PHASE I/II STUDY OF 2-CHLORO-2¢-DEOYXADENOSINE (CDA) IN COMBINATION WITH CYCLOPHOSPHAMIDE (CP) IN PATIENTS (PTS) WITH ADVANCED LOW GRADE LYMPHOID MALIGNANCIES

E. Van Den Neste*, I. Louviaux*, A. Delannoy, J.L. Michaux, A. Bosly, L. Michaux*, A. Sonet*, C. Doyen*, M. Meyns*, M. André*, P. Mineur*, N. Straetmans*, A. Ferrant*

Full title: 

PHASE I/II STUDY OF 2-CHLORO-2¢-DEOYXADENOSINE (CDA) IN COMBINATION WITH CYCLOPHOSPHAMIDE (CP) IN PATIENTS (PTS) WITH ADVANCED LOW GRADE LYMPHOID MALIGNANCIES

Abstract: 

Given their respective spectrum of antitumor activity and their synergy in preclinical studies, we initiated a phase I/II trial of CdA in combination with low dose CP in pts with advanced chronic lymphoid malignancies in order to determine the maximum tolerable dose (MTD) and the activity of this combination. CdA was given IV for 2 h, immediately followed by a 1-h infusion of CP, from d1 to d3, monthly. Dose levels studied were (CdA in mg/m2/d-CP in mg/m2/d): 5.6-200, 5.6-300, 5.6-400. Preventive administration of growth factors and antiemetics was not allowed during the first cycle. All patients received prophylactic trimethoprim (320 mg)-sulfamethoxazole (1600 mg), biw. The dose-limiting toxicities (DLT) were defined as non-hematological NCI-CTC grade >2 toxicity, platelets grade 4, granulocytes grade 4 lasting >7 days, or febrile neutropenia. So far, 26 pts have been included. Pt characteristics: median age-65 (range: 44-76); sex: M/F-16/10; malignancy: chronic lymphocytic leukemia (CLL)-11, low grade non-Hodgkin's lymphoma (NHL)-7, mantle cell lymphoma (MCL)-4, Waldenström's disease (WD)-3, maltoma-1. All pts were pretreated. Prior chemotherapy regimens: 2 (median, range: 1-7); prior treatment with purine analogs-12; prior autografting-3; prior radiotherapy-4; refractoriness to last treatment-12. At study entry, 16 pts had grade 1/2 anemia, 14 grade 1/2 thrombocytopenia and 4 grade 1/2 neutropenia. Among the 26 pts included, 25 are assessable for toxicity and 19 for response. A median of 2 cycles (range: 1-5) was given per pt. The MTD of the first cycle was defined for CdA at 5.6 mg/m2/d for 3 d, in association with 400 mg/m2/d of CP for 3 d, the DLT being prolonged grade 4 neutropenia. When all courses are taken into account, grade 4 neutropenia, febrile neutropenia and grade 3/4 infections were seen in 40%, 3%, and 6% of the cycles, respectively. Neutropenia, which was not clearly cumulative, was abolished in 3 of 5 pts who received G-CSF after their second or subsequent cycles. Grade 3/4 thrombocytopenia, which occurred in 24% of the cycles and 48% of the pts, was dose-limiting in 16% of the pts. Grade 3/4 anemia occurred in 1 pt. No grade 3/4 nausea or vomiting were seen. Grade 3/4 infections (aspergillus pneumonia [3 pts] and herpes zoster infection [1 pt]), led to toxic death in 1 pt (aspergillus). No other serious toxicities did occur. Overall response rate in evaluable pts was 53% (16% CR, 37% PR). Responses were seen in CLL (6 of 8 pts), MCL (1 of 4 pts), NHL (2 of 5 pts), and WD (1 of 1 pt). All responses persisted at a median follow-up of 155d (range: 5-308). In conclusion, based on the toxicity after the first cycle, the recommended dose of this combination is CdA 5.6 mg/m2/d followed by CP 300 mg/m2/d, from d1 through d3. At this dose, neutropenia is significant, although possibly prevented by G-CSF. The study is ongoing at the level 5.6-300 in order to further characterize the potential risk of late-onset thrombocytopenia. This regimen shows encouraging activity in pts with advanced CLL and WD, 78% of whom had previous treatment with a purine analog in monotherapy.
1998
    • ASH 40th (1999)

abstract No: 

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Full conference title: 

40th Annual Meeting of the American Society of Hematology.