MRD-guided preemptive therapy in patients with acute myeloid leukemia – results from the phase II RELAZA2 study

Intensive chemotherapy can help patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) to achieve complete remission (CR), but many of them relapse even after subsequent allogeneic (allo) hematopoietic stem cell transplantation (HSCT).

In an article published in Lancet Oncology, Uwe Platzbecker and colleagues reported results from the prospective phase II measurable residual disease (MRD)- guided RELAZA2 trial (NCT01462578) conducted by the Study Alliance Leukemia (SAL) group. The aim of this study was to evaluate the role of azacitidine (AZA) in the setting of MRD-guided preemptive therapy in order to prevent or delay relapse in patients with MDS or AML in CR after first-line treatment with standard chemotherapy and allo-HSCT.

In the prospective phase II RELAZA2 study, patients were prospectively screened for MRD during 24 months from baseline either by the quantification of NPM1 mutation level, leukemia-specific fusion genes (DEK-NUP214, CBFb-MYH11 or RUNX1-RUNX1T1) or sensitive donor chimerism (DC) analysis of CD34 on peripheral blood cells (in patients undergoing allo-HSCT). Patients in CR with measurable MRD above the threshold defining imminent relapse were administered six cycles of AZA (75 mg/m² subcutaneously, days 1–7) followed by a MRD risk-adapted AZA-based therapy for up to 18 additional months.

Of the 198 patients screened in this study, 53 patients (median age = 59 years; range: 52–69) with AML (n = 48) and MDS (n = 5) in CR after receiving either standard chemotherapy (n = 29) or allo-HSCT (n = 24) were eligible. MRD positivity in the eligible 53 patients was detected by CD34-positive donor chimerism (n = 19) or mutations in NPM1 (n = 32) or RUNX1-RUNX1T1 (n = 2).

The primary endpoint of the study was relapse-free survival (RFS) at 6 months from the start of MRD treatment.

Key findings:

• Six months after initiation of MRD-guided AZA therapy with a median follow-up of 13 months (8.5–22.8), 58% (31/53) patients were relapse-free, P < 0.0001
• Overall survival at 12 months was 75% with a median follow-up of 13 months (8.5–22.8)
• 12-month RFS was 46% (95% CI, 32–59)
• After six cycles of treatment, 58% (31/53) achieved an overall response
• Major response was observed in 19 responders (61%) with either a decline of MRD below a predefined threshold (increasing CD34+ DC to ≥ 80% or mutation level ≤ 1%)
• Minor response was observed in 12 responders (39%) with MRD of CD34+ DC to < 80% or mutation level ≤ 1% but no relapse
• Compared to MRD^pos patients, RFS (HR = 6.6, P < 0.0001) and OS (HR = 3.1, P = 0.0046) were significantly longer in MRD^neg patients (138 patients who were screened and did not have MRD positivity at baseline)
• The most common grade 3–4 adverse event was neutropenia occurring in 45 (85%) of 53 patients
• One patient died due to neutropenic infections which was possibly treatment-related

In summary, the findings of this RELAZA2 study demonstrates that “MRD monitoring can identify patients who are likely to relapse and MRD-guided treatment with AZA could be an effective strategy to prevent or substantially delay relapse with an acceptable safety profile in MRD-positive patients with MDS or AML”. In addition, RELAZA2 study supports the prognostic importance of MRD monitoring in AML and may serve as a platform for future studies combining hypomethylating agents with novel targeted therapies.

Key limitations of this study include the small sample size, the heterogeneity of the patient group, the non-randomized design and time bias.