High incidence of infections after 2-chlorodeoxyadenosine (2-CDA) therapy in patients with malignant lymphomas and chronic and acute leukaemias

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Abstract
Background: 2-chlorodeoxyadenosine (2-CDA) is a new purine analogue which has been shown to be highly active in lymphoproliferative disorders. In this clinical trial we assessed 2-CDA toxicity and response rate in patients with various haematological malignancies who were heavily pre-treated and mostly refractory to standard treatment regimens. Patients and methods: Twenty-two refractory patients, 51 relapsing after standard chemotherapy and seven non-pretreated patients were treated in a non-randomized prospective phase II multicentric study. Their median age was 54 years (range 18–84) and 56 of them were male. Thirty-one had non-Hodgkin's lymphoma (NHL), 11 chronic lympho-cytic leukaemia (CLL), 1 prolymphocytic leukaemia (PLL), 13 hairy-cell leukaemia (HCL), 2 mycosis fungoides (MF), 3 multiple myeloma, 7 acute myeloblastic leukaemia (AML), 2 acute lymphoblastic leukaemia (ALL), 6 chronic myeloid leukaemia (CML) in blast crisis, 2 Hodgkin's disease, 1 Waldenstrom's macroglobulinemia and 1 Langerhans hisio-cytosis. 2-CDA 0.1 mg/kg/day was given as a continuous intravenous infusion for 7 days and recycled every 4 weeks. Results: One hundred thirty-two courses of 2-CDA were administered to 80 patients, 76 of whom were evaluable for response. A) Toxicity: Myelosuppression: Neutropenia to over 50% of initial value occurred in 46% of patients, throm- bocytopenia in 8%, and lymphopenia ±0.5 × 109/l was seen in 41%. Infections occurred in 34/80 patients (43%). The risk of severe infections (WHO grades 3–4) correlated with increasing number of years after first diagnosis (p = 0.01) and low lymphocyte counts on days 1 and/;or 14 (p = 0.04); 21 infections were opportunistic. B) Response: 70% patients with lymphoproliferative disorders of low malignancy attained complete or partial response (low-grade NHL 12/16, CLL + PLL 9/12, HCL 13/13, MF 2/2, myeloma 0/p3); in patients with AML, ALL, CML in myeloid (n = 4) or lymphoid (n = 2) blast crisis and high-grade lymphoma responses were seen in only 11%;. Response was inversely elated to the number of pretreatments (p = 0.045). In responding NHL patients the mean lymphocyte count on day 14 of cycle 1 was significantly lower (median 0.6 times; 109/l) than that of non-responders (1.2 × 109/l, p = 0.04). Conclusion: 2-CDA had a high activity even in heavily pretreated and refractory patients with low-grade lymphoproliferative disorders. In contrast to previously published studies, infections, mainly opportunistic, were a serious side effect in our study. In patients with severe lymphopenia at therapy initiation, the value of prophylactic anti-infective treatment should be studied.