Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia

Abstract

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n = 53, 36%) and negative pre-transplant (overall survival (OS): p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.

Fig. 1. Clinical outcomes of flow cytometry MRD for IDH1-mutated AML patients after allogeneic hematopoietic cell transplant based on pre-transplant measurable residual disease (MRD) status.

Overall survival (left) and cumulative incidence of relapse (with non-relapse mortality as competing risk; right) for patients with available flow cytometry MRD (n = 144) grouped by site-reported flow MRD positive (blue) or negative (yellow).

Fig. 2. Detection of residual variants in pretransplant blood of IDH1-mutated AML patients during complete remission.

a NGS MRD assay limit of detection for IDH1 R132 variants was determined to be 0.1% variant allele fraction (VAF) by serial dilution of two IDH1 mutations (R132C and R132H). The anticipated VAFs of IDH1 variants were plotted versus the observed ones with a value of equivalence line displayed as a dotted line and the correlations for the two types respectively. b The total number and c VAF of variants per gene as detected by targeted next-generation sequencing (NGS) during remission prior to transplant in the peripheral blood of IDH1-mutated AML patients. d A total of 51 of the 53 detected variants in IDH1 had an assay available for orthogonal validation by digital droplet PCR (ddPCR). The VAFs of IDH1 variants detected by NGS (x-axis) were plotted versus ddPCR (y-axis), with a value of equivalence line displayed as a dotted line. A significant correlation was observed in the VAF as detected by NGS compared to ddPCR with an orthogonal validation rate of 100%. The Pearson correlation coefficient is shown on the inset of the graph.

Fig. 3. Clinical outcomes of IDH1-mutated AML patients after allogeneic hematopoietic cell transplant based on pre-transplant IDH1 mutation persistence.

Overall survival (left) and Cumulative Incidence of Relapse (with non-relapse mortality as competing risk; right) in patients with IDH1-mutated AML (n = 148) based on the presence (NGS MRD IDH1pos, blue) or absence (NGS MRD IDH1neg, yellow) of detectable residual IDH1 variants in the blood pre-transplant during first complete remission.

Fig. 4. Clinical outcomes for IDH1-mutated AML patients after allogeneic hematopoietic cell transplant based on pre-transplant measurable residual disease (MRD) status stratified by co-mutated NPM1 and/or FLT3-ITD at baseline.

a Overall survival (OS; left) and cumulative incidence of relapse (CIR; with non-relapse mortality as competing risk; right) in patients with IDH1-mutated AML co-mutated with NPM1 and/or FLT3-ITD (n = 69). Patients are stratified based on the presence of residual NPM1 and/or FLT3-ITD variants regardless of residual IDH1 (red, NGS-MRD NPM1/FLT3-ITDpos); the presence of residual IDH1 variants in the absence of residual NPM1/FLT3-ITD (purple, NGS-MRD IDH1pos only); and the absence of residual IDH1, NPM1, or FLT3-ITD variants (green, NGS-MRD negative). b OS (left) and CIR (with non-relapse mortality as competing risk; right) in patients with IDH1-mutated AML without baseline NPM1 and/or FLT3-ITD variants (n = 79). Patients are stratified based on the presence (NGS MRD IDH1pos, blue) or absence (NGS MRD IDH1neg, yellow) of detectable residual IDH1 variants in the blood pre-transplant during CR1.