Biology and treatment of chronic lymphocytic leukemia

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Introduction. B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of a clone of malignant B cells in lymphoid tissues, bone marrow ...
Annals of Oncology 16 (Supplement 2): ii113 – ii123, 2005 doi:10.1093/annonc/mdi731

Biology and treatment of chronic lymphocytic leukemia P. Kokhaei, M. Palma, H. Mellstedt & A. Choudhury Departments of Hematology and Oncology, and Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska University Hospital, Stockholm, Sweden

Introduction

Prognostic factors Clinical stage The most common and validated prognostic factors are the clinical staging systems proposed by Binet et al. [6] and Rai et al. [7], which define early (Rai 0, Binet A), intermediate (Rai I/II, Binet B) and advanced (Rai III/IV, Binet C) stages of the disease on the basis of the extent of lymphoid areas involvement and on the presence of anemia and thrombocytopenia (Table 1). Estimated median survival times for these stages are >10, 5–7 and 1 –3 years, respectively. These systems have, however, two major drawbacks. The first is the fact that BM involvement is inferred by the hemoglobin level (3 lymphoid areas

30

Intermediate

I

Lymphoadenopathy

25

5–7

II

Hepato or splenomegaly ± lymphoadenopathy

25

III

Haemoglobin 50% over a 2-month period, or an anticipated doubling time of 18 months) [38]. Despite the high OR rate in untreated patients, the short follow-up does not yet allow superiority to be claimed over conventional therapy. In the study, the drug was administered subcutaneously to avoid infusion-related toxicity; however, though results were promising, this approach should still be avoided out of the context of clinical

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Fludarabine is the purine analog that has been most extensively studied and employed in the treatment of CLL patients. Like all purine analogs, it acts by inhibiting DNA polymerase and ribonucleotide reductase, finally promoting apoptosis [30]. In a large randomized trial [31], fludarabine both as single agent and in combination with chlorambucil was compared with chlorambucil alone in >500 previously untreated patients. After an interim analysis showing that the combined treatment resulted in excessive toxicity without increasing the response rate compared with fludarabine alone, patients were assigned only to the single-agent arms (170 patients in the fludarabine arm and 181 patients in the chlorambucil arm). Overall response (OR), median duration of remission and median progression-free survival (PFS) were significantly higher in the fludarabine arm. Response rate was 63% (20% CR+43% PR) versus 37% (4% CR+33% PR), respectively, while median duration of remission was 25 and 14 months and median PFS 20 and 14 months, respectively (P