Abstract
Introduction
The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed using datasets from patients (pts) with untreated MDS. The cytogenetic risk groups used in IPSS-R were expanded to 5 groups from the 3 used in IPSS. Among the new groups introduced in IPSS-R is the “very complex” karyotype (VCK) where ≥4 karyotypic abnormalities are seen compared to “complex karyotype (CK)” with only 3 abnormalities. However, the prognostic impact of VCK vs CK, as well as individual cytogenetic abnormalities and TP53 mutation (TP53mut) status within the CK and VCK subgroups in pts with MDS treated with hypomethylating agents (HMAs) has not been well studied. Hence, we analyzed these questions in a large cohort of HMA-treated MDS pts in the icMDS VALIDATE database.
Methods
The icMDS VALIDATE database contains MDS pts treated with frontline HMA monotherapy or HMA-based combinations from 22 specialized international centers. Pts with unknown HMA type, date of HMA initiation, missing age, missing sex, missing cytogenetic data, bone marrow or peripheral blood blasts ≥20%, or missing survival status were excluded. We performed time-to-event analyses using the Kaplan-Meier method and compared groups by the log-rank test. We measured overall survival (OS) from time of HMA initiation. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from Abbvie.
Results
A total of 1940 pts were included. Median age was 70 (range: 18-99) years and 66% were men. According to IPSS-R cytogenetic risk groups, 1.9% (37) were very good, 43.4% (841) good, 15.5% (301) intermediate, 11.6% (226) poor, and 27.6% (535) very poor. By HMA type, 71% of pts were treated with azacitidine, 14% with decitabine, 6% with HMA and venetoclax, and 9% with another HMA combination. Approximately 28% of pts underwent allogeneic hematopoietic stem cell transplant (alloHSCT). The IPSS-R cytogenetic risk groups had different OS (p<0.001)with median OS (mOS; months [mo], 95% CI) as follows: very good (43.4, 34.7-72.5), good (41.7, 36.4-46.8), intermediate (24.5, 23.1-32.4), poor (24.2, 19.2-28.5), and very poor (13.6, 12.5-14.5). The difference remained significant (p=0.001) after censoring at time of alloHSCT with mOS as follows: very good (40.4, 23.2-64.3), good (24.3, 22.2-26.3), intermediate (19.3, 15.1-22.2), poor (12.2, 10.3-14.8), and very poor (9.1, 8.2-19.7). Interestingly, the difference between mOS for intermediate and poor risk cytogenetics became more apparent after censoring at time of alloHSCT.
Next, we compared the outcomes of pts with CK and VCK to non-complex karyotype (NCK) MDS. The mOS for pts with VCK MDS (13.6 mo, 12.5-14.5) was worse compared to pts with CK (19.9 mo, 19.9-16.8; p=0.004) and NCK (36.1 mo, 32.7-37.8; p<0.001) MDS. Among the 1458 pts with available molecular data, more pts with VCK (75%, 330) MDS had a concurrent TP53mut compared to pts with CK (40%, 21; p<0.001) and NCK (7%, 64 p<0.001) MDS. Considering only patients with TP53mut MDS, mOS for pts with VCK (12.2, 11.1-13.9) was worse compared with NCK (24.2, 16-1-53.1; p<0.001) but not with CK (19.9, 9.5-NR; p=0.9); the difference between CK and NCK was not significant (p=0.16). Among pts with TP53 wildtype (TP53WT) MDS, VCK (15.0, 13.2-18.2) had a similar mOS to TP53WT CK (18.8, 12.6-41.1; p=0.19) while both groups had worse mOS compared to TP53WT NCK (33.4, 30.1-37.0) (p=0.01). In a survival analysis of 616 pts with MDS with ≥3 cytogenetic abnormalities, -17/del(17p) (12.8 mo; p=0.009), inv(3)/t(3q)/del(3q) (10.9 mo; p=0.006), and del(7q) (12.1mo; p=0.024), though not -7 (12.6mo; p=0.23), were associated with lower mOS compared to the pts with MDS without these abnormalities (14.3mo).
Conclusions
Using one of the largest databases of HMA-treated MDS pts, we show that IPSS-R cytogenetic risk categories associate with significantly different survivals among HMA-treated MDS pts, even after censoring at time of alloHSCT. Importantly, VCK MDS was associated with worse mOS compared to CK and NCK MDS but not in pts with a concurrent TP53mut. Among pts with MDS with ≥3 chromosomal abnormalities, having -17/del(17p), inv(3)/t(3q)/del(3q), or del(7q) was associated with worse survival.
Stempel:Sobi: Other: Advisory Board Participation. DeZern:Appellis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Keros: Membership on an entity's Board of Directors or advisory committees; servier: Membership on an entity's Board of Directors or advisory committees; geron: Other: dsmb; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibbs: Membership on an entity's Board of Directors or advisory committees. Sekeres:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Schroedinger: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees. Desai:Rigel: Consultancy; Servier: Consultancy; BMS: Consultancy, Other: Research Support; Kura Oncology: Consultancy, Other: Research Support; Janssen: Other: Research Support. Griffiths:Servier: Consultancy; Abbvie: Consultancy; MJH Health: Honoraria; ASH: Honoraria; MDS International Foundation: Honoraria; Apellis Pharmaceuticals: Consultancy, Research Funding; CTI Biopharma: Consultancy; Novartis: Consultancy, Research Funding; Partner Therapeutics: Consultancy; MediCom Worldwide: Honoraria; MedscapeLive: Honoraria; AAMDS: Honoraria; Picnic Health: Consultancy; Alexion Pharmaceuticals/ AstraZeneca Rare Disease: Consultancy, Research Funding; Physicians Educational Resource: Honoraria; Astex Pharmaceuticals/Taiho Oncology/Otsuka: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Oncology: Consultancy; Blueprint Medicines: Research Funding; Celldex Pharmaceuticals: Research Funding; Genentech: Consultancy, Research Funding; NextCure: Research Funding. Stein:Agios Pharmaceuticals: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Genentech: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees. Brunner:i-Mab Biopharma: Consultancy; Keros Therapeutics: Consultancy; Lava Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; Geron: Consultancy; AstraZeneca: Research Funding; Servier: Consultancy; BMS: Consultancy, Research Funding; Agios: Consultancy. McMahon:Syros Pharmaceuticals: Research Funding; Syndax Pharmaceuticals, Inc.: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Shallis:Servier: Consultancy, Honoraria, Other: Steering Commitee; Rigel: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria; Gilead Sciences, Inc: Consultancy, Honoraria. Savona:Astex Pharmaceuticals for travel grant.: Other: Financial or Material Support; AbbVie; Bristol Myers Squibb; CTI BioPharma Corp.; Geron; Karyopharm; Novartis Pharmaceuticals Corporation; Ryvu Therapeutics; and Sierra Oncology, Inc.: Consultancy; Empath Biosciences; Karyopharm and Ryvu Therapeutics: Current holder of stock options in a privately-held company; ALX Oncology Inc.; Astex Pharmaceuticals; Incyte Corporation; and Takeda Pharmaceutical Company Limited.: Research Funding. Roboz:Janssen: Research Funding; OncoPrecision: Current holder of stock options in a privately-held company, Honoraria; Novartis, Pfizer, Roche, GlaxoSmithKline, BMS, Syndax, Rigel: Consultancy; AbbVie, Amgen, Astrazeneca, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses pharma, Geron, GSK, Glycomimetics, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Oncoverity: Consultancy. Wang:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Speakers Bureau; Qiagen: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or adviso