Patients with AML and an IDH2-R172 Mutation Exhibit a Unique Response to Intensive Induction Chemotherapy, Suggesting Futility of Mid-Cycle Bone Marrow Biopsy and Caution When Considering Re-Induction

Background:

The utility of a mid-cycle bone marrow (BM) biopsy for early assessment of response in patients with acute myeloid leukemia (AML) after intensive chemotherapy (IC) induction has long been contested. Currently, many treatment algorithms, including National Comprehensive Cancer Network (NCCN) guidelines, suggest re-induction if mid-cycle BM (day 14-21) is not hypoplastic (defined as < 5% blasts and cellularity <20%). Even when this practice is challenged, there is little consideration as to the possibility of different response dynamics among different cytogenetic or molecular subgroups.

Mutations in isocitrate dehydrogenase 2 (IDH2) are found in up to 10% of patients with AML, 20% of these occur in the R172 residue (R172-m), and most of the others are in the R140 residue (R140-m). Clinical observations led to the hypothesis that patients with R172-m exhibit particularly slow blast reduction dynamics following induction with IC.

Objective:

The purpose of this study was to analyze response kinetics of patients with R172-m after IC induction, compared to a control group of patients with R140-m.

Methods:

A retrospective single center analysis was conducted among newly diagnosed patients with IDH2-mutated AML who received IC induction from 03/2012 to 12/2023 at Memorial Sloan Kettering Cancer Center. Dynamics of blast reduction were compared between the two groups and correlated with outcome measures. Statistical analysis was performed in R. Continuous variables were compared using Welch’s t-test. Kaplan Meier curves were constructed to estimate time to blast clearance (defined as days from induction to first BM with ≤ 5% blasts, censored at time of second treatment or death). Association with mutation type was assessed by a log-rank test. Associations with efficacy endpoints used Fisher’s exact and log-rank tests.

Results:

52 patients were identified, 33 with R140-m and 19 with R172-m. Among the R140-m, 58% had hypoplastic mid-cycle BM biopsies (defined as BM with ≤ 5% blasts and cellularity <20%), comparable to rates of 47%-69% reported in the general AML population (Terry et al., Am J Hematol., 2017). Strikingly, none of the patients with R172-m had hypoplastic mid-cycle BMs. Median mid-cycle blast count was 5% among the R140-m (range 0%-81%) compared to 70% among patients with R172-m (range 25%-87%; p<0.001). Mid-cycle BMs were significantly more cellular in the R172-m group compared to R140-m (p=0.045).

Among the R172-m, 8 patients did not receive re-induction. Of these, half exhibited a pattern of delayed achievement of complete response (CR), defined as CR after day 40, with evidence of gradual blast reduction (CR on days 42,43,45 and 53 from single induction with no additional therapy). Of the 24 patients with R140-m who received single induction, there was one case of delayed CR (on day 42). Overall, it took significantly longer for patients with R172-m to achieve blast clearance after single induction, compared to those with R140-m (median days to blast clearance 44 versus 24; p=0.017).

However, there was no significant difference in overall survival between the two groups, and outcomes were similar, with 90% and 89% ultimately achieving CR. Seventy nine percent of patients with R172-m achieved CR after 1 or 2 cycles of treatment, versus 85% among those with R140-m. A total of 79% of patients with R172-m underwent allogeneic stem cell transplant, and 68% achieved long term CR (defined as CR for more than a year), versus 61% and 54% respectively, among patients with R140-m.

Conclusions:

These data suggest a unique and yet undescribed response pattern to IC in patients with AML and R172-m. Firstly, mid-cycle BM biopsy results do not appear to be predictive of response in these patients. Moreover, blast reduction is slower than that observed among the control group of patients with R140-m, despite comparable (and favorable) outcomes. Future studies should corroborate these findings, as well as investigate the role of the particularly elevated 2-hydroxyglutarate levels reported among patients with R172-m, in the mediation of response dynamics. Taken together, these findings question the utility of conducting mid-cycle BM biopsies in patients with R172-mutated AML. Furthermore, awareness of the possibility for slower-than-expected achievement of CR in these patients can potentially minimize additional cycles of chemotherapy.