TK and JPB Co-first; RK and AMZ are Co-senior authors.

Introduction

MDS are genetically heterogenous neoplasms with diverse prognoses. While hypomethylating agents (HMA) can improve outcomes, HSCT remains the only potentially curative therapy. The IPSS-M incorporates clinical and molecular features to improve outcome prediction beyond traditional risk stratification tools. The IPSS-M has been validated in studies that either variably included pts who underwent HSCT, were limited by sample size, or were single-institution analyses. We aimed to validate the performance of the IPSS-M in predicting outcomes among pts with MDS who were treated with HMAs and subsequently underwent HSCT.

Methods

The VALIDATE database includes MDS pts treated with frontline HMA from 14 specialized centers. Only pts with available molecular data pre-HMA therapy and subsequently underwent HSCT were included. Time-to-event analyses used Kaplan-Meier estimator and the log-rank test. Overall survival (OS) was measured from time of HSCT. Multivariate-adjusted survival analysis used Cox proportional hazards. We compared the different scoring scores by Harrell's c-index. This study was supported by an independent research grant from AbbVie.

Results

A total of 350 pts met eligibility ( Panel A). Median age was 63 years (IQR: 58-68). MDS with excess blasts 1/2 (66%) was the most common type. Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. The most prevalent mutations were TP53 (29%), ASXL1 (21%), RUNX1 (13%), STAG2 (12%), SRSF2 (12%), and DNMT3A (11%); 53% of pts had disease harboring >1 gene mutation. Only 44% had TP53 CN-LOH and 40% had MLL-PTD testing. The most common donor types were matched unrelated donors (MUD, 46%), haploidentical donors (21%), and matched related donors (MRD, 17%). Myeloablative, non-myeloablative, and reduced-intensity conditioning were used in 38%, 27%, and 27% of the pts, respectively. Only 14% of pts received post-HSCT maintenance therapy.

Our cohort was enriched with very high risk (41%) and high risk (30%) IPSS-R groups at time of diagnosis, while very low (1%), low (9%), and intermediate (20%) IPSS-R risk groups accounted for remaining 29% of pts. According to the IPSS-M, pts were classified into very low (2%), low (10%), moderate low (13%), moderate high (14%), high (27%) and very high (34%) risk groups. The IPSS-M re-stratified 198 (57%) pts, of whom 77 (39%) pts were up-staged and 121 (61%) pts were down-staged. More specifically, 35% and 26% of pts with intermediate risk IPSS-R MDS, and 32% and 35% of pts with high risk IPSS-R MDS were up-staged and down-staged, respectively. Importantly, 45% of pts with very high risk IPSS-R MDS were down-staged.

Median follow-up time was 20 (IQR:8-36) months (mo). The median OS for the entire cohort was 32 mo (IQR:10-Not reached [NR]). The IPSS-M groups showed significantly different OS (p-value= 0.001, Panel B)withmedian OS (mo, 95%CI) of: very low (NR, 11.5-NR), low (55, 22-NR), moderate low (48, 25-NR), moderate high (35, 22-NR), high (29, 23-NR), and very high (20, 13-28). The 5-year OS (%) were as following: very low (56%), low (47%), moderate low (37%), moderate high (40), high (43%), and very high (17%). IPSS-M risk (HR: 1.3, 95% CI:1.1-1.5) was significantly associated with OS in a multivariable model (HR, 95%CI) adjusted for age (1.01, 1.00-1.03), sex (1.2, 0.9-1.7), type of HMA used before HSCT (1.0, 0.9-1.1), number of HMA cycles (1.0, 0.9-1.05), donor type (1.0, 0.9-1.1), and conditioning regimen used (1.3, 1.1-1.5).

For OS, the IPSS-M significantly stratified pts assigned to the very high risk IPSS-R subgroup (p=0.009). However, the IPSS-M showed comparable performance to IPSS-R with c-index (95%CI): 0.597 (0.555-0.640) vs. 0.599 (0.554-0.643), respectively, for OS. When IPSS-M/IPSS-R were analyzed as continuous scores, the c-index (95%CI) for OS were: 0.606 (0.561-0.651) vs. 0.611 (0.559-0.662). When focusing on the higher risk group defined as IPSS ≥.1.5, the IPSS-M (c-index: 0.584) still had performance comparable to the IPSS-R (c-index: 0.606).

Conclusions

To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

Stahl:Kymera: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Curis Oncology: Other: GME activity ; Clinical care options: Other: GME activity ; GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Haymarket Media: Other: GME activity ; Boston Consulting: Consultancy; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Dedham group: Consultancy. DeZern:Sobi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Appellis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres:Geron: Membership on an entity's Board of Directors or advisory committees; Kurome: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Jazz: Other: Advisory Board. Carraway:Agios: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Takeda: Other; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Research Funding; Syndax: Other: DSMB; Astex Pharmaceuticals: Other; AbbVie: Other; Stemline Therapeutics: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau. Desai:Abbvie: Consultancy, Other: Advisory role; BMS: Consultancy, Other: Advisory role; Janssen Research & Development: Research Funding; Servier: Consultancy, Other: Advisory role; Janssen Pharmaceuticals: Current Employment. Griffiths:Artis Ventures: Membership on an entity's Board of Directors or advisory committees; Picnic Health: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy; CTI Biopharma: Consultancy; Astex Pharmaceuticals: Research Funding; American Society of Hematology: Honoraria; Physicians Educational Resource: Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; S. Karger Publishing: Honoraria; Takeda Oncology: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Celldex Therapeutics: Research Funding; NextCure, Inc: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; AAMDSIF: Honoraria; Abbvie: Consultancy; MDS International Foundation: Honoraria; Apellis Pharmaceuticals: Consultancy, Research Funding; MediCom Worldwide, Inc.: Honoraria; Novartis: Consultancy, Research Funding; Blueprint Medicines, Inc: Research Funding; Partner Therapeutics: Consultancy; AstraZeneca Rare Disease: Consultancy, Research Funding; Medscape: Honoraria; Vera and Joseph Dresner Foundation: Membership on an entity's Board of Directors or advisory committees. Stein:Calithera: Consultancy; Daiichi: Consultancy; Foghorn: Consultancy; Servier: Consultancy; CTI Biopharma: Consultancy; Menarini: Consultancy; Genentech: Consultancy; Genesis: Consultancy; Syndax: Consultancy; OnCusp: Consultancy; Abbvie: Consultancy; Neoleukin: Consultancy; Jazz: Consultancy; Bristol Myers Squib: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Eisai: Research Funding; Janssen: Consultancy; PinotBio: Consultancy; Aptose: Consultancy; Syros: Consultancy; Astellas: Consultancy; Ono Pharma: Consultancy; Blueprint: Consultancy. Brunner:Agios: Consultancy, Research Funding; AstraZeneca: Research Funding; Celgene/BMS: Consultancy, Research Funding; Gilead: Consultancy; Taiho: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Research Funding; Keros Therapeutics: Consultancy; Takeda: Consultancy; Acceleron: Consultancy; GSK: Research Funding. Zeidner:Merck: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Servier: Consultancy, Honoraria; Jazz: Research Funding; Shattuck Labs: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Arog: Research Funding; Astex: Research Funding; Daiichi Sankyo: Honoraria; Stemline: Research Funding; Takeda: Research Funding; Sellas: Consultancy; Novartis: Consultancy; Foghorn: Consultancy; Immunogen: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Savona:Karyopharm Therapeutics Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Research Funding; Sierra Oncology, Inc.: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; ALX Oncology: Research Funding; AbbVie Inc.: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Boehringer Ingelheim: Patents & Royalties; TG Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda Pharmaceutical Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees. Roboz:Agios: Consultancy; Actinium: Consultancy; Amgen: Consultancy; Astellas: Consultancy; AZ: Consultancy; BMS: Consultancy; Jazz: Consultancy; MEI: Consultancy; Mesoblast: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Syndax: Consultancy; Blueprint: Consultancy; Jasper: Consultancy; Bluebird bio: Consultancy; GSK: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Wang:Gilead: Consultancy; GlaxoSmithKline: Consultancy; Jazz: Consultancy; Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; PharmaEssentia: Consultancy; Takeda: Consultancy; Dava oncology: Speakers Bureau; Kura Oncology: Speakers Bureau; BMS: Consultancy; Astellas: Consultancy, Speakers Bureau; Abbvie: Consultancy. Shallis:Bristol Myers Squibb: Consultancy; Curio Science: Consultancy; Rigel: Consultancy; Servier: Consultancy; Gilead Sciences: Consultancy. Xie:Novartis: Speakers Bureau; Moffitt Cancer Center: Current Employment. Padron:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Kura: Research Funding; Incyte: Research Funding; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Gillead: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Regeneron: Consultancy, Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Omeros: Consultancy. Sallman:Aprea, Jazz: Research Funding; AbbVie, Affimed Gmbh, Gilead, Incyte, Intellisphere, LLC, Molecular Partners AG, PGEN Therapeutics, Inc., Takeda, Zentalis; Advisory board for AvenCell, BlueBird Bio, BMS, Intellia, Jasper Therapeutics, Kite, Magenta Therapeutics, NKARTA, Novartis, Orbita: Consultancy. Della Porta:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Komrokji:Geron: Consultancy; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, CTI biopharma, Jazz, Pharma Essentia, Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel, Taiho, DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Zeidan:Incyte: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Astex: Research Funding; Shattuck Labs: Research Funding; AbbVie: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria.

Figure 1
Figure 1
View largeDownload slide
2023
Sign in via your Institution