Cyclophosphamide, Ara-C and Topotecan (CAT) for Patients With Refractory or Relapsed Acute Leukemia

Abstract

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.

A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia

“…The agent O 6 -benzylguanine has been shown to deplete tumor AGT in solid tumor clinical trials, but combinations of O 6 -benzylguanine with BCNU or temozolomide have resulted in substantial hematological toxicity at doses of the latter agents that are much lower than their single-agent MTD, possibly eliminating any potential therapeutic gain from the addition of O 6 -benzylguanine (22,25,26). Similar studies of O 6 -benzylguanine in combination with an alkylating agent such as VNP40101M could be considered for patients with leukemia where greater levels of marrow suppression are acceptable.…”

Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia

“…Current data suggest that most will require combination with standard cytotoxic agents in therapeutic antileukemia regimens (3 -7). The development of more active, better tolerated cytotoxic agents continues to be important in attempting to improve therapy for patients with leukemia.DNA alkylating agents are an important class of antileukemia agents, sharing the ability to damage DNA and/or impair its replication (5,7,8). Among the class, there is a broad spectrum of antitumor activity and toxicity, attributable to individual biological properties of the agents, including the type of DNA damage, relative specificity of attacking DNA versus other cellular components, the DNA repair mechanisms used by the cell in response to the agent, uptake and distribution of the agent in malignant and normal cells, and the relative susceptibility of the agent to leukemia resistance mechanisms (9 -12).…”

A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia

“…15 The combination of topotecan, plus either cyclophosphamide, 16 idarubicin, 17 etoposide, 18 cisplatin, 19 or cytarabine 9,11,16,18 exhibits antitumor activity in adult patients with leukemia 9,11,[16][17][18] and solid tumors. 19 In hematologic malignancies, thiotepa is an active antileukemic agent that is successfully used in the cytoreduction regimens preceding allogeneic stem cell transplantion (SCT).…”