Chronic Lymphocytic Leukemia

Definition Clonal B cell malignancy. Progressive accumulation of long lived mature lymphocytes. Increase in anti-apoptotic protein bcl-2. Intermediate stage between pre-B and mature B-cell.

Cancer statastics 2000; CA J Clin 2000; 50:7-33 Epidemiology Most common leukemia of Western world. Less frequent in Asia and Latin America. Male to female ratio is 2:1. Median age at diagnosis is years. In US population incidence is similar in different races.

Etiology & Risk factors High familial risk with two-fold to seven- fold higher risk. No documented association with environmental factors. No established viral etiology.

Blood 1996; 87: 4990 Diagnostic Criteria Defined by NCI & IWCLL. Persistent lymphocytosis. Absolute count more than Mature appearing B-cells with <10% of prolymhocytes

Flow Cytometry CD 19 and/or CD 20 are always co expressed with CD 5. Weak expression of surface immunoglobulins (sIgM & sIgD). CD 21, CD 23, CD 24 may be expressed.

Bone Marrow Not required for diagnosis. Recommended to estimate the extent for prognostic implications. Diffuse infiltration has poor prognosis.

J Mol Med 1999; 77:266 Cytogenetics Deletions in chromosome 13 at q 14 Chromosome 11 at q22 or q23. Trisomy-12. Less common are deletions in chromosome 17 & 6.

Clinical Features Disease of elderly with wide spectrum of clinical features. 20% are asymptomatic. Classic B symptoms. Variable physical findings with normal to diffuse LAD, hepato/splenomegaly.

Other Labs Hypogammaglobulinemia seen >50%. 5-10% have small monoclonal peak. Positive Coombs’ test in 30%. Autoimmune hemolytic anemia & thrombocytopenia in <10%

The Rai Staging System Stage 0Lymphocytosis only (> 15,000/mm 3 ) Stage 1Lymphocytosis and lymphadenopathy Stage 2Lymphocytosis and splenomegaly with or without lymphadenopathy Stage 3Lymphocytosis and anemia (Hgb <11 g/dL) with or without lymphadenopathy or hepatosplenomegaly Stage 4Lymphocytosis and thrombocytopenia (Plt < 100,000/UL) with or without anemia, lymphadenopathy or hepatosplenomegaly

Modified Rai Stagingg. Low-risk: stage 0, MS > 13 years. Intermediate-risk: stage I & II with MS about 8 years. High-risk: stages III & IV with MS about 3 years

The Binet Staging System Stage ANo anemia, no thrombocytopenia, <3 involved nodal areas Stage BNo anemia, no thrombocytopenia, >=3 involved nodal areas Stage CAnemia (Hgb < 10 g/dL) and/or thrombocytopenia (Plt < 100,000/uL)

Blood 94: , 1999 Other Prognostic Features Bone marrow pattern of lymphoid infiltration. Lymphocyte doubling time. Serum beta-2-microglobulin. Mutational status of Ig V and CD 38 expression have recently been identified.

Blood 1996; 88 (suppl 1): 141a Treatment Nucleoside analogs like Fludarabine is the drug of choice. More effective in higher CR & longer PFS compared to alkyalating agents. No survival advantage. Fludarabine in various combinations with Cytoxan & Rituxan are widely used.

Blood 1999; 94 (suppl 1); 705a Monoclonal antibodies Campath (anti-CD 52) is recently approved for refractory CLL. Results in profound lympocytopenia, both B and T cells are destroyed. Rituxan (anti CD 20) is widely used both as single agent and in combination.

J Clin Oncol 16: Bone marrow transplantation Allogenic BMT is a viable option in younger patients. Durable response rates seen in advanced, refractory disease. Autologous BMT using purged marrow have been investigated in elderly.

Transformation Large- cell lymphoma/ Richter’s –Aggressive presentation –Extranodal involment –Sharp rise in LDH –CHOP is standard treatment. Prolymphoctic leukemia. –> 55% increase in prolymphocytes –Progression of splenomegaly & cytopenias –Refractoriness to treatment.