Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML

Abstract

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established, independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in remission after myeloablative conditioning (MAC; n=515) or non-MAC (n=295) who underwent multiparameter flow cytometry-based MRD testing before and 20-40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85/104 [81.7%]) than non-MAC (33/57 [57.9%]) regimen (P=0.002). Although non-MAC regimens were less likely to clear MRD, if they did the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P=0.020), RFS (P=0.002), and OS (P=0.001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared to the isolated use of pre-HCT MRD status and post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments.

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

“…Best responses were assessed after 1–2 cycles of induction chemotherapy and defined according to standard criteria [ 14 ]. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) as described, with any level of residual disease considered MRD pos [ 15 , 16 , 17 , 18 ]. Relapse after study treatment was defined by standard morphologic criteria [ 14 ] or any disease recurrence at the MRD or cytogenetic level if leading to therapeutic intervention.…”

Relative impact of residual cytogenetic abnormalities and flow cytometric measurable residual disease on outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia

“…Data from 440 of the 506 patients in the final study cohort have been partially reported. [22][23][24][25][26][27][28][29][30][31][32] The HCT-specific comorbidity index (HCT-CI) was calculated as described. 33 Related or unrelated donors were selected by high resolution HLA-typing.…”

“…2,34 Cytogenetically normal AML was considered in patients with a normal karyotype regardless of how many metaphases were available for analysis. [30][31][32]35 Since molecular data at time of diagnosis were lacking in many patients, only cytogenetic risk could be used to classify patients.…”

“…Secondary AML was defined as disease following an antecedent hematologic disorder or treatment with systemic chemotherapy and/or radiotherapy for a different disorder. [30][31][32] Treatment responses were categorized as proposed by the European LeukemiaNet 2 except that post-HCT relapse was defined as emergence >5% blasts by morphology or MFC in blood or bone marrow, emergence of cytogenetic abnormalities seen previously, or presence/emergence of any level of disease if leading to a therapeutic intervention. [30][31][32]…”

“…[22][23][24]26,28,30,36 Any measurable level of MRD was considered positive, consistent with prior analyses. [22][23][24][25][26][27][28][29][30][31][32]…”