Phase I/II study of 2-chloro-2 '-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent. non-Hodgkin's lymphoma

Because of their substantial in vitro synergy, we conducted a dose-escalati on study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-H odgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m(2)/day) as a 2h intravenous (i.v.) infusion, immediately followed by a l-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m(2), and was escalat ed by 100 mg/m(2) increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were in cluded at the MTD to extend toxicity and response analysis. Twenty-six pati ents received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m(2 ), was 300 mg/m(2). Acute neutropenia was the dose-limiting toxicity of thi s regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytope nia. Severe infections were seen in three of 68 cycles (4%). The overall re sponse rate was 58% (15 of 26; 95% CI, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the associat ion of CdA with CP. Given the response rate observed, further studies of th is regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenstrom macroglobulinemia.