Sequential monitoring of MRD via sensitive phenotyping (e.g., multicolor flow cytometry [MFC]) or molecular methods (e.g., quantitative PCR [qPCR], digital droplet PCR [ddPCR], deep error-corrected next-generation sequencing [NGS]) to detect AML associated immunophenotypes or mutations respectively, at a sensitivity of at least 1 × 10−3, is applicable to the vast majority of AML and provides a useful guide to post-remission AML management. Indeed, MRD negativity is emerging as an alternative therapeutic endpoint that supplements (and may replace) morphologic AML remission criteria.
As reviewed by Dohner et al., mutational assessment at early post remission time points can distinguish patients at a differing probability of relapse. As they highlight, MRD status has been found to be a better predictor of relapse risk than the presence of cooperating mutations involving KIT and FLT3-ITD in CBF-AML, or FLT3-ITD, DNMT3A, and WT1 in NPM1-mutated AML. Sequential MRD-monitoring studies have shown that persistent high-level PCR positivity, or a rising level of leukemic transcripts after an initial molecular response, invariably predict relapse. Validated AML-associated mutations for MRD monitoring include RUNX1-RUNX1T1, CBFB-MYH11, and PML-RARA translocations (KMT2A and DEK-NUP214 translocations are also AML-associated). Other likely prognostic MRD mutations include NPM1, RAS pathway mutations (FLT3-ITD and -TKD), N- and K-RAS, PTPN11 or KIT, whose persistence in CR indicates a likely higher risk of relapse. However, in the non-transplant context, the persistence of AML-associated mutations needs to be distinguished from the persistence of underlying clonal-hematopoiesis (CH) or MDS-associated mutations (e.g., DTA: DNMT3A, TET2, ASXL1). Future studies will help further distinguish mutations that are reliable indicators of leukemic clones associated with AML relapse versus mutations associated with preleukemic clones that are poorly predictive of relapse, despite persistence at high levels after chemotherapy and during remission. Whether MRD-based early interventions can prevent overt relapse remains under investigation. Preemptive therapy may be particularly relevant with allogeneic HSCT where MRD status may inform conditioning strategy, or post-hematopoietic cell transplantation (HCT) measures aiming to avoid frank relapse. These data support routine inclusion of MRD assessment to help inform transplant decision making in AML-CR1.
Patients with persistent MRD or with early MRD reoccurrence can receive salvage therapy as a bridge to allogeneic HSCT before hematologic relapse or proceed directly to transplant depending on donor availability and the likelihood of success with salvage therapy. The GIMEMA AML1310 study undertook risk-adapted treatment assignment of young adults with newly diagnosed intermediate-risk AML to allogeneic HSCT based on MFC-based MRD assessments, reporting promising 2-year disease-free survival and overall survival of 67% and 70% respectively for MRD+ intermediate-risk AML patients assigned allogeneic HSCT. Importantly, their finding of similar survival of MRD+ intermediate-risk AML patients (assigned allogeneic HSCT) versus those who were MRD− (assigned autologous HSCT) suggests that allotransplantation may ameliorate the negative impact of persistent MRD, although other studies suggest it does not fully abrogate the negative effect of unfavorable pre-trans plant MRD. For instance, in NPM1-mutant AML, high-level MRD for NPM1, or low-level MRD for NPM1 plus presence of FLT3-ITD, had impaired post-transplant survival. More intensive conditioning may offer therapeutic benefit for patients with persistent MRD pre transplant. Deep error-corrected 13-gene NGS-based reanalysis of the BMTCTN 0901 study randomizing older AML patients to MAC versus RIC documented relapse protection and survival benefit for pre-transplant MRD+ patients assigned MAC HSCT.28 Importantly, the benefit was restricted to those with persistent AML-associated mutations, but not for those with CH-associated (DNMT3A, TET2, ASXL1) mutations pre-transplant. These findings need to be vali dated prior to incorporation in routine clinical practice.
In the post-transplant context, persistent or recurrent recipient MRD positivity is also associated with an increased risk of AML relapse. However, many uncertainties remain, for instance with regards to MRD assessment modalities, thresholds, assessment frequency and timepoints, and the prognostic implications of recurrence or persistence of specific mutations and their recrudescence patterns. Importantly, for post-transplantation testing, detection of either AML- or CH-associated mutations would be concerning for recrudescent donor hematopoiesis and disease. However, therapeutic interventions based on the post-transplant assessment of MRD, ranging from immune suppression (IS) taper, donor lymphocyte infusion (DLI) and modified DLI (mDLI), hypomethylating agents (HMAs), and AML mutation-specific targeted therapies (e.g., FLT3 inhibitors) may offer utility and are currently undergoing prospective evaluation.
