Pre- and post-transplant quantification of measurable ('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia

Abstract

Measurable ('minimal') residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas two patients developed new evidence of disease. The 214 MRD(neg)/MRD(neg) patients had excellent outcomes, whereas both MRD(neg)/MRD(pos) patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was only observed among the 58 patients with decreasing but not the seven patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with overall survival and risk of relapse. These data indicate that MRD(pos) patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.

Figure 1. Association between pre-transplant disease status and outcome for 279 AML patients undergoing myeloablative HCT while in morphologic remission

Estimates of (A) overall survival, (B) relapse-free survival, (C) cumulative risk of relapse, and (D) cumulative risk of non-relapse mortality following myeloablative allogeneic HCT for adults with AML who underwent bone marrow assessments with MFC before as well as on day +28 (± 7 days) after transplantation. Outcome estimates are shown individually for patients in MRD^neg remission 1 (n=167), MRD^neg remission 2 (n=49), MRD^pos remission 1 (n=43), and MRD^pos remission 2 (n=20) at the time of transplantation, respectively.

Figure 2. Association between pre-HCT or post-HCT MRD status and outcome following myeloablative HCT

Kaplan-Meier estimates of (A) overall survival (OS) and relapse-free survival (RFS) as well as (B) cumulative incidences of relapse and non-relapse mortality (NRM), shown individually for patients with (n=63) or without (n=216) MFC-evidence of MRD in the pre-HCT bone marrow examination. Kaplan-Meier estimates of (C) OS and RFS as well as (D) cumulative incidences of relapse and NRM, shown individually for patients with (n=16) or without (n=263) MFC-evidence of MRD on day +28 (± 7 days) after transplantation.

Figure 3. Association between peri-HCT MRD dynamics and outcome for AML patients following myeloablative HCT, stratified by positive/negative MRD status

Kaplan-Meier estimates of (A) overall survival and (B) relapse-free survival as well as cumulative incidences of (C) relapse, and (D) non-relapse mortality following myeloablative allogeneic HCT for adults with AML, shown individually for patients with MRD^neg/MRD^neg (n=214), MRD^neg/MRD^pos (n=2), MRD^pos/MRD^neg (n=49) and MRD^pos/MRD^pos (n=14) disease status in the pre/post-HCT bone marrow assessment.

Figure 4. Association between peri-HCT MRD dynamics and outcome for AML patients following myeloablative HCT, stratified by increasing/decreasing MRD levels

Kaplan-Meier estimates of (A) overall survival and (B) relapse-free survival as well as cumulative incidences of (C) relapse, and (D) non-relapse mortality following myeloablative allogeneic HCT for adults with AML, shown individually for patients with MRD^neg/MRD^neg (n=214), MRD^decr (n=58), and MRD^incr (n=7) disease status in the pre/post-HCT bone marrow assessment.