Molecular Taxonomic Features of MDS/CMML Patients Influence Response to Hypomethylating Agent Therapy and Clinical Outcomes
Authors: Molina Alfonso , Khanna Vishesh , Lu Rong , Stehr Henning , Tan Brent , Greenberg Peter L. 
Published: December 2024

The related myeloid malignancies myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) may be classified into hierarchically characterized molecular taxonomic subgroups delineated by their oncogenic mutations and other molecular features (Bernard E et al, Blood 2024, PMID:38958467, ASH 2023, 997a, reference 1). In this single-center study, we evaluated an independent group of 267 patients (212 MDS and 55 CMML) at our institution between 2018 through 2023 to determine the impact of their molecular taxonomic features on patient's clinical outcomes and responsiveness to therapy with hypomethylating agents (HMA).
Classification of patients was performed by WHO 2022 and ICC, all of whom had NGS testing: 88% performed at Stanford utilizing an internal NGS panel targeting 164 recurrently mutated genes in myeloid and lymphoid malignancies with a minimum variant allele fraction (VAF) of 2%, the remaining 12% had NGS testing done externally with similar gene coverage. The median age at diagnosis was 72 years (yr) (IQR 66-79 yr); 238 (89%) patients were primary and 29 (11%) were therapy-related; 66% were male. 20% patients transformed to AML. Median follow-up was 3.2 yr.
Patients were delineated into 18 hierarchical molecular taxonomic groups and subdivided into four previously described hierarchical clusters (per reference 1): Group1: Well-established (26%: DDX41, AML-like, TP53-complex, t(1;17), SETBP1/-7, del(5q)); Group 2: Previously reported (27%: EZH2-ASXL1, IDH-STAG2, BCOR/L1, bi-TET2); Group 3: Splice gene (22%: U2AF1, SRSF2, ZRSR2, SF3B1); and Group 4: Residual [25%: CCUS-like (DNMT3A, TET2), mNOS (other recurrent mutations), & No-event molecular groups]. Although nearly all groups were present in both MDS and CMML, increased Group 1 (31 v 2%) and taxa SF3B1 (15 v 0%) were noted in MDS and increased bi-TET2 (47 v 4%) in CMML patients, p=0.001, 0.002, 0.001, respectively,related to their known genetic propensities.
With a median of 4 (IQR 3-6) cycles of HMA-based regimens, 54% (N=144) patients were treated. Most patients (78%) received decitabine or azacitidine monotherapy, the remainder in combination with other agents. The overall response rate (ORR), based on the International Working Group 2023 criteria (CR or CR equivalent + Hematologic Improvement), was 34%, with similar findings for MDS and CMML patients: 35% & 34%, respectively. Focused evaluation of specific taxonomic subgroups demonstrated ORR in:TP53-complex 39%, SETBP1/-7 33%, IDH-STAG2 36%, bi-TET2 41%, U2AF1 50%, SF3B1 40%, CCUS-like 7%, mNOS 33%, No event 33%. The HMA responses were not associated with the patients' IPSS-M prognostic risk categories/scores, ie, the ORR varied unrelatedly for each taxa (p=0.61, Logistic regression).The medianoverall survival (OS) of the entire cohort was 3.2 yr with OS 56% & AML transformation 20% at 3 yr. For the specific taxa these features were: TP53-complex 1.1 yr & 33%, IDH-STAG2 2.4 yr & 42%, BCOR 2.8 yr & 38%, SRSF2 2.8 yr & 33%, SETBP1/-7 2.9 yr & 8%, bi-TET2 3.9 yr & 20%, U2AF1 3.9 yr & 11%, SF3B1 3.7 yr & 0, CCUS-like 2.8 yr & 20%, mNOS 4.1 yr & 17%, No event 3.4 yr & 13%. In contrast to ORR, these two clinical outcome features for the specific taxa were both related to the patient's IPSS-M categorization (p ≤0.001 & ≤0.001, Cox regression, respectively).
These data indicate that despite OS and PFS of MDS/CMML patients being related to both their molecular taxonomic subgroups and IPSS-M classification, there is not a significant association between patients' HMA responses and their IPSS-M classification, albeit findings being limited by small taxa sample sizes. These features provide data supporting the potential for focusing on specific molecular subgroups of MDS and CMML patients for more precise therapeutic targeting of HMAs.