Paper Details

ABSTRACT

Introduction
The IWG Proposed Criteria in 2015 represented the first dedicated framework for measuring response in MDS/MPN and have since been used in dozens of clinical trials and emerged as the standard. Meanwhile, the verity of isolated marrow responses has been challenged in MDS, and iterations of updated response criteria in myeloid malignancies have introduced concepts directly applicable to MDS/MPN. Likewise, specific nuances of the 2015 MDS/MPN Criteria were difficult to apply in real world application. Therefore, the IWG undertook an effort to develop updated response criteria.

Methods
A Steering Committee (SC) of 22 experts from 8 countries used a modified Delphi process over 12 monthly meetings. A survey first identified priority areas, followed by iterative voting. Priorities achieving ≥70% SC agreement were adopted as proposed revisions. Subcommittees with expertise in molecular medicine and PROs met in parallel to inform domain-specific criteria.

Key areas of consensus and controversies
SC consensus was reached on a CR definition that retained ≤5% BM blasts, and resolution of all cytopenias and cytoses, as applicable. To address the lack of support for marrow CR, novel categories incorporating return of hematopoiesis (e.g. CR_uni/bi), were adopted from higher-risk MDS criteria (PMID: 36724453). As these response criteria are also applicable to proliferative MDS/MPN, CR with persistent myeloproliferative features (CR_MP), and CR with persistent splenomegaly (CR_S) were introduced and achieved consensus for inclusion; however, these were relegated as provisional given their uncertain prognostic value.

Given the emerging evidence of impact on OS (PMID: 41803403), cytoreductive responses measuring normalization of elevated WBC and absolute monocyte count were added as provisional responses, congruent with HI criteria that mirrored previously published responses in MDS (PMID: 30404811). Similarly included was spleen response requiring volumetric measurement and reduction of ≥35%. Symptom responses are critical to measure in modern tools testing novel drugs in MDS/MPN, and the SC endorsed MPN-SAF TSS reduction ≥50%; and/or QUALMS-P or -total improvement ≥8 points. Due to the expanded use and prognostic relevance of mutational response in related diseases such as MPNs, the SC also developed a provisional category of complete molecular response, defined as clearance of previously identified disease associated mutations. Although there was general consensus for inclusion of mutational response, debate regarding discerning driver mutations from age-related clonal hematopoiesis continues.

Defining overall response rate (ORR) generated the most iterative and complicated debate. Marrow-only responses, now removed from the criteria, are no longer part of ORR. Nonetheless, the SC recognized the value of composite responses in overlap syndromes, and elected to define ORR as any response type, highlighting the importance of measuring response types in addition to CR+PR in these inflammatory disease states.

Disease progression proved challenging to define given the range of possible dyssynchronous results (e.g. improvement in splenomegaly while blast percentage increases), and desire to remain flexible based on MOA of tested drug. Death from disease or transformation to acute myeloid leukemia (AML) with ≥50% increase in blasts were determined to be PD, but specific progression otherwise should be developed in clinical trial protocols appropriate for the drug being tested.

Conclusions
During the MDS/MPN IWG response criteria revision process, the debate among the SC revealed a strong desire to ensure simplified criteria that align across related myeloid diseases, while acknowledging the biologic complexity of MDS/MPNs requiring a spectrum of response metrics. In the discussions, it was a priority to measure and track responses outside of CR that are biologically relevant and may translate into improved patient outcomes. The revision process also highlighted the need to systematically capture provisional response for future validation and iteration, with the goal of accelerating therapeutic development in MDS/MPNs. These new criteria position the field to more rigorously evaluate novel agents in MDS/MPNs, better capture patient-relevant outcomes, and ultimately translate scientific advances into meaningful OS and QOL benefits for patients with these underserved diseases.