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Maintenance therapy with the hypomethylating agent CC-486 significantly prolongs the overall and relapse-free survival of AML patients in remission after induction chemotherapy

Maintenance therapy with an investigational oral formulation of azacitidine (CC-486) results in a significant improvement in the overall and relapse-free survival of older patients with newly diagnosed acute myeloid leukemia who are in remission following standard induction chemotherapy with or without consolidation therapy. Moreover, maintenance therapy with CC-486 was associated with a manageable safety profile and, as such, it has the potential to become a new therapeutic standard for acute myeloid leukemia patients in post-induction remission.

Background

Many older patients with acute myeloid leukemia (AML) respond to intensive induction chemotherapy (IC), but these responses are often short-lived and the overall survival (OS) prospects for patients are poor. The benefit of post-remission maintenance in AML is unclear. In fact, while several agents have shown to increase the relapse-free duration in the maintenance setting, demonstration of a survival benefit has so far been elusive. CC-486 is a new formulation of azacitidine and its oral administration allows for prolonged drug exposure during each treatment cycle, which in turn could lead to sustained therapeutic activity. In the phase III, randomized QUAZAR AML-001 trial, CC-486 was evaluated as maintenance therapy for patients aged ≥55 years with AML in first remission following IC.

In order to be eligible for the study, patients had to have de novo or secondary AML with intermediate- or poor-risk cytogenetics, with an ECOG performance status of ≤3. Patients had to be in a first complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC (with or without consolidation chemotherapy) and were ineligible for hematopoietic stem cell transplantation (HSCT). Within 4 months of attaining their CR/CRi to induction therapy, patients were randomized (1:1) to receive maintenance therapy with either CC-486 or placebo (both at a dose of 300 mg once daily on days 1–14 of repeated 28-day treatment cycles). A 21-day dosing schedule was permitted for patients who experienced AML relapse with 5–15% blasts in blood or bone marrow while on-study. The treatment was continued indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. The primary endpoint of the study was OS, with relapse-free survival (RFS), health-related quality of life (HRQoL), and safety as key secondary objectives.

Results

In total, 472 patients were enrolled in the study with a median age of 68 years. The majority of patients had an ECOG PS of 0 (49%) or 1 (42%) and approximately 90% of patients had de novo AML. Overall, 86% of patients had an intermediate cytogenetic risk and approximately 4 out of 5 patients obtained a CR after induction therapy. Eighty percent of patients in the study received consolidation therapy and 46% of patients were MRD-negative at study randomization.

After a median follow-up of 41.2 months, patients who received CC-486 maintenance had a significantly better OS than patients in the placebo arm (median OS: 24.7 versus 14.8 months; HR 0.69 [95% CI: 0.55-0.86]; p=0.0009). In addition to this, the RFS was significantly prolonged from a median of 4.8 months with placebo to 10.2 months with CC-486 maintenance (HR 0.65 [95% CI: 0.52-0.81]; p=0.0001). At one year, the relapse rate was 53% (95% CI: 46-59%) in the CC-486 arm as compared with 71% (95% CI: 65-77%) with placebo.

Patients in the CC-486 arm received a median of 12 treatment cycles, which was twice as much as the median of 6 cycles in the placebo arm. The safety profile of CC-486 was generally consistent with that of injectable azacitidine. The incidence of grade 3/4 adverse events was 72% with CC-486 as compared to 63% in the control arm. Maintenance treatment with CC-486 led to a higher rate of gastrointestinal adverse events (nausea 65% versus 24%, vomiting 60% versus 10%, diarrhea 50% versus 22%) compared to placebo, but these adverse events rarely reached grade 3 in severity. The gastrointestinal adverse events with CC-486 arm were most commonly seen during the first 2 treatment cycles. The most common grade 3/4 adverse event with CC-486 was neutropenia, which was seen in 41% of patients (versus 24% with placebo). Serious adverse events were reported in 34% and 25% of patients in the CC-486 and placebo arms, respectively. Treatment discontinuation due to adverse events was infrequent and there were no treatment-related deaths.

Conclusions

Results of the QUAZAR AML-001 trial identify CC-486 as the first maintenance therapy to provide a statistically significant and clinically meaningful improvement in both OS and RFS in patients with AML in remission following induction chemotherapy, with or without consolidation. In fact, the median OS was prolonged by 9.9 months with CC-486, while the median RFS was more than doubled with CC-486 versus placebo. The safety and tolerability profile of CC-486 was comparable to injectable azacitidine, with no unexpected events. Based on these findings, the authors conclude that it is reasonable to expect that this therapy will become an integral part of treatment for older people with AML in remission and may help them to defer the need for further AML therapy.

Reference

Wei A, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission. Presented at ASH 2019; Abstract LBA-3.

Speaker Andrew Wei

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Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, The Alfred Hospital, Melbourne, Australia

 

See: Keyslides

 

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