Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia

Abstract

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.

Efficacy of common salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia

“…As a consequence, the methylation of DNA has been remarkably impaired due to the reduction of methyl donors and repression of DNA methyltransferase, thereby increasing cell death in leukemic blasts. [ 11 , 31 – 34 ]…”

A new intensive conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia

“…Furthermore, cladribine promotes apoptosis via inhibiting DNA methyl-transferase (DNMT) activity indirectly, by enhancing DNA demethylation through sequestration of methyl groups. [ 9 ] A wealth of studies have confirmed that intravenous infusion with high doses of Ara-C is an effective salvage therapy for R/R AML patients, due to increase in Ara-C concentration in plasma, and in cerebrospinal fluid. As a result, 40% of patients can achieve remission again.…”

“…This inference was further confirmed by the analysis of influencing factors for survival, which showed that fungal infection was correlated with unfavorable LFS, and OS, and aGVHD was considerably, associated with shorter LFS, and OS (although no significance was discovered). In general, CLAG plus modified BuCy therapy in our research was considered to be effective due to successful WBC, and PLT engraftment, and high probability of survival, and these outcomes may be due to: firstly, cladribine, which exerts a direct cytotoxic effect on leukemic cells by interfering with cell metabolism leading to cell death; [ 9 , 15 ] secondly, Ara-C, which impairs DNA synthesis, and then inhibits proliferation of leukemic cells. Additionally, cladribine increases cellular uptake of Ara-C thus acting synergistically with Ara-C; [ 16 , 17 ] thirdly, G-CSF, which reduces incidence of GVHD, and relapse, and it enhances the anti-leukemia effects.…”

“…Cladribine (2-chloro-2’-deoxyadenosine) is a new generation purine analogue that kills proliferative and non-proliferative cells by promoting cellular apoptosis. [ 9 , 10 ] In addition, it was demonstrated in vitro that cladribine can increase cellular uptake of Ara-C; Ara-C is converted intracellularly into the active metabolite Ara-C-5’ triphosphate (Ara-CTP), thus exerting its cytotoxic effect on leukemic blasts. [ 11 ] The accumulated Ara-CTP concentration reaches between 50 to 65%, suggesting that cladribine treatment plus Ara-C is a potential choice for intensive induction therapy.…”

Comparison of clinical remission and survival between CLAG and FLAG induction chemotherapy in patients with refractory or relapsed acute myeloid leukemia: a prospective cohort study

“…It is reported that FLAG achieves CR ranging from 46 to 63% in R/R AML patients and the efficacy of fludarabine is on account of its triphosphate which inhibits RNR and elevates Ara-CTP in leukemic cells [ 7 – 9 ]. While another cytotoxic agent cladribine, as a new generation of purine analog, has been considered to be a substitute for fludarabine in the combination with Ara-C plus G-CSF (CLAG) as a treatment in R/R AML patients [ 10 ], which is not only due to its same mechanism as fludarabine, but also attribute to its additional effects that cladribine induces cells apoptotic process through changing the membrane potential of mitochondria, repressing DNA methyltransferase (DNMT) as well as consuming methyl donors and, thus, we hypothesized that CLAG might be more effective than FLAG [ 2 , 11 – 13 ]. Based on the above advantages of CLAG, it has attracted the attention of Polish Adult Leukemia Group (PALG) and PALG has conducted a multicenter, open and non-controlled phase II clinical trial in R/R AML patients in which CLAG achieves CR of 50% and 1-year OS of 42% [ 14 ].…”