A Phase II Study (Biov-121) of Clofarabine Monotherapy First Line in Patients Aged 65 Years or Older with Acute Myeloid Leukemia for Whom Standard Intensive Chemotherapy Is Not Considered Suitable.

Background: The treatment of older patients with AML is unsatisfactory and not improving. A substantial proportion of patients are not offered a standard intensive (“3+7”) chemotherapy approach because they are not considered medically fit (Juliusson et al, Leukemia, 2006 (20):42-7). Such patients are usually treated with best supportive care or low-dose Ara-C with a median survival of approximately 3 months. BIOV-121 is an open-label non-randomised multicentre international study of clofarabine, a next generation purine nucleoside analogue, in elderly patients (≥ 65 yrs) with previously untreated acute myeloid leukaemia (AML) who are unsuitable for standard (“3+7”) treatment.

Methods: 66 patients aged ≥ 65 with untreated AML (WHO classification) were enrolled in study BIOV-121. Clofarabine was administered at a dose of 30mg/m² for 5 days repeated every 28–42 days (1 course) for a maximum of 3 courses. All patients were considered unsuitable for standard intensive treatment based primarily on age, comorbidity and/or performance status. The primary endpoint of the study was overall response rate defined as the number of patients achieving a CR, CRi or PR according to the international working group guidelines.

Results: 66 patients were recruited with a median age of 71 (range 64–81). 48 patients had de novo and 16 had secondary AML. 72% had an ECOG performance sore of <2; 74% had one or more comorbidities. 31% had an adverse cytogenetic profile; 69% had intermediate cytogenetics (Grimwade D et al Blood 1998). The principal reasons patients were considered unsuitable for standard intensive chemotherapy were age and comorbidity. Nineteen patients achieved a CR; 10 CRi and 3 PR, giving an overall response rate of 48%. 14 patients died (any cause) within 30 days of study start date. The CR/CRi rate in patients over 70 years (49%) was similar to that observed for younger patients (36%). 42% (8/19) of patients with adverse cytogenetics and 31% (5/16) of patients with secondary AML achieved a CR/CRi. The median times to recovery of neutrophils to 1.0 x 10⁹/L and platelets to 100 x 10⁹/L following course 1 were 18 and 27 days respectively. 26% of patients developed neutropenic sepsis. Liver and renal adverse events (NCI CTC grade 3+) were both observed in 23% of patients. The median duration of remission is 6 months; 12 patients have relapsed to date. The median overall survival for all patients is 5 months with a 1 year survival of 26%.

Conclusion: A complete response rate of 44% achieved with clofarabine in older AML patients unsuitable for standard intensive treatment is encouraging and potentially superior to the current standard of care, low dose Ara-C. Of note a good proportion of patients with an adverse cytogenetic profile and/or secondary disease achieved a CR/CRi when treated with clofarabine.