Complete response, minimal residual disease negativity linked to lower relapse risk in relapsed/refractory AML
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ORLANDO — Achieving complete remission and minimal residual disease negativity appeared to be independently associated with reduced cumulative incidence of relapse and longer RFS among patients with relapsed or refractory acute myeloid leukemia receiving initial salvage therapy, according to results of a retrospective study presented at ASH Annual Meeting and Exposition.
Researchers observed the impact of hematologic recovery and minimal residual disease (MRD) response in the salvage setting mostly among patients who did not undergo subsequent hematopoietic stem cell transplantation.
The results support the idea that complete remission with undetectable MRD is the optimal response to salvage therapy for patients with relapsed or refractory AML, researchers noted.
“In the front-line setting, studies have shown that patients who achieve complete remission with hematologic recovery and MRD negativity have improved survival,” Nicholas J. Short, MD, assistant professor in the division of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation. “Based on this data, the [European Leukemia Net] 2017 guidelines introduced new criterion of complete response without MRD, which is considered the optimum response.”
Data had been lacking, however, to establish the prognostic role of complete response and undetectable MRD in relapsed or refractory AML.
Short and colleagues retrospectively analyzed 141 patients (median age, 58 years; range, 17-84) with relapsed or refractory AML who received first salvage therapy with an intermediate- or high-dose cytarabine regimen.
All patients achieved morphological remission, with or without full hematologic recovery, and had MRD measured via 8color multiparameter flow cytometry on bone marrow specimens at the time of best response.
Among all patients, 95 (67%) achieved complete remission with full hematologic recovery, 26 (18%) achieved complete remission with incomplete hematologic recovery and 20 (14%) achieved morphological leukemia-free state (MLFS) as their best response. Eighty-six patients (61%) had undetectable MRD.
Rates of MRD negativity appeared similar across response groups (64% complete response; 46% complete response with incomplete hematologic recovery; 65% MLFS).
Patients with diploid karyotype had a higher complete response rate than those who had nondiploid karyotype (78% vs. 59%; P = .02) as did patients with first complete response lasting 1 year or more vs. less than 1 year (87% vs. 57%; P = .001).
Patients with higher baseline bone marrow blasts had a higher rate of undetectable MRD (median blasts, 35% vs. 26%; P = .03), but MRD negativity rate did not appear to be associated with other pretreatment parameters.
Cumulative incidence of relapse, RFS and OS served as the study’s primary endpoints.
Median follow-up was 30.5 months.
Results showed that patients who achieved complete remission had a lower cumulative incidence of relapse (P = .01) and better RFS (P = .004), but no significant difference in OS, compared with patients who had a lesser response. Patients who achieved MRD negativity also had a lower cumulative incidence of relapse (P = .01) and better RFS (P = .05), but not OS, compared with those who had detectable MRD.
Sixty-two patients (44%) underwent allogeneic HSCT following first salvage therapy, with a median 1.4 months between second remission and HSCT. Transplantation after first salvage therapy proved to be the most significant prognostic factor for cumulative incidence of relapse, RFS and OS (P < .001 for all).
Rates of HSCT were higher among patients who achieved complete response compared with a lesser response (52% vs. 28%; P = .008) and those who had undetectable vs. detectable MRD (52% vs. 31%; P = .01)
Relapse rates within 1.4 months of second remission appeared higher among patients who achieved complete response without full hematologic recovery or MLFS and/or had detectable MRD compared with those who had MRD-negative complete response (16% vs. 3%; P = .01). This was a major driver of the inferior outcomes in these groups, researchers noted.
When researchers stratified 57 patients who did not relapse 1.4 months after second remission and did not undergo HSCT in second remission into groups based on response, they observed associations between hematologic response and MRD response and differences in cumulative incidence of relapse (P = .004) and RFS (P = .008), but not OS.
Among the 62 patients who underwent HSCT, neither hematologic nor MRD response was associated with cumulative incidence of relapse, RFS or OS. MRD status immediately prior to HSCT also did not appear to be associated with outcomes.
A multivariate analysis using known predictors for outcomes in relapsed or refractory AML and HSCT as a time-dependent variable showed independent associations of complete response and MRD negativity with lower cumulative incidence of relapse (P = .001 and P = .003) and longer RFS (P < .001 and P = .02), but no association with OS.
Overall, patients who achieved complete response with undetectable MRD (n = 61) had the best outcomes (2-year cumulative incidence of relapse, 58% vs. 73%; P = .004; 2-year RFS, 28% vs. 15%, P = .008; 2-year OS, 46% vs. 21%).
“Among patients with relapsed or refractory AML, both complete response and MRD negativity were independently associated with lower risk for relapse and longer relapse-free survival,” Short said. “The superior outcome of patients with complete response with MRD negativity was driven largely by the ability of these patients to undergo transplant. The rate of early relapse was nearly 20% in patients with lesser responses. However, among those who did receive a transplant, post-outcomes were similar regardless of hematologic or MRD response. Immediate transplant should be considered for any patients with relapsed or refractory AML who achieve remission regardless of hematologic recovery or MRD response.”– by John DeRosier
Reference:
Short NJ, et al. Abstract 735. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Short reports advisory/consultant roles with AstraZeneca and Takeda, research funding from Takeda, and honoraria from Amgen. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to TopMichael R. Grunwald, MD
We are learning in AML and other hematologic malignancies that MRD is an increasingly important prognostic marker and, in some cases, a predictive marker, as well. With upfront therapy for AML, we know that achieving complete remission with MRD negativity confers a better prognosis than a less stringent remission. However, until now, we did not know that the same held true in relapsed/refractory AML. This study showed that achieving complete remission with MRD negativity leads to improved RFS for these patients.
There are many different biomarkers in AML, including molecular and cytogenetic markers, as well as cell surface markers, and investigators have looked at remission criteria in myriad ways over the years. MRD, for the purpose of this study, was assessed with flow cytometry. There are various ways to assess MRD with flow cytometry and molecular techniques. MRD is not new, nor are biomarkers, but this application of an MRD-negative remission status to patients with relapsed or refractory AML is providing new information.
We now have a prognostic biomarker in relapsed/refractory AML; however, we don’t yet know how to use this information to help our patients live longer. For example, if we knew that achieving a less stringent remission required us to give more therapy to a patient or that achieving a more stringent remission allowed us to stop treating a patient, this would certainly be practice changing.
One important question is whether we should aim to get patients into an MRD-negative remission before pursuing allogeneic transplant. If we have a patient who is a little bit short of an MRD-negative complete response, should we push harder to try to get him or her to MRD negativity before he or she undergoes transplant? I think this may be the next step in researching this topic. On the one hand, if we push for MRD negativity prior to transplant, some patients may experience overt relapse while we aim for MRD negativity; therefore, in trying to achieve MRD negativity, we may prevent some patients from ever undergoing transplant. On the other hand, by pushing for MRD negativity, we may improve results for the patients who do ultimately undergo transplant.
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