Validation of International Working Group (IWG) Response Criteria in Higher-Risk Myelodysplastic Syndromes (MDS): A Report on Behalf of the MDS Clinical Research Consortium (MDS CRC)
Authors: Komrokji Rami S. , DeZern Amy E. , Zell Katrina , Al Ali Najla H. , Estling Christopher , Zimmerman Cassie , Hand Wesley , Brown Francis , Rizzo Nicole , Barnard John , Roboz Gail J , Garcia-Manero Guillermo , Steensma David P. , Sekeres Mikkael A. 
Published: October 2019

Introduction
The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival (OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These criteria were originally proposed by an international group of experts based on available data and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG criteria, pts who achieved hematological improvement (HI), complete response (CR), marrow CR (mCR), or partial response (PR) demonstrated improved OS. The aim of this study is to validate the IWG 2006 response criteria among a large cohort of higher-risk MDS pts.
Methods
Pts with higher-risk MDS (intermediate-2 (Int-2) or High Risk by International Prognostic Scoring System (IPSS)) who had received treatment and for whom details of response and outcome were available were included from the MDS CRC database. Pts were also classified per IPSS-R. The best response to treatment was categorized per the published IWG 2006 response criteria as CR, PR, mCR, HI, stable disease (SD) or progressive disease (PD). The primary endpoint was OS.
Results
We identified 646 treated higher-risk MDS pts. Table-1 summarizes baseline characteristics. The first line treatment was hypomethylating agent-based therapy (HMA) in 470 pts (74%). The median duration of follow up was 23.2 months (mo) (95% CI: (19.9, 26.5). Median OS from diagnosis was significantly longer for pts with int-2 IPSS risk disease IPSS (26.2 mo (21.5, 29.7)) compared to those who were High Risk (18.8 mo (15.9, 23.6); (p = 0.026). Median OS from diagnosis also differed by IPSS-R category (p < 0.001): for pts with Low risk (n = 6) it was not reached; Intermediate risk it was 41.7 mo (31.8, NR); High Risk it was 28.4 mo (24.1, 33.2); and for pts with Very High it was 16.5 mo (15.3, 19.1).
The best IWG 2006 response rate for first line therapy among evaluable pts (n=597) was CR in 93 pts (16%), mCR in 10 (2%), PR in 57(10%), HI in 60 (10%), SD in 233 (39%), and PD in 144 (24%).
The median OS based on IWG 2006 best response for first line therapy was 41 mo for CR, 12 mo for mCR, 26 mo for PR, 13 mo for HI, 14 mo for SD and 7 mo for PD. (p <0.001). CR was associated with better outcome compared to all other response groups. Pts with PR, HI, and SD had better outcome compared to PD, and similar outcome among the 3 groups. There was no difference in rate of AML transformation among response groups except in PD pts compared to others.
For pts who were treated with HMA as first line therapy, the best response rates by IWG 2006 criteria were CR in 15%, mCR in 2%, PR in 10%, HI in 12%, SD in 40% and PD in 21%. Median OS in mo from time of HMA therapy based on response was: CR 19 (16.3, NR), mCR: 9 (7.1, NR), PR: 13 (8.8, NR), HI: 11 (7.7, 19.0), SD: 11.0 (8.5, 12.6), and PD: 3 (2.3, 3.9). (p <0.001)
The best response by IWG 2006 criteria remained predictive of OS after adjusting for IPSS-R risk group. HR 0.30 (95% CI 0.2-0.4) for CR, and 0.57 (95% CI 0.45-0.7) for mCR/PR/HI compared to PD, (p <0.001)
Conclusions:
The best response by IWG 2006 criteria to first line therapy in higher-risk MDS correlates with OS. Pts who achieved CR had the best OS, while pts who achieved SD or better response had improved outcome compared to PD, with mCR having an OS equivalent to SD. The CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts in randomized Phase II studies determining comparison arms of Phase III trials, and for regulatory purposes.
Table 1. Baseline characteristics Variable Total n=646 Age Median 68 Gender Male 399/645(62%) Race White 566/633 (89%) t-MDS Yes 161/545/514 (30%) WHO RA RARS RCMD RAEB-I RAEB-II MDS-U MDS/MPN CMML 5/527 (1%) 7/527 (1%) 69/527 (13%) 1153/527 (29%) 284/527 (54%) 3/527 (1%) 5/527 (1%) 1/527 (1%) IPSS Intermediate-II High 468/646 (72%) 178/646 (28%) R-IPSS Very low Low Intermediate High Very High 0 6/621 (1%) 74/621 (12%) 211/621 (34%) 330/621 (53%) IPSS karyotype Good Intermediate Poor 135/642 (21%) 118/642 (18%) 389 /642 (61%) IPSS-R karyotype Very good Good Intermediate Poor Very poor 7/642 (1%) 137/642 (21%) 134/642 (21%) 118/642 (18%) 246/642 (38%) Allogeneic transplant Yes 158/554 (29%) First line therapy HMA Chemotherapy IMiDClinical trial other 470/634 (74%) 57/634 (9%) 43/634 (7%) 25/634 (4%) 38/634 (6%) Lab (mean) Hgb (n=514) Platelets (n=514) ANC (n=514) Bone marrow blasts (n=639) 9.2 94 1.6 10%

Disclosures
Komrokji: Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy; Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.