B-chronic lymphocytic leukemia: practical aspects

HEMATOLOGICAL ONCOLOGY Hematol Oncol 2002; 20: 103–146.

Published online 26 April 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002 / hon.696

REVIEW ARTICLE B-CHRONIC LYMPHOCYTIC LEUKEMIA: PRACTICAL ASPECTS GERASSIMOS A. PANGALIS*, THEODOROS P. VASSILAKOPOULOS, MARIA N. DIMOPOULOU, MARINA P. SIAKANTARIS, FLORA N. KONTOPIDOU AND MARIA K. ANGELOPOULOU

Hematology Section, 1st Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece

SUMMARY B-CLL is the most common adult leukemia in the Western world. It is a neoplasia of mature looking B-monoclonal lymphocytes co-expressing the CD5 antigen (involving the blood, the bone marrow, the lymph nodes and related organs). Much new information about the nature of the neoplastic cells, including chromosomal and molecular changes as well as mechanisms participating in the survival of the leukemic clone have been published recently, in an attempt to elucidate the biology of the disease and identify prognostic subgroups. For the time being, clinical stage based on Rai and Binet staging systems remains the strongest predictor of prognosis and patients’ survival, and therefore it affects treatment decisions. In the early stages treatment may be delayed until progression. When treatment is necessary according to well-established criteria, there are nowadays many different options. Chlorambucil has been the standard regimen for many years. During the last decade novel modalities have been tried with the emphasis on fludarabine and 2-chlorodeoxyadenosine and their combinations with other drugs. Such an approach offers greater probability of a durable complete remission but no effect on overall survival has been clearly proven so far. Other modalities, included in the therapeutic armamentarium, are monoclonal antibodies, stem cell transplantation (autologous or allogeneic) and new experimental drugs. Supportive care is an important part of patient management and it involves restoring hypogammaglobulinemia and disease-related anemia by polyvalent immunoglobulin administration and erythropoietin respectively. Copyright # 2002 John Wiley & Sons, Ltd. key words: chronic lymphocytic leukemia; biology; treatment

INTRODUCTION B-chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in the Western world,1 but is rare in Asia and Japan.1,2 Environmental factors such as ionizing radiation, chemicals or viruses do not seem to be associated with the pathogenesis of the disease.3–5 On the contrary, hereditary factors seem to play a role, since members of the same family are at increased risk for developing B-CLL or other lymphoproliferative disorders.6,7 The diagnosis of B-CLL is based on the following criteria proposed by the National Cancer Institute (NCI):8 (1) absolute lymphocytosis in the blood (>5r109/l) with predominance of mature small lymphocytes and 10 cm in longest diameter) or progressive lymphadenopathy (6) Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months (7) Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for protocol therapy

Copyright # 2002 John Wiley & Sons, Ltd.

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molecular methods. Two systems for the definition of response have been formulated by the International Workshop in CLL (IWCLL)207 and by the NCI group.8 The latter has recently been updated. These systems are presented in detail in Tables 8 and 9.

TREATMENT OPTIONS Conventional treatment options, including drug dosing and administration schedules, for B-CLL patients are listed in Tables 10, 11 and 12.

Treatment of early stages There is sufficient evidence from randomized trials that chlorambuciltprednisone does not confer a survival advantage over deferring therapy in Binet stage A patients. In the CLL-80 trial of the French Cooperative Group on CLL, 609 patients with stage A disease were randomized to either continuous chlorambucil 0.1 mg/kg/day, until the development of clinical resistance to the drug or no treatment until progression to stage B or C.185 In the CLL-85 trial of the same group, 926 stage A patients were randomized to intermittent chlorambucil 0.3 mg/kg/day plus prednisone 40 mg/m2r5 days per month for 3 years or no treatment until progression to stage B or C.185 At a median follow-up of 11 and 6 years respectively, both trials failed to demonstrate an overall or malignancy-specific survival benefit for patients treated immediately. Furthermore, neither patients with ‘smouldering’ (Ak) nor patients with ‘active’ (Akk) early stage CLL seemed to benefit from early treatment.149 It is also of interest that a significantly increased incidence of secondary tumours was observed in patients treated with the continuous chlorambucil schedule in the CLL-80 trial. This finding was not confirmed in other trials, in which chlorambucil was given intermittently at lower doses.185,211 Several other randomized trials have also suggested that early treatment with intermittent chlorambuciltprednisone does not confer a survival advantage in early stage CLL210,211 and this was confirmed in a recently published meta-analysis.254 The watch and wait policy is also usually applied in Binet stage B patients not fulfilling the criteria for treatment initiation (Table 7), although there is no relevant support from randomized trials. Table 8. Definition of response to treatment of B-CLL patients According to IWCLL criteria207 Complete response

Partial response Stable disease Progressive disease

Complete resolution of lymphadenopathy, hepatomegaly, splenomegaly and disease-related symptoms Normalization of blood parameters Lymphocytes 1.5r109/l Platelets >100r109/l Hemoglobin: not stated Normal bone marrow. Nodular or focal infiltration by lymphocytes is consistent with CR Downshift in stage No change in clinical stage Upshift in stage

CR, complete remission; PR, partial remission. Copyright # 2002 John Wiley & Sons, Ltd.

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Table 9. Definition of response to treatment of B-CLL patients according to NCI-sponsored working group criteria8

Parameter (1) Constitutional symptoms (2) Physical examination1 (a) Lymphadenopathy (b) Liver/spleen (3) Blood (a) Lymphocytes (r109/l) (b) Hemoglobin (g/dl untransfused) (c) Neutrophils (r109/l)

Complete response (CR)*

Partial response (PR){

Progressive disease (PD){

Absent

NS

NS

Absent

i50% reduction

Not palpable

i50% reduction

i50% increase/ new lesions, i50% increase/ new lesions

j5 11 or >50% improvement i1.5 or >50% improvement >100 or >50% improvement NS –

i1.5 >100

(d) Platelets }

(4) Bone marrow lymphs (%), (5) Others

9) and/or rapid TTM doubling time. The same investigators have suggested that this regimen may be superior to mini-CHOP182 and at least comparable to fludarabine.256,257 Purine analogues Fludarabine. The initial report on the efficacy of fludarabine (FAMP) in previously untreated CLL patients revealed an overall response rate of 79%, including 33% CR and 39% nPR.258 Similar results were obtained with the combination of FAMP and prednisone (overall response 79% with 28% CR and 34% nPR).222,259 These data were verified in large-scale randomized trials,214,225,260 using FAMP at a dose of 25 mg/m2/day for 5 days every 4 weeks. Thus, it is now considered that FAMP produces 70–80% responses with 30% CRs in previously untreated CLL patients, given according to the schedules listed in Table 11. Whether first-line FAMP is capable of improving the survival of CLL patients is not yet clear. Although FAMP is definitely better than CAP, it is not superior to mini-CHOP.225 The results of a large intergroup trial were recently published, comparing FAMP 25 mg/m2 for 5 days per month versus chlorambucil 40 mg/m2 once monthly versus the combination of these agents at lower doses (20 mg/m2 for both).214 The maximum treatment duration was 12 cycles. The accrual to the arm of the combination therapy was stopped earlier because of excessive rates of life-treatening toxic events. With approximately 180 patients evaluable in each monotherapy arm, FAMP was superior to chlorambucil in terms of CR (20 vs. 4%, p250 and >120 cases having been published so far, respectively.331x341 Both procedures and particularly alloSCT are applied to patients