Clinical experience with fludarabine and its immunosuppressive effects in pretreated chronic lymphocytic leukemias and low-grade lymphomas.
Fludarabine monophosphate (FAMP) is a new adenine nucleoside analogue with a promising efficacy in B-cell chronic lymphocytic leukemia (B-CLL) and low-grade non-Hodgkin lymphomas (NHLs). Here, the clinical experience and side effects with FAMP are reported in 77 patients with pretreated CLL (59 B-CLL, 2 T-CLL) and low-grade NHLs (9 immunocytic lymphomas including 5 Waldenström's macroglobulinaemia, 2 centrocytic (cc) and 5 centroblastic-centrocytic (cb-cc) NHLs). 70/77 patients are evaluable for response. All except 8 patients were pretreated with one to four different regimens and had progressive disease. FAMP was administered at a dosage of 25 mg/m2 daily for 5 days as 30 minute infusion every fifth week. Partial (PR) or complete remission (CR) was achieved in 38/56 (68%) and 3/56 (5%) of evaluable patients with CLL, respectively. In 7/8 (1 x CR, 6 x PR) evaluable patients with immunocytic lymphoma and in 3/6 (3 x PR) patients with cc or cb-cc lymphoma remissions were obtained. The probability of progression-free survival was 66% and the event-free survival was 25% and 22% at 12 and 18 months. The median progression-free survival until relapse or death, however, was only 7 months (2-20+). Major toxic effects included infections in 22 patients (grade 3 and 4 WHO), granulocytopenia (mainly grade 3) and nausea in 8 patients (mainly grade 1). 19/22 patients were in PR at the time of occurrence of infectious complications. Meanwhile, 14 patients died due to septicaemia, pneumonia or other infections. Nine patients developed severe septicaemia, 4 patients had pneumocystis carinii or aspergillus pneumonias. The high infection rate may not only be due to hypogammaglobulinaemia and granulocytopenia induced by FAMP but also to a remarkable decrease of CD4+ cells from a median of 2479 to 241 CD4+ cells/microliters after 6 cycles of FAMP. In one case a tumor lysis syndrome was observed. No CNS toxicity was noted. It is concluded that FAMP is effective even in patients with advanced CLL and low-grade NHLs refractory to multiple chemotherapy regimens. However, FAMP has a marked suppressive effect on granulocytes and T-lymphocytes, predominantly CD4+ lymphocytes.
Medical Clinic III, J. W. Goethe University, Frankfurt/M., Federal Republic of Germany.
K
K
Fenchel
L
L
Bergmann
P
P
Wijermans
A
A
Engert
H
H
Pralle
P S
PS
Mitrou
V
V
Diehl
D
D
Hoelzer
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D007958:Leukocyte Count; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016019:Survival Analysis; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D014740:Vidarabine; C024352:fludarabine