An MRD-Guided Azacitidine Treatment Strategy Delays Hematologic Relapse in MDS and AML

According to results from the phase II RELAZA2 trial, minimal residual disease (MRD)–guided treatment with the hypomethylating agent azacitidine delayed hematologic relapse in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), with nearly half of MRD-positive patients remaining relapse-free at one year.

“Continuous MRD-negativity translates into a very good prognosis, and azacitidine can in turn abrogate the dismal prognosis of MRD-positive patients, especially after allogeneic haemopoietic cell transplantation (alloHCT),” lead author Uwe Platzbecker, MD, of King’s College London, told ASH Clinical News. The findings of the trial were published in Lancet Oncology.

The RELAZA2 trial enrolled 198 patients with advanced MDS (n=26) or AML (n=172) from nine health centers in Germany. All patients had previously achieved complete remission (CR) following conventional chemotherapy or alloHCT.

During a 24-month follow-up period, patients who achieved a CR were prospectively screened for MRD by either quantitative polymerase chain reaction for mutant NPM1, leukemia-specific fusion genes (DEK–NUP214, RUNX1–RUNX1T1, CBFb–MYH11), or analysis of donor-chimerism in flow cytometry-sorted CD34-positive cells (for alloHCT recipients). MRD-positivity was defined as a >1-percent increase in NPM1 mutation or fusion genes (RUNX1–RUNX1T1, CBFb–MYH11, and DEK–NUP214) or a ≤80-percent reduction in CD34-positive donor chimerism or in the bone marrow or blood without hematologic relapse.

Participants who experienced disease relapse or severe, unresolved toxicity discontinued study treatment.

During follow-up, 138 patients were MRD-negative; 60 patients remained MRD-positive and were given subcutaneous azacitidine 75 mg/m2 per day on days one through seven of a 29-day cycle for a total of 24 cycles. Patients who achieved MRD-negativity were able to de-escalate treatment to azacitidine for five days every four weeks for a total of six cycles.

Fifty-three MRD-positive patients were considered eligible for pre-emptive azacitidine therapy. Median age was 59 years (range = 52-69) and most patients (n=48; 91%) had AML.

At a median follow-up of 13 months (interquartile range = 5-22.8) from the start of MRD-guided treatment, the study met its primary endpoint: 31 patients (58%) were alive and relapse-free at six months after the start of azacitidine treatment.

Nineteen of the 31 responders (61%) developed MRD-negativity and 12 (39%) remained MRD-positive, but without disease relapse.

Of the patients who achieved MRD-negativity, all were alive and relapse-free at a median follow-up of 23 months (range = 8-29). However, seven patients (37%) became MRD-positive at a median of 280 days (range = 62-817) post-azacitidine initiation.

Nearly half of patients (n=24/53; 45%) continued to receive azacitidine after the first six treatment cycles, and seven (13%) completed the entire two years of protocol-specified treatment.

At one year after the patients started azacitidine, the overall survival (OS) rate was 75 percent and the relapse-free survival (RFS) rate was 46 percent among MRD-positive patients. Compared with MRD-positive patients, MRD-negative patients had higher rates of both 12-month OS (hazard ratio [HR]=3.1; 95% CI 1.4=6.7; p=0.005) and RFS (HR=6.6; 95% CI 3.7-11.8; p<0.0001), the authors wrote.

“The observation that OS of MRD-positive patients who achieved a response with azacitidine was similar to that of MRD-negative patients suggests that the treatment-mediated delay of disease recurrence might be of substantial benefit to patients, as they can potentially be more efficiently salvaged by subsequent treatment,” they added.

Responses did not differ significantly between patients who did or did not undergo alloHCT (71% vs. 48%; p=0.097), but in a multivariate analysis, the researchers observed significant differences in RFS and OS favoring MRD-low versus MRD-high patients:

  • RFS: HR=3.0 (95% CI 1.3-7.0; p=0.0096)
  • OS: HR=2.5 (95% CI 0.7-9.6; p=0.17)

During the first six cycles of therapy, infections and gastrointestinal toxicity were the most common grade ≥3 non-hematologic adverse events (AEs). The most common grade ≥3 hematologic AEs included neutropenia (85%), leukopenia (32%), and thrombocytopenia (6%). Dose reductions due to myelosuppression were required in nine patients (17%) by the end of the first six cycles of azacitidine and most events were considered “both reversible and manageable.”

One patient died because of neutropenic infection at three months after the first cycle of azacitidine, which was considered possibly related to treatment. No other serious AEs were considered related to the study drug.

Because an across-the-board treatment recommendation increases the risk of overtreatment in patients who would never develop MRD, the researchers suggested that azacitidine could be used on an individual, personalized pre-emptive treatment basis based on MRD detection. “The advantage of this approach is to treat only patients at risk for relapse compared with a flat maintenance strategy, which implies over-treatment of a cohort of patients who will not relapse,” Dr. Platzbecker concluded.

Limitations of the study include its lack of randomization and a placebo or active control. The small number of patients included in the final analysis represented an additional limitation of the study.

The authors report relationships with Celgene.


Reference

Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19:1668-79.

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