NPM1 Mutations, MRD Responses Linked to Long-Term Survival Benefits With Azacitidine in AML

Andrew H. Wei, MBBS, PhD

Oral azacitidine (Onureg, CC-486) was associated with improved long-term survival in patients with acute myeloid leukemia (AML) who harbored NPM1 mutations, had intermediate-risk cytogenetics at diagnosis, had a longer treatment duration, or a minimal residual disease (MRD) response during treatment, according to a survival analysis of the phase 3 QUAZAR AML-001 trial (NCT01757535).¹

The findings presented at the 2022 EHA Congress showed that the long-term survival cohort included 29.7% of all enrolled patients who survived at least 3 years after trial randomization (n = 140 of 472), including 34.9% of patients in the azacitidine arm (n = 83 of 238) and 24.4% of patients in the placebo arm (n = 57 of 234).

Of the patients in the long-term survival cohort who received azacitidine, 45% harbored NPM1 mutations compared with 19% in the non–long-term survival cohort. In patients who received placebo, 46% in the long-term survival cohort harbored NPM1 mutations vs 26% in the non–long-term survival cohort.

Additionally, 75.9% of patients in the long-term survival cohort received at least 24 cycles of azacitidine, and 62.7% of patients received at least 36 cycles of the agent.

Furthermore, 94% of patients in the long-term survival cohort who received azacitidine had intermediate-risk cytogenetics at diagnosis compared with 81% in the non–long-term survival cohort. In the placebo arm, 96% of patients in the long-term survival cohort had intermediate-risk cytogenetics compared with 84% of patients in the non–long-term survival cohort.

Although lead study author Andrew H. Wei, MBBS, PhD, and colleagues, noted MRD response could be associated with longer time on treatment, 83.3% of all patients who achieved an MRD response did so within 6 months of randomization (n = 50 of 60).

“More than one-third of patients receiving oral azacitidine maintenance therapy were alive at 3 or more years from study randomization compared with approximately one-fourth of placebo patients,” Wei, a professor at the Alfred Hospital at Monash University in Melbourne, Australia, said in a presentation of the data.

Although intensive chemotherapy can lead to remission for many patients with AML, the majority will eventually relapse, leading to poor prognosis. The QUAZAR AML-001 trial investigated the use of oral azacitidine plus best supportive care vs placebo plus best supportive care in patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy.

In September 2020, the FDA approved oral azacitidine for the continued treatment of adult patients with AML who achieved CR or CRi following intensive induction chemotherapy who are not able to complete intensive curative therapy, based on the results of the QUAZAR AML-001 trial.²

The trial enrolled patients who were at least 55 years of age with de novo AML or AML secondary to myelodysplastic disease or chronic myelomonocytic leukemia. Patients were required to have achieved a CR/CRi to intensive chemotherapy, have an ECOG performance status of between 0 and 3, have intermediate- or poor-risk cytogenetics, not be a candidate for hematopoietic stem cell transplantation (HCST), have an absolute neutrophil count of at least 0.5 x 10⁹/L, and have a platelet count of at least 20 x 10⁹/L.

Patients were randomized 1:1 to receive 300 mg of oral azacitidine once daily for 14 days or placebo on the same schedule in 28-day cycles. Responses were assessed every 3 or 6 cycles. After assessment, patients who achieved a CR or CRi were allowed to continue treatment. Patients with bone marrow blasts between 5% and 15% received oral azacitidine or placebo for 21 days before continuing treatment. For patients with bone marrow blasts above 15%, treatment was stopped. When the study was unblinded, patients in the placebo arm discontinued treatment, and patients still receiving treatment in the azacitidine arm were permitted to continue treatment in an extension phase.

The primary end point of the trial was overall survival, and secondary end points included relapse-free survival, time to relapse, time to treatment discontinuation, and safety.³

Among patients who received azacitidine in the long-term survival cohort (n = 83) and the non–long-term survival cohort (n = 155), the median ages were 67 years (range, 55-80) and 69 years (range, 55-86), respectively. Most patients had de novo AML (89% and 90% in the long-term survival and non–long-term survival cohorts, respectively), had a CR after induction chemotherapy (80% and 78%), received consolidation therapy (77% and 79%), and were MRD negative at randomization (65% and 52%).

In patients who received placebo in the long-term survival cohort (n = 57) and the non–long-term survival cohort (n = 177), the median ages were 67 years (range, 55-79) and 69 years (range, 55-82), respectively. Most patients had de novo AML (96% and 91% in the long-term survival and non–long-term survival cohorts, respectively), had a CR after induction chemotherapy (84% and 84%), and received consolidation therapy (88% and 80%). Notably, 70% of patients in the long-term survival cohort were MRD negative at baseline, and 44% of patients in the non–long-term survival cohort were MRD negative.

Additional data showed that factors that were associated with long-term survival only in patients in the placebo arm were MRD negativity following induction chemotherapy and receipt of HSCT following study treatment.

Notably, 6.3% of patients who received azacitidine underwent HSCT after treatment discontinuation, including 9.6% of patients in the long-term survival cohort and 4.5% of patients in the non–long-term survival cohort. For patients who received placebo, 13.7% underwent HSCT following treatment, including 28.1% in the long-term survival cohort.

Study authors noted that there was no significant correlation between baseline hematological or immune parameters and long-term survival among all patients.

When controlling for all covariates, azacitidine was independently predictive for long-term survival compared with placebo.

References

1. Wei AH, Döhner H, Sayar H, et al. Clinical and biological markers associated with long-term survival for patients with acute myeloid leukemia (AML) in remission after chemotherapy in the QUAZAR AML-001 trial of oral azacitidine. Presented at: European Hematology Association Hybrid Congress; June 9-12, 2022; Vienna, Austria. Poster 498
2. US Food and Drug Administration approves Onureg (azacitidine tablets), a new oral therapy, as continued treatment for adults in first remission with acute myeloid leukemia. Bristol Myers Squibb. September 1, 2020. Accessed June 10, 2022. https://bwnews.pr/2QJJsx1
3. Efficacy of oral azacitidine plus best supportive care as maintenance therapy in subjects with acute myeloid leukemia (AML) in complete remission (QUAZAR AML-001). ClinicalTrials.gov. Updated June 8, 2022. Accessed June 10, 2022. https://clinicaltrials.gov/ct2/show/NCT01757535