International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

Abstract

Key Points• Azacitidine increased median overall survival by 3.8 months vs current commonly used AML treatments (10.4 vs 6.5 months; P 5 .1009).• Azacitidine safety in patients age $65 years with AML (.30% blasts) was consistent with its known safety profile in other trials.This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ‡65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n 5 241) or CCR (n 5 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P 5 .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P 5 .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047. (Blood. 2015;126(3):291-299)

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

“…In total 7 patients with MDS or CMML and 2 patients with AML receiving CC‐486 monotherapy in this study attained CR or PR, including, importantly, patients for whom previous DNMTi therapy had failed. While multiple studies have shown injectable azacitidine can improve OS in higher‐risk MDS and AML without requiring CR5, 7, 8, 9, 37; the effect of CC‐486 on OS has not yet been reported and was not captured in this phase 1 study, but is under investigation in an ongoing phase 3 trial of CC‐486 in patients with MDS (NCT01566695).…”

“…Since approval for treatment for MDS in 2004,31 parenteral azacitidine has been shown to induce remissions and HI in a range of settings, from first‐line treatment of higher‐risk MDS, CMML and AML to maintenance therapy after alloHSCT 5, 6, 7, 12, 19, 20, 32, 33, 34. CC‐486, is an oral drug formulation of azacitidine.…”

“…Parenteral azacitidine has been extensively evaluated in patients with MDS, chronic myelomonocytic leukemia (CMML), and AML in large randomized clinical trials,5, 6, 7 in regional registry studies,8, 9, 10, 11, 12, 13 and in numerous smaller retrospective analyses of patients treated in community practice 14, 15. These studies show azacitidine reduces cytopenias in select lower‐risk MDS and prolongs overall survival (OS) in higher‐risk MDS and AML,5, 6, 7, 16 may be effective maintenance therapy after induction chemotherapy (IC) or allogeneic hematopoietic stem cell transplant (alloHSCT),17, 18, 19, 20 and can induce responses in patients with relapsed/refractory disease 12, 21.…”

“…These studies show azacitidine reduces cytopenias in select lower‐risk MDS and prolongs overall survival (OS) in higher‐risk MDS and AML,5, 6, 7, 16 may be effective maintenance therapy after induction chemotherapy (IC) or allogeneic hematopoietic stem cell transplant (alloHSCT),17, 18, 19, 20 and can induce responses in patients with relapsed/refractory disease 12, 21. Importantly, the study of azacitidine has revealed nuances of treatment with DNMTi therapy not seen with the use of traditional chemotherapy.…”

“…Importantly, the study of azacitidine has revealed nuances of treatment with DNMTi therapy not seen with the use of traditional chemotherapy. These include improved OS, which can occur in the absence of a complete remission (CR),7, 8, 22 a need to treat with as many as 6 treatment cycles prior to achieving maximal response, and hematologic toxicities seen during early treatment tend to decrease if patients can remain on treatment 7, 8, 23…”