Outcomes of patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) treated with hypomethylating agents (HMA) + venetoclax (VEN) – a large analysis from the international consortium for MDS (icMDS) validate database
Abstract
Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.
Article Details
Authors (57)
Jan Philipp Bewersdorf
Tariq Kewan
1Cleveland Clinic, Department of Translational Hematology and Oncology Research, Cleveland, United States
Luca Lanino
3Yale University, New Haven, United States
Wei Wei
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
Hayley Hawkins
17Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 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
Benjamin Rolles
1Brigham and Women's Hospital, Harvard Medical School, Division of Hematology, Department of Medicine, Boston, United States
Eunice Wang
13Roswell Park Comprehensive Cancer Center, Buffalo, United States
Amyah Harris
11Harvard Medical School, Division of Hematology/Oncology, Massachusetts General Hospital, Boston, United States
Maria Amaya
2University of Colorado School of Medicine, Division of Hematology, Aurora, 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
Jaclynn Campos
20Mayo Clinic, Division of Hematology-Oncology, Jacksonville, United States
Talha Badar
Mayo Clinic, Jacksonville, Florida, 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
Max Stahl
1Yale School of Medicine and Yale Cancer Center, Internal Medicine; Section of Hematology, New Haven, United States
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