Report of a Phase1/2 Study of 5-Azacitidine and Cytarabine in Patients with Relapsed, Refractory Acute Myelogenous Leukemia.

Background: Epigenetic silencing, particularly of tumor suppressor genes, is known to play a significant role in development of leukemia, and is thought to play a role in acquired drug resistance. In vitro, 5-azacitidine (azacitidine) can reverse methylation and activate expression of genes involved in response to chemotherapy, including proapoptotic genes, DNA repair genes and genes that regulate cell cycle. Thus, reversal of DNA methylation can potentially restore chemosensitivity in leukemia and combined use of DNA hypomethylating agent with chemotherapy can be an effective treatment strategy for leukemia.

Methods: We developed a phase 1/2 study of azacitidine and cytarabine administered concurrently in patients with relapsed/refractory AML. Newly diagnosed patients deemed ineligible for standard therapy were eligible. Two dose levels of azacitidine were explored, dose level 0= 37.5 mg/m2 intravenously (I.V) daily for 7 days and dose level 1=75 mg/m2 IV daily for 7 days. Similarly two dose levels of cytarabine explored were; low dose- 100 mg/m2 IV continuously (CI) for 7 days and high-dose - 1 gm/m2 CI for 4 days. This resulted in 4 potential groups (Table1). After 2 cycles of induction therapy as in table 1, patients were to receive maintenance therapy upon recovery of counts. In the phase 1 portion of the study groups were opened sequentially in a “3+3” design. The phase 2 part was designed in a 2 by 2 factorial maner with adaptive randomization.

Results: Twenty-seven patients with AML (male=13) have been enrolled so far, Group 1= 7, group 2= 6, group 3=11 and group 4= 3. One patient (group 1) did not receive treatment as she withdrew consent. Median age was 61 years (range, 31 to 79) and median number of prior therapies was 2 (range, 0 to 4). Twenty-one patients had received prior cytarabine including 19 who received high-dose cytarbine. Karyotype was complex in 7 patients, deletion 7 in 3 and 11q abnormality in 2. The median number of cycles administered on study was 1 (range, 1–5). One patient (group 2) developed dose-limiting toxicity (DLT) of grade 3 mucositis. No other DLTs were encountered. There was limited efficacy seen, with no patient achieving complete remision (CR). The combination achieved transient control of WBC counts in most patients treated, and one patient had reduction in marrow blasts from 24% to 3% after the 3^rd cycle without recovery of blood counts and had progression of disease after 5 cycles.

Conclusion: The simultaneous combination of azacitidine with cytarabine as administered in this study is safe. Efficacy evaluation of the combination was compromised by the small number of cycles of azacytidine given, but appears to be limited in a patient population composed predominantly of relapsed/refractory AML.