v. daily for 5 d q4wk, consider precautions against tumor lysis during first cycle; cumulative toxicity includes myelosuppression and prolonged immunosuppression; response rate around 50% in previously treated patients and 70%–80% in untreated patients


0.1 mg/kg i.v. continuous infusion for 7 d q wk, or 0.14 mg/kg daily over 2 h for 5 d q4wk; response rate comparable to fludarabine, with shorter remission duration


A humanized chimeric antibody active against CD20; dose escalation improves the response rate in CLL (30%–50% in pretreated cases, 60%–80% in untreated cases)


A humanized antibody that targets CD52, widely distributed on all lymphocytes; 33% response rate in previously treated patients

Fludarabine-based combinations

Fludarabine + cyclophosphamide + rituximab (FCR); early reports show higher complete and overall responses in untreated and previously treated patients

Allogeneic stem cell transplantation

Potentially curative therapy for patients with multiple relapses; nonmyeloablative approaches allow older patients and patients with comorbidities to undergo transplant; toxicities: graft versus host disease and opportunistic infections

Complications can occur as an intrinsic component of the disorder or as a result of therapy. Table 24.6 is a summary of such complications.

TABLE 24.6. Complications



CLL, chronic lymphocytic leukemia; AIHA, autoimmune hemolytic anemia; ALL, acute lymphoblastic leukemia.


May be secondary to a suppressive effect of CLL or secondary to AIHA; AIHA may require high-dose prednisone and/or splenectomy for treatment


Also can be secondary to marrow suppression or can be of autoimmune nature


Secondary to either CLL or chemotherapy


Suggested by frequent sinopulmonary infections, CLL patients often have an inadequate humoral response to infections and immunizations; infections with encapsulated organisms and gram-negative bacteria constitute the major etiologies of mortality and morbidity in CLL

Pure red cell aplasia

Possibly caused by a suppressive effect of suppressor cytotoxic T cells; cyclosporine has been used successfully as treatment, with a reticulocyte response seen within 2 wk after starting therapy

Paraneoplastic pemphigus

Autoantibody-induced oral mucocutaneous lesions


Transformation to more aggressive malignancies occurs in 10% of cases; these transformations include prolymphocytic, Richter syndrome (large B-cell lymphoma), ALL, and multiple myeloma

T-cell Chronic Lymphocytic Leukemia

T-cell CLL occurs in 2% to 5% of patients with CLL. A large amount of variability exists in the clinical findings and clinical course. PLL is shown in Table 24.7 and HCL in Table 24.8.

TABLE 24.7. Prolymphocytic Leukemia



Ig, immunoglobulin; CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia.


Large cells with abundant cytoplasm and prominent nucleolus within a convoluted nucleus with immature chromatin


Mostly a B-cell neoplasm; high-density immunoglobulin, CD19, CD20, and CD22, with absence of CD5


t(11;14), which represents the translocation of the bcl-1 oncogene in proximity to the Ig heavy chain gene

Clinical findings

High blast counts with splenomegaly, usually lacking significant adenopathy, occurs as a terminal finding in up to 10% of CLL


Fludarabine alone and in combination with cladribine, Rituximab, and allogeneic stem cell transplantation

T-cell PLL

20% of PLL cases, usually a more aggressive course than the B-cell form; expression of CD3, CD4, occasionally CD8, with rearrangement of the T-cell–receptor gene; reports of successful treatment with pentostatin, alemtuzumab, and allogeneic transplantation

TABLE 24.8. Hairy Cell Leukemia



TRAP, tartrate-resistant acid phosphatase; sIg, surface membrane immunoglobulin; Hb, hemoglobin; CI, continuous infusion; CR, complete response.

Clinical findings

Male predominance, pancytopenia, splenomegaly, lymphadenopathy is uncommon, necrotizing vasculitis, opportunistic infections, lytic bone abnormalities


Lymphocytes with cytoplasmic projections, TRAP-stain positive

Bone marrow

Aspiration frequently unsuccessful secondary to fibrosis; marrow biopsy reveals “hairy” cells and classic “fried-egg” appearance


High-intensity sIg, CD19, 20, 21, 22, 11c, 25, PCA-1 and Bly7, and light and heavy chain Ig rearrangements

Treatment indications

Life-threatening infections, vasculitis, bony involvement, symptomatic splenomegaly, neutropenia (<0.5–1.0 × 109/mL), anemia (Hb, <8–10 g/dL), thrombocytopenia (<50–100 × 109/mL), leukocytosis with a significant number of hairy cells


First-line: Cladribine provides a >95% response, given at 0.1 mg/kg/d by CI over 7 d; 2-deoxycoformycin produces response rates of 40%–80% and is administered at 4 mg/m2 every other week for 3–6 mo

Second-line: interferon-α produces a >70% response rate and is administered three times/wk s.c. at 2 million units/m2; splenectomy is currently reserved for those with thrombocytopenia and bleeding or those for whom systemic chemotherapy has failed

Promising: BL22, anti-CD22 monoclonal antibody linked to pseudomonas exotoxin. 70% CR in cladribine-refractory patients






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