A Phase 2 Evaluation of Single Agent Clofarabine as First Line Treatment for Older Patients with AML Who Are Not Considered Fit for Intensive Chemotherapy.

Patients over 70 years represent a significant proportion of patients with AML. They respond poorly to intensive chemotherapy. Although 50% of patients can achieve CR, only 8% are alive at 2 years (MRC Database). In addition significant numbers of these patients either do not wish to undergo, or are not considered fit for intensive chemotherapy. This represents a significant unmet medical need. Nucleoside analogues (Ara-C) provide an active group of agents in AML, Fludarabine however is ineffective at tolerable doses. Clofarabine has been modified by introducing a Fluorine in the 2′ position which confers reduced susceptibility to cleavage of the glycosidic linkage and also reduced toxicity caused by halogenated nucleobases. As such the drug has potential use as an oral formulation. Previous clinical and in vitro studies have established a dose schedule at 40mg/m² days 1–5. This is associated with CRs in relapse/refractory AML, but with grade ¾ liver toxicity in 25% of patients.

Because of these characteristics we undertook a non-randomised study using a dose of 30mg/m² days 1-5 IV, which could be repeated for up to 4 courses at a minimum of 28 days apart. The target patient group were patients >70 years, or patients 60–70 with a cardiac history, who were not considered fit for conventional chemotherapy.

Twenty-eight patients entered the study: 16 males, 12 females of a median age 71 years (range 60 – 79). The FAB distribution was, M0=1;M1=9; M2=8; M4=2; M5=4; M6=3; Unknown=1. The cytogenetic risk group (MRC criteria) were 26 standard and 2 unfavourable risk. All patients received course 1. Five patients died before response could be assessed from causes which were not thought to be associated with the drug. One patient is too early to assess response. Five did not enter complete remission although there was a reduction in bm blasts from 58 to 18%, 55 to 20% and 30 to 15% in 3 cases. Sixteen patients (59%) achieved complete remission after course 1. Grade 3 toxicity was seen in 3 patients, but this recovered in all cases in a few days. Patients who did not enter CR did not show haematological recovery after course 1 and were considered treatment failures. Of the 16 patients who entered CR, haematological recovery to ANC 1.0 x 10⁹/l took 28 days (range 21–42) Platelets to 50x10⁹/l took 25 days (range 21–38).

Conclusions: Clofarabine is an active agent when used alone as first line treatment. It is well tolerated but is associated with cytopenia of an average 28 days. At the dose chosen for this study grade ¾ liver toxicity was uncommon. The drug is a candidate for evaluation in a randomised trial and/or in combination schedules, and lower doses should be explored in older patients. This study was partially supported by an unrestricted grant from Bioenvison Inc.