Can Azacitidine Delay Relapse in MRD-Positive AML?

Azacitidine may delay or prevent relapse among patients with MRD-positive acute myeloid leukemia or myelodysplastic syndrome.

Azacitidine can delay or prevent relapse among patients with minimal residual disease (MRD)-positive acute myeloid leukemia (AML) or myelodysplastic syndrome, according to findings from the open-label, multicenter, phase II RELAZA2 trial. The findings were published in The Lancet Oncology.

“Preemptive therapy with azacitidine can prevent or substantially delay hematological relapse in MRD-positive patients with myelodysplastic syndrome or AML who are at high-risk of relapse,” reported lead study author Uwe Platzbecker, MD, hematology and cellular therapy, University Hospital Lepzig, Germany, and coauthors. “Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.”

From 2011–2015 the researchers prospectively screened myelodysplastic syndrome in 198 patients with advanced AML (n=172) or myelodysplastic syndrome (n=26) for 24 months from baseline, using quantitative PCR for NPM1 mutation or leukemia-specific fusion genes. (For patients who had received allogeneic hemopoietic stem-cell transplantation, MRD monitoring involved donor CD34 chimerism.) Fifty-three patients were MRD-positive and eligible for treatment with six cycles of azacitidine.

Six months after starting azacitidine, 58% of MRD-positive patients who received azacitidine were relapse free (P < .0001). The 12-month relapse-free survival (RFS) rate was 46%. Among MRD-negative patients, 12-month RFS was 88%.

“As was the case in RELAZA1 trial, the preemptive therapy was limited to those in complete response showing MRD-positivity, and the study lacked a concurrent control group,” cautioned Fernando Ramos, MD, PhD, MPH, clinical hematology, Head Hospital and Institute of Biomedicine at the University of León in Spain, who authored a commentary published alongside the study findings.

“Onco-hematologists should refrain from treating with preemptive azacitidine MRD-negative allo-transplanted patients until an adequately powered randomized study demonstrates its eventual efficacy, since they seem to have a very low relapse risk,” Ramos told Cancer Network. “We do not know whether the reported activity is a class effect, or if it is specific to azacitidine. The role of other first- and second-generation hypomethylating agents ought to be compared with azacitidine, if Platzbecker et al’s results are confirmed by other international groups.”

Patients with a heavy disease burden did not seem to benefit from MRD-guided azacitidine therapy, Ramos noted.

“The benefit of azacitidine preemptive treatment seems mainly confined to those allo-transplanted and to dissect whether the therapeutic effect observed in allo-transplanted patients is a direct anti-leukemic effect of azacitidine, or-more likely-an immunomodulatory effect on the graft vs leukemia response, would need additional research work,” Ramos said. “The same is true for the individual contribution of azacitidine and donor lymphocyte infusion and their eventual synergism to fight impending relapse.”

Eighty-five percent of patients suffered grade III or IV neutropenia and one neutropenic patient died of infection that was deemed “possibly related” to study treatment.

“Most of the MRD-positive AML patients were included because of a high number of mutated gene RNA copies by qPCR were actually NMP1-mutated cases,” Ramos added. “Consequently, only a few patients with a different genetic configuration were treated by azacitidine and assuming any potential therapeutic benefit in them with the present data would be premature.”

The findings are nevertheless relevant to AML management, offering insight into the relative contributions of MRD positivity, allo-SCT and preemptive azacitidine therapy in clinical relapse after post-remission consolidation therapy, Ramos said.

Correction: The original version of this article, published on December 12, 2018, incorrectly referred to both myelodysplastic syndrome monitoring and myelodysplastic syndrome positivity in multiple instances. It has been updated as of March 6, 2019, to correctly refer to minimal residual disease (MRD) monitoring and MRD positivity instead.