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Preprint WatchMildSeptember 9th, 2026

Genetic predictors of clonal contraction and hematologic response in IDH mutant myeloid malignancies

Song, A.; Chen, Y.; Iyer, S.; Fernando, S.; Sudunagunta, V. S.; Stewart, E.; Deng, R.; Scoca, V.; Xu, J. J.; May, B.; Varabyeva, A.; Hsiao, S. J.; Freeman, C.; Mansukhani, M.; Lipsky, A. H.; Lamanna, N.; Rosenblat, T. L.; Kasbekar, M.; Jurcic, J. G.; Chernak, B.; Viny, A. D.

Reports that ivosidenib-treated patients achieving composite complete hematologic response showed significant IDH1 variant allele frequency reduction, absent under enasidenib, and that RUNX1 and BCOR co-mutations were enriched among incomplete responders and independently associated with shorter treatment duration.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The mechanistic claim is that IDH1 inhibition produces measurable clonal contraction in responders and that RUNX1 and BCOR co-mutations mark patients who will not get there. The Claidex record carries one IDH1 entry, olutasidenib-idh1-cmml-mds-mpn-mdacc-pi-withdrawal, which was withdrawn on a sponsor and investigator decision rather than on any readout of IDH1 biology, so the empirical burden on this target is light. The flag is raised because the preprint supplies exactly the kind of enrichment variable that the withdrawn programme did not have. A next IDH1 study in these overlapping myeloid indications now has a stated, testable stratification hypothesis available at design time. The severity is MILD, reflecting a single non-efficacy failure on file.

Abstract excerpt

IDH inhibitors promote differentiation and hematological improvement in myeloid malignancies by reversing epigenetic dysregulation. However, molecular predictors of response remain poorly defined. We retrospectively analyzed 79 patients with IDH mutated myeloid malignancies treated with either ivosidenib (IDH1; n=36) or enasidenib (IDH2; n=43). Hematologic benefit was assessed using a composite complete hematologic response (CHR), defined by neutrophil and platelet recovery, and transfusion independence. Targeted sequencing was performed at baseline and at best hematologic response. Associations between co mutations, hematologic response, and treatment duration were evaluated using multivariable models. Overall, 43% of patients achieved CHR, with similar rates between inhibitors. Ivosidenib treated patients achieving CHR demonstrated a significant reduction in IDH1 VAF (p=0.010), which was not observed in enasidenib-treated CHR patients. Within the CHR cohort, ivosidenib patients had a greater reduction in IDH VAF relative to enasidenib patients (mean VAF change -16.74% vs -0.05%, p=0.034). Ivosidenib responders demonstrated a trend toward more durable treatment duration compared with enasidenib responders (p = 0.0908). RUNX1 and BCOR mutations were significantly enriched among patients with incomplete hematologic response and were independently associated with shorter treatment duration after adjustment for clinical factors (RUNX1: HR 2.53, p=0.0024; BCOR: HR 2.31, p=0.0058). IDH1 inhibition was associated with clonal contraction and durable hematologic benefit, a pattern not observed with IDH2 inhibition. Co mutations in RUNX1 and BCOR identified patients unlikely to achieve sustained hematologic improvement, suggesting a secondary block to differentiation. These findings support the integration of mutational and molecular profiling to refine patient selection and guide combinatorial strategies in IDH mutated myeloid malignancies.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.