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

Abstract

Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2′-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m 2 /day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m 2 , and was escalated by 100 mg/m 2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients 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 this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response 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 association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenströ m macroglobulinemia. Leukemia (2000) 14, 1136-1142. Keywords: 2-chloro-2′-deoxyadenosine; cladribine; cyclophosphamide; chronic lymphocytic leukemia; non-Hodgkin's lymphomaThe purine nucleoside analogs 2-chloro-2′-deoxyadenosine (CdA) and fludarabine have established activity in the treatment of B cell chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma (NHL). The hallmark of these compounds is their ability to kill both non-dividing and dividing cells via an apoptotic pathway. This may explain why they are effective in indolent lymphoproliferative disorders that usually have a low growth fraction rate and acquired resistance to apoptosis, together with the potential to accumulate active phosphorylated derivatives of purine analogs. 1In B-CLL, purine analogs yield an unprecedented rate of complete remissions (CR) compared to alkylating agents at standard dose.2,3 CdA and fludarabine are also active in follicular lymphoma (FL), Waldenströ m macroglobulinemia (WM), mantle-cell lymphoma (MCL), and lymphoplasmacytic lymphoma. [4][5][6][7][8] To date however, these drugs have not been shown to confer a survival advantage over standard therapy. 9-11In an attempt to increase the rate of CRs -as a step towards prolonged survival -one approach is to incorporate purine analogs into regimens that include agents such as chlorambuCorrespondence: E Van Den Neste, Hematology, Cliniques Universitaires Saint-Luc, 10, Av. Hippocrate, 1200 Brussels, Belgium; Fax: 32 2 764 8959 Received 17 November 1999; accepted 25 January 2000 cil (CLB) or cyclophosphamide (CP). This strategy relies on a variety of rationales including the individual activity of ...

2-Chloro-2′-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes

“…[42][43][44]50 Favorable interactions have been shown between various nucleoside analogs and DNA-damaging agents, leading to clinical trials. 6,19,51,52 In conclusion, we demonstrate for the first time that CdA inhibits the resynthesis step of DNA repair in B-CLL cells, and that this may be the basis (entirely or partially) for the synergism between CdA and UV light or alkylating agents. This advocates the combination of CdA with agents provoking DNA damage, a strategy that could help to circumvent resistance due to enhanced DNA repair.…”

Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines

“…[50][51][52][53][54] Because alkylating agents and nucleoside analogues have been shown to be effective, combinations of these agents have been tested, and response rates of 58% to 88% have been observed. [55][56][57] The addition of rituximab to these agents has been well tolerated with little additional toxicity and appears to further increase the response rate. 58-60 Recent studies using the proteasome inhibitor bortezomib in combination with rituximab have found this combination to be effective.…”

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia

“…In the trials finished to date, alkylating drugs and anthracyclines with mitoxantrone were most often combined with either FAMP or with 2-CdA. [10][11][12][13][14][15][16][17][18]29,30 Our study is the first, to our knowledge, in which previously Table 4 CMC-induced grade III and IV non-hematological side-effects n, number of patients; n1, number of courses; FUO, fever of unknown origin; DIC, disseminated intravascular coagulation; IHD, ischemic heart disease. untreated CLL patients received two other drugs in combination with 2-CdA: cyclophosphamide and mitoxantrone (CMC programme).…”

“…Some preclinical studies and early clinical reports may support such a hypothesis. [10][11][12][13][14][15][16] Among cytotoxic agents, alkylating drugs and anthracyclines were the primary candidates for use in combination with purine analogs. Synergistic action of 2-CdA with cyclophosphamide and its derivatives has been shown both in in vitro and in vivo experiments.…”

“…10,11 These results have been confirmed recently by early clinical trials, which have shown that the combination of 2-CdA with cyclophosphamide and prednisone is feasible and active in patients with CLL and other low-grade lymphoid malignancies. 13,14 Mitoxantrone is also a useful drug in the treatment of lowgrade lymphomas and can be combined with purine analogs. [17][18][19][20] However, the advantage of such a combination in patients with refractory or relapsing disease over 2-CdA alone has not yet been proven.…”