Allotransplants for Patients 65 Years or Older with High-Risk Acute Myeloid Leukemia

Abstract

The outcome of persons > 65 years with acute myeloid leukemia (AML) is poor. A transplant from an HLA-identical sibling or an HLA-matched unrelated donor can cure some of these patients but is associated with a substantial transplant-related mortality and a high relapse risk. We analyzed 185 subjects > 65 years with high-risk AML receiving conventional (n = 42) or reduced-intensity (n = 143) pretransplant conditioning and a transplant from an HLA-identical sibling (n = 66) or a 10/10 loci HLA-matched unrelated donor (n = 119). Two-year survival was 37%. Subjects with serious adverse events during before chemotherapy for their leukemia had a poor outcome after stem cell transplantation. Patients who had active leukemia or measurable residual disease (MRD) before transplantation had a worse outcome. Delayed hematologic recovery after induction or consolidation chemotherapy, high-risk AML genetics, donor-recipient HLA-DRβ3/4/5-DP mismatches, and history of cardiovascular disease were also correlated with survival in multivariate analyses. The 57 MRD-negative patients with few other adverse prognostic factors had an excellent outcome (2-year overall survival, 76%), whereas the 58 patients with detectable leukemia and more than 1 other additional factor fared poorly (2-year overall survival, 8%). These data indicate it is possible to identify persons > 65 years with high-risk AML likely to benefit from an allotransplant. Validation of this prediction is needed.

Keywords: Stem cell transplant; acute myeloid leukemia; elderly; minimal residual disease.

Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Two-year probability of OS and 2-year TRM and CIR in the whole cohort and according to the remission status of the patient prior to transplantation.

Panel A shows the 2-year probability of survival. Panel B and Panel C shown the 2-year TRM and 2-year CIR respectively. The 64 MRD-negative patients had superior probability of survival (Panel-D) and a lower cumulative incidence of TRM (Panel-E) and relapse (Panel-F) than the 82 patients in remission but with evidence of MRD or the 39 patients who were not in morphological remission (active leukemia) at the time of transplantation. MRD-positive patients and patients with active leukemia had very similar outcomes, namely 2-year CIR (adjusted HR= 1 vs 0.897, CI=0.424-1.899, p=0.77), TRM (adjusted HR=1 vs 1.115, CI=0.506-2.459, p=0.78) and OS (adjusted HR=1 vs 1.033, CI=0.794-1.987, p=0.76). HR were adjusted for age, degree of HLA-match, regimen conditioning intensity, HCT-CMI and leukemia genetic risk group. Vertical ticks indicate censored survival times, vertical bars indicate the 95CI.

Figure 1.. Two-year probability of OS and 2-year TRM and CIR in the whole cohort and according to the remission status of the patient prior to transplantation.

Panel A shows the 2-year probability of survival. Panel B and Panel C shown the 2-year TRM and 2-year CIR respectively. The 64 MRD-negative patients had superior probability of survival (Panel-D) and a lower cumulative incidence of TRM (Panel-E) and relapse (Panel-F) than the 82 patients in remission but with evidence of MRD or the 39 patients who were not in morphological remission (active leukemia) at the time of transplantation. MRD-positive patients and patients with active leukemia had very similar outcomes, namely 2-year CIR (adjusted HR= 1 vs 0.897, CI=0.424-1.899, p=0.77), TRM (adjusted HR=1 vs 1.115, CI=0.506-2.459, p=0.78) and OS (adjusted HR=1 vs 1.033, CI=0.794-1.987, p=0.76). HR were adjusted for age, degree of HLA-match, regimen conditioning intensity, HCT-CMI and leukemia genetic risk group. Vertical ticks indicate censored survival times, vertical bars indicate the 95CI.

Figure 1.. Two-year probability of OS and 2-year TRM and CIR in the whole cohort and according to the remission status of the patient prior to transplantation.

Panel A shows the 2-year probability of survival. Panel B and Panel C shown the 2-year TRM and 2-year CIR respectively. The 64 MRD-negative patients had superior probability of survival (Panel-D) and a lower cumulative incidence of TRM (Panel-E) and relapse (Panel-F) than the 82 patients in remission but with evidence of MRD or the 39 patients who were not in morphological remission (active leukemia) at the time of transplantation. MRD-positive patients and patients with active leukemia had very similar outcomes, namely 2-year CIR (adjusted HR= 1 vs 0.897, CI=0.424-1.899, p=0.77), TRM (adjusted HR=1 vs 1.115, CI=0.506-2.459, p=0.78) and OS (adjusted HR=1 vs 1.033, CI=0.794-1.987, p=0.76). HR were adjusted for age, degree of HLA-match, regimen conditioning intensity, HCT-CMI and leukemia genetic risk group. Vertical ticks indicate censored survival times, vertical bars indicate the 95CI.

Figure 1.. Two-year probability of OS and 2-year TRM and CIR in the whole cohort and according to the remission status of the patient prior to transplantation.

Panel A shows the 2-year probability of survival. Panel B and Panel C shown the 2-year TRM and 2-year CIR respectively. The 64 MRD-negative patients had superior probability of survival (Panel-D) and a lower cumulative incidence of TRM (Panel-E) and relapse (Panel-F) than the 82 patients in remission but with evidence of MRD or the 39 patients who were not in morphological remission (active leukemia) at the time of transplantation. MRD-positive patients and patients with active leukemia had very similar outcomes, namely 2-year CIR (adjusted HR= 1 vs 0.897, CI=0.424-1.899, p=0.77), TRM (adjusted HR=1 vs 1.115, CI=0.506-2.459, p=0.78) and OS (adjusted HR=1 vs 1.033, CI=0.794-1.987, p=0.76). HR were adjusted for age, degree of HLA-match, regimen conditioning intensity, HCT-CMI and leukemia genetic risk group. Vertical ticks indicate censored survival times, vertical bars indicate the 95CI.

Figure 2.. Adjusted HR for 2-year TRM according to HCT-CI

Forest plots show the adjusted HR for 2-year TRM according to the calculated HCT-CI (Panel A) and the individual comorbidities that constitute the score (Panel B). The numerical value of the score is calculated by adding the points assigned to each comorbidity. HRs were adjusted by age, conditioning regimen, genetic risk, MRD and remission status and the other comorbidities. Vertical bars represents the HRs, horizontal lines represent the HR CI. Panel A shows the HCT-CI categorized into 3 groups (scores 0, 1-2 and ≥3) or 7 groups (scores 0, 1, 2, 3, 4, 5 and ≥6). The HIT-CI was not a statistically significant predictor for TRM, although there was a trend toward higher TRM for patients with scores of 1-2 and ≥3. This can be explained by the fact that only seven comorbidities (arrhythmia, cardiovascular, heart valve disease, diabetes, pulmonary and moderate hepatic) were associated with an increased TRM (and only diabetes and pulmonary were statistically significant predictors), while the other comorbidities either did not have an influence on outcome or had a protective effect. Moreover when we combined the comorbidities to calculate the score, we did not find an additive effect (i.e. the TRM for patients with a score of 1 and for patients with a score ≥6 is practically identical, Panel A).

Figure 3.. Survival according to prognostic groups.

The 6 independent predictors identified in the multivariate analysis for 2-year OS (see text) were used to define three prognostic groups, low risk (n=57, 30.8%), intermediate risk (n=70, 37.8%) and high risk (n=58, 31.4%) groups. At 24 months, the probabilities for survival, according to risk group, were 76.2% (CI 63.3-85.6), 32.2% (CI 22.1-44.3%) and 7.7% (CI 3.1-17.8%) (p