The prognostic significance (or lack) of achieving marrow complete remission (mCR) with hypomethylating agent-based therapy in patients with myelodysplastic syndrome
Abstract
Abstract Introduction: Marrow complete remission (mCR) in 2006 IWG criteria for MDS (Cheson B et al, Blood 2006) reflects achieving bone marrow (BM) blast percentage below 5% but is frequently not associated with meaningful count recovery. While mCR + hematologic improvement (HI) does reflect wide ranges of count improvement or transfusion reductions, HI is difficult to measure accurately in routine clinical practice. The 2023 International Working Group (IWG) response criteria (Zeidan A et al, Blood 2023) eliminated the mCR category without meaningful count recovery and reclassified mCR associated with meaningful count recovery into specific “less-than-CR” categories. Still, many clinical trials continue to use mCR as a secondary efficacy endpoint or as a part of overall response rate (ORR). Within the icMDS VALIDATE database, we assessed the association of mCR with OS in hypomethylating agent (HMA)-treated higher risk (HR)-MDS patients among both (1) transplanted and (2) non-transplanted patients. Methods We included patients with HR-MDS (defined as IPSS ≥1.5 and/or IPSS-R >3.5) who received HMA-based therapies from the international icMDS VALIDATE dataset. We evaluated the best response by IWG 2006 criteria into CR, mCR, or no CR/mCR. We then reclassified patients with mCR per IWG 2023 criteria into either (A) having achieved a composite CR (cCR) defined as CR + CR equivalent (CRequ) + CR with bilineage count recovery (CRbi) + CR with unilineage count recovery (CRuni) + CR with partial hematologic recovery (CRh) or (B) not having achieved cCR (no cCR). OS was calculated from time of HMA initiation to date of death or last follow-up by using 6-month landmark analyses. We used Kaplan-Meier methods to estimate OS, and the Log-rank test to compare OS. VALIDATE is supported by an independent grant from AbbVie. Results A total of1049 patients met eligibility.Median age of patients was 69 (range 21-95), 64% were men. While 61% received azacitidine, 17% received decitabine, and 22% received HMA-based combination therapy. In total, 37% underwent subsequent allogenic stem cell transplantation (allo-HCT). Based on IWG 2006 criteria, 17%, 33%, and 50% achieved CR, mCR, and no CR/mCR as their best response, respectively. Patients achieving CR had superior median OS (25 months, 95% CI: 21-34 months) compared to those with mCR (16 months, 95% CI: 13-18 months; p=0.038) and no CR/mCR (15 months, 95% CI: 12-17 months; p=0.001). In patients who received a subsequent allo-HCT, the median OS for patients with mCR (30 months, 95% CI: 21-54 months; 1 year OS: 71%, 2 year OS: 55%) did not significantly differ compared to patients with CR (59 months, 95% CI: 25 months-not reached, p=0.80; 1 year OS: 73%, 2 year OS 62%) and patients with no CR/mCR (32 months, 95% CI: 21-45 months, p=0.46; 1 year OS: 69%, 2 year OS 54%). In contrast, in patients treated with HMA therapy alone without subsequent allo-HCT, median OS for patients with mCR (11 months, 95% CI: 9-15 months; 1 year OS: 46%, 2 year OS: 23%) did not significantly differ compared to patients with no CR/mCR (11 months, 95% CI: 9-14 months, p=0.85; 1 year OS: 47%, 2 year OS: 22%) but was significantly shorter compared to patients with CR (20 months, 95% CI: 17-28 months, p<0.001; 1 year OS: 69%, 2 year OS: 46%). Patients with mCR by IWG 2006 (N=347) were reclassified per IWG 2023 into having either achieved a cCR (N=219, 63%) or no cCR (N=128, 37%). Specifically, patients with mCR were reclassified per IWG 2023 into CR (4.9%), CRequ (0.6%), CRbi (26.8%), CRuni (29.4%), CRh (1.4%), PR (0%), HI (10%), no response (21.9%) and PD (4.9%). Patients with mCR who were reclassified into cCR had an improved median OS (16 months, 95% CI: 15-26 months; 1 year OS: 62%; 2 year OS: 43%) compared to patients reclassified into no cCR per IWG 2023 (13 months, 95% CI: 11-17 months, p=0.023; 1 year OS: 52%; 2 year OS: 31%). Conclusions Using the large icMDS VALIDATE dataset, we found that achievement of mCR by 2006 IWG criteria was not associated with improved OS compared to patients who did not achieve CR/mCR. Reclassification of mCR using IWG 2023 highlights the heterogeneity within the mCR group and suggests that IWG 2023 criteria stratifies outcomes in patients previously labeled as mCR by IWG 2006. IWG 2023 should be the standard used for ORR assessment in all future clinical trials involving patients with HR-MDS.
Article Details
Authors (57)
Benjamin Rolles
1Brigham and Women's Hospital, Harvard Medical School, Division of Hematology, Department of Medicine, Boston, United States
Jan Philipp Bewersdorf
Tariq Kewan
1Cleveland Clinic, Department of Translational Hematology and Oncology Research, Cleveland, United States
Ondrej Blaha
5Yale University, School of Public Health, Yale Center for Analytical Sciences, New Haven, United States
Jessica Stempel
5Yale University, School of Public Health, Yale Center for Analytical Sciences, New Haven, United States
Luca Lanino
3Yale University, New Haven, United States
Najla Al Ali
9Moffitt Cancer Center, Department of Malignant Hematology, Tampa, United States
Amy DeZern
1Johns Hopkins University School of Medicine, Oncology, Baltimore, United States
Mikkael Sekeres
13Sylvester Cancer Center, University of Miami Health System, Miami, United States
Geoffrey Uy
18Washington University School of Medicine, Saint Louis, United States
Samuel Urrutia
10Washington University School of Medicine, Saint Louis, United States
Hetty Carraway
1Cleveland Clinic, Internal Medicine, Cleveland, United States
Pinkal Desai
Elizabeth Griffiths
8Roswell Park Comprehensive Cancer Center, Buffalo, United States
Eytan Stein
3Memorial Sloan Kettering Cancer Center, Medicine, New York, United States
Andrew Brunner
3Dana-Farber Cancer Institute, Boston, United States
Christine McMahon
2University of Colorado School of Medicine, Division of Hematology, Aurora, United States
Rory Shallis
1H. Lee Moffitt Cancer Center, Tampa, United States
Joshua Zeidner
5University of North Carolina, Chapel Hill, United States
Michael Savona
7Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, United States
Namrata Chandhok
9Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, United States
Constantine Logothetis
10Washington University School of Medicine, Saint Louis, United States
Aram Bidikian
3Yale University, Department of Internal Medicine, Section of Hematology, New Haven, United States
Theodore Getz
3Yale University, Department of Internal Medicine, Section of Hematology, New Haven, United States
Gail Roboz
3Weill Cornell Medicine and The New York Presbyterian Hospital, New York, United States
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
Maria Amaya
2University of Colorado School of Medicine, Division of Hematology, Aurora, United States
Hayley Hawkins
17Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States
Somedeb Ball
2Vanderbilt University School of Medicine, Division of Hematology and Oncology, Nashville, United States
Justin Grenet
12Weill Cornell Medicine, New York City, United States
Zhuoer Xie
Moffitt Cancer Center, Tampa, Florida, United States
Yazan Madanat
Yasmin Abaza
19Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Division of Hematology and Oncology, Leukemia Program, Chicago, United States
Talha Badar
Mayo Clinic, Jacksonville, Florida, United States
Jaclynn Campos
20Mayo Clinic, Division of Hematology-Oncology, Jacksonville, United States
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Jaroslaw Maciejewski
1Department of Translational Hematology and Oncology Research, Cleveland, United States
David Sallman
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Anoop Enjeti
22Calvary Mater Hospital, Australia and Australasian Leukaemia and LymphomaGroup (ALLG), Department of Haematology, Newcastle, Australia
Kamal Alrabi
23King Hussein Cancer Center, Amman, Jordan
Khalid Halahleh
10Department of Internal Medicine, Adult BMT Program, King Hussein Cancer Center, Amman, Jordan
Devendra Hiwase
24The Royal Adelaide Hospital, Department of Haematology, Adelaide, Australia
Maria Diez-Campelo
11Hospital Clínico Universitario de Salamanca, Salamanca, Spain
David Valcárcel
Claudia Haferlach
8Munich Leukemia Laboratory, Munich, Germany
Lisa Pleyer
Ioannis Kotsianidis
29Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
Vassiliki Pappa
2University General Hospital Attikon, Second Department of Internal Medicine and Research Institute, Athens, Greece
Valeria Santini
7DMSC University of Florence, AOUC, MDS Unit, Hematology, Florence, Italy
Angela Consagra
30University of Florence, MDS Unit, Hematology, AOU Careggi - Department of Experimental and Clinical Medicine, Florence, Italy
Aref Al-Kali
1Mayo Clinic, Division of Hematology, Department of Medicine, Rochester, United States
Seishi Ogawa
Yasuhito Nannya
Matteo Della Porta
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Rami Komrokji
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Amer Zeidan
18Yale School of Medicine - Yale Cancer Center, New Haven, United States
Maximilian Stahl