Rates of CR with and without Measurable Residual Disease after Induction Treatment with "7+3" or Azacitidine/Decitabine for Newly-Diagnosed AML

Introduction

The importance of measurable residual disease (MRD) at time of complete remission (CR) as a predictor of relapse and/or survival either after allogeneic transplant (HCT) or chemotherapy without HCT is widely recognized (Chen et al. JCO 2015;33:1258-64). Hence, a goal of induction therapy might be not only to produce CR, but CR without MRD. Here we compare rates of CR with and without MRD after induction therapy with either (1) "7+3", (2) azacitidine (aza) or decitabine (dec) alone (aza/dec alone), or (3) regimens containing aza or dec with other low intensity treatment (aza/dec combos). Given reportedly similar survival rates with 7+3 and aza/dec alone, and the contribution of CR without MRD to survival, we hypothesized that while CR rates are higher with 7+3, there would be relatively less difference in rates of CR without MRD.

Methods

We analyzed 272 patients with newly diagnosed, high-risk MDS (10-20% blasts) or AML (> 20% blasts) treated with the following regimens: 7+3 (139 patients), aza/dec alone (64) or aza/dec combos (69), the latter most commonly involving gemtuzumab ozogamicin +/- vorinostat. Cytogenetic risk and response to treatment were assessed per ELN guidelines, and MRD was assessed via 10- color multiparametric flow cytometry as previously described (Chen et al. JCO 2015;33:1258-64).

Results

As expected, patients given 7+3 were younger, with median ages of 53 for 7+3, 63 for aza/dec alone, and 58 for aza/dec combos. In 7+3, cytogenetic risk was favorable in 29%, intermediate in 26%, and poor in 45%; for aza/dec alone 5% were favorable, 44% intermediate, and 51% poor; and for aza/dec combos, 12% were favorable, 30% intermediate, and 58% poor. As expected, CR rates were higher with 7+3: 72% vs. 14% for aza/dec alone and 17% for aza/dec combos. Rates of CR w/o MRD were also higher with 7+3: 58% vs. 9% for aza/dec alone and 13% for aza/dec combos (p<0.001), while rates of CR with MRD were more similar (14% 7+3 vs. 5% aza/dec alone and 4% for aza/dec combos. Rates of CR w/o MRD were higher with favorable risk cytogenetics (78%) than intermediate risk (24%) or poor risk (22%). The same was true considering only either the aza/dec alone group (67% vs 4% vs 9%) or the aza/dec combo group (50% vs 5% vs 10%.)

Conclusion

The higher CR rate seen with 7+3 than with aza/dec or its combinations is paralleled by a higher rate of CR without MRD. Multivariate analyses are currently analyzing the relation between relapse/survival and CR without MRD, cytogenetic risk, and treatment, and whether the effect of CR without MRD on these outcomes is the same with 7+3 and aza/dec or its combinations. Assuming, as expected, RFS and survival in the current population is approximately similar regardless of treatment with 7+3, aza/dec or its combinations, the failure of 7+3 to produce better survival despite higher rates of CR without MRD would suggest limitations in the use of CR without MRD as a surrogate for RFS and survival. The similar effect of cytogenetics on CR without MRD rates with 7+3, aza/dec alone or aza/dec combos suggests a qualitative similarity between these regimens that is perhaps more than often appreciated.