Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia

Abstract

One hundred seventy-seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara-C) and cyclophosphamide (cyclo) would improve disease-free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6-mercaptopurine plus methotrexate. Forty-seven of 101 patients with non-T ALL and 18 of 26 patients with T-cell ALL received ara-C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non-T-cell ALL had similar DFS with or without ara-C/cyclo pulses (36% versus 48%; P = 0.32). Ara-C/cyclo pulses significantly improved DFS in children with T-cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara-C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara-C/cyclo used during continuation therapy is selectively beneficial in T-cell ALL.

Amphiphilic Oligomers: A New Kind of Macromolecular Carrier of Antimitotic Drugs

“…Arabinofuranosylcytosine (Ara-C), the clinically useful antimetabolite of cytidine, is one of the most important antitumor agents, especially used in the treatment of various leukemias and carcinomas of the colon, breast and ovary [51]. Like many inhibitors of DNA synthesis, the therapeutic use of Ara-C is largely hindered by its toxicity to normal dividing cells.…”

“…Moreover, this drug is subject to rapid enzymatic deactivation by cytidine deaminase to arabinofuranosyluridine (Ara-U) [54]. Several modifications have been envisaged in order to minimize such drawbacks [51]. Several modifications have been envisaged in order to minimize such drawbacks [51].…”

Lessons from 20 years of curative therapy of childhood acute leukaemia

“…This hypothesis was supported by studies in mice which demonstrated that thymic leukaemia was more sensitive to cyclophosphamide and cytarabine than methotrexate and mercaptopurine (Frei et al, 1974). A comparative clinical Months in continuous complete remission Figure 8a Children with non-T lymphoid leukaemia were not benefited by addition of cyclophosphamide and cytarabine to their continuation chemotherapy (Lauer et al, 1987). b, For T-cell lymphoid leukaemia, only children who received cyclophosphamide and cytarabine remained in remission (Lauer et al, 1987).…”

Species-Specific Therapy of Acute Lymphoid Leukemia

“…However, in mice it was demonstrated that cyclophosphamide and cytarabine were more effective in AKR leukemia, a T-cell line, and Sullivan et al suggested that cytarabine was specifically effective in human T-cell lymphoma/leukemia [42,47]. A comparative study in children with ALL in remission demonstrated that the cure rate of T-cell ALL approached that of non-T ALL when the T-cell patients received cyclophosphamide and cytarabine in addition to methotrexate and mercaptopurine [26]. On the other hand, the cyclophosphamide and cytarabine provided no curative benefit, only additional toxicity, to children with non-T ALL receiving methotrexate and mercaptopurine.…”

“…Survival and cure depend on the administration of appropriate drugs in appropriate schedules. For example, when T-cell ALL was 30 treated with conventional non-TALL chemotherapy it had a rapidly fatal course in most patients [26]. Features associated with T-cell ALL such as thymic mass, male sex, high white cell count, and older age were calculated to be "highrisk" or "bad-prognosis" factors.…”