WORKUP	Section 5 of 11
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Lab Studies:

• CBC count with differential shows absolute lymphocytosis with more than 5000 lymphocytes/mL. Some authors consider this to be a prerequisite for the diagnosis of CLL and classify cases that would otherwise meet the criteria as small lymphocytic lymphoma/diffuse well-differentiated lymphoma.

• Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, which are artifacts due to damaged lymphocytes during the slide preparation.

• Peripheral blood flow cytometry is the most valuable test to confirm CLL.

• It confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.

• Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (<500 mg) may be beneficial in reducing the frequency of infectious episodes.

• The differential diagnosis of CLL includes several other entities, such as hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and typically negative for CD5 and CD21. Prolymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin and negative for CD5. Large granular lymphocytic leukemia has a natural killer cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8). The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma.

Imaging Studies:

• Liver/spleen scan may demonstrate splenomegaly.

• Computed tomography of chest, abdomen, or pelvis generally is not required for staging purposes. However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures.

Procedures:

• Bone marrow aspiration and biopsy with flow cytometry is not required in all cases but may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration.

• Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known CLL to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome.

• The Rai-Sawitsky staging system divides CLL into 5 Stages, 0-IV.

• Stage 0 is lymphocytosis in the blood and marrow only, with a survival of longer than 120 months.

• Stage I is lymphocytosis and adenopathy, with a survival of 95 months.

• Stage II is lymphocytosis plus splenomegaly and/or hepatomegaly, with a survival of 72 months.

• Stage III is lymphocytosis plus anemia (hemoglobin <10 g), with a survival of 30 months.

• Stage IV is lymphocytosis plus thrombocytopenia (platelets <100,000), with a survival of 30 months.

• The Binet staging system uses 3 stages, A, B, and C.

• Stage A requires a hemoglobin of greater than or equal to 100 g/L, platelets greater than or equal to 100 X 10^-9, and fewer than 3 lymph node areas involved (Rai-Sawitsky stages 0, I, II). Survival is longer than 120 months.

• Stage B requires hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved (Rai-Sawitsky stages I and II). Survival is 61 months.

• Stage C is a hemoglobin less than 100 g/L, platelets less than 100 X 10^-9, or both (Rai-Sawitsky stages III and IV). Survival is 32 months.

• The IWCLL has recommended integrating the Rai-Sawitsky and Binet systems as follows: A(0), A(I), A(II), B(I), B(II), C(III), and C(IV).

	TREATMENT	Section 6 of 11
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Medical Care: At the time of diagnosis, most patients do not need to be treated with chemotherapy unless they have weight loss of more than 10%, extreme fatigue, fever related to leukemia, night sweats, progressive marrow failure, autoimmune anemia or thrombocytopenia not responding to prednisone, progressive splenomegaly, massive lymphadenopathy, or progressive lymphocytosis. Progressive lymphocytosis is defined as an increase of greater than 50% in 2 months or a doubling time of less than 6 months.

Patients at stage 0 whose disease is stable require only periodic follow-up. Early treatment has not been demonstrated to be advantageous.

• Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease.

• Nucleoside analogs (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including CLL.
  • Fludarabine is the most extensively studied and currently is the most commonly used second-line therapy in CLL.

  • Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients.

  • Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission rate.

  • Studies using purine analogs, especially fludarabine, compared to alkylator-based therapies have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature.

  • The combination of fludarabine and cyclophosphamide has shown higher response rates, but direct comparative trials of fludarabine and cyclophosphamide to fludarabine alone are lacking.

  • The combination of fludarabine and chlorambucil recently has been shown to result in more infections than either single agent alone.

• Various combination regimens have shown improved response rates in several randomized trials but failed to show any survival advantage. Common combination regimens include chlorambucil and corticosteroids; cyclophosphamide, doxorubicin, and prednisone (CAP); cyclophosphamide, vincristine, and prednisone (CVP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

• Therapy with monoclonal antibodies has been evaluated in patients with CLL. The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future.

• Patients with CLL demonstrate autoimmune anemia and or thrombocytopenia up to 25% of the time, and, at the same time, immune incompetence is present, characterized by a progressive profound hypogammaglobulinemia.
  • This hypogammaglobulinemia eventually develops in almost all patients, predisposing them to a number of infections, the most common being bacterial pneumonias.

  • Patients showing frequent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of intravenous immunoglobulins. In a randomized double-blind study, intravenous immunoglobulin, 400 mg/kg, or placebo was administered every 3 weeks for 1 year in 84 patients. The study showed significant reductions in the bacterial infections in the group treated with immunoglobulins, but no statistically significant difference was observed in the number of life-threatening infections requiring parenteral antibiotics.

  • The autoimmunity in B-CLL is observed much more commonly in patients treated with fludarabine, which is known to suppress the circulating CD4⁺ T cells.

• Extremely high white blood cell counts (>300,000/mL) may produce a hyperviscosity syndrome with altered central nervous system function and/or respiratory insufficiency. Leukocytapheresis and urgent therapy with prednisone and chemotherapy may be required. Virtually all patients requiring therapy also should be given allopurinol to prevent uric acid nephropathy.

Surgical Care:

• Refractory splenomegaly and pancytopenia is a common problem in patients with advanced CLL that occasionally necessitates splenectomy.

• Substantial improvements in hemoglobin and platelet counts are observed in up to 90% of patients undergoing splenectomy.

• All patients who are to undergo splenectomy should be immunized at least a week in advance with Pneumovax and Haemophilus and Neisseria meningitides vaccines.

Consultations:

• General surgery

• In selected patients who require blood to be drawn frequently or who require intravenous chemotherapy, consider placing a Portocath or similar venous access device.

• Splenectomy, when indicated, may require consultation with a general surgeon.

	MEDICATION	Section 7 of 11
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Chlorambucil (alkylating agent) and fludarabine (antimetabolite) are commonly used in the treatment of CLL. Purine analogs and, in particular, fludarabine are very active against CLL. Fludarabine produces remissions in a significant proportion of patients. It appears to induce apoptosis in malignant lymphocytes upon exposure.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Mantle cell lymphoma can have a clinical presentation very similar to CLL, but the prognosis is much poorer. It does not respond to treatment as well as CLL. It can be distinguished from CLL by careful flow cytometric examination to show the presence of B lymphocytes expressing CD5 and CD19 but not CD23 antigen, which is expressed in CLL. Mantle cell lymphoma typically expresses FMC-7. Importantly, mantle cell lymphoma expression of CD20 is bright, although in CLL it is dim.

Special Concerns:

• Patients with CLL are prone to usual and unusual infections. Pneumococcal and flu vaccines are recommended.