-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1866 A Phase 2 Study of Canakinumab in Patients with Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
clinical trials, Research, Biological therapies, MDS, adult, CHIP, Clinical Research, Chronic Myeloid Malignancies, CMML, Diseases, Therapies, Myeloid Malignancies, Monoclonal Antibody Therapy, Biological Processes, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Juan Jose Rodriguez Sevilla1*, Vera Adema2*, Kelly S. Chien, MD3, Irene Ganan-Gomez, PhD, MSc1*, Guillermo Montalban-Bravo, MD3, Samuel Urrutia, MD4, Joby Joseph1*, Hui Yang, MD, PhD3*, Gautam Borthakur, MD3, Nicholas J. Short, MD3, Ghayas C. Issa5, Tapan M. Kadia, MD3, Koichi Takahashi, MD, PhD3, Danielle E. Hammond, MD3 and Guillermo Garcia-Manero, MD6

1Leukemia, MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houst, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
5The University of Texas MD Anderson Cancer Center, Houston, TX
6University of Texas MD Anderson Cancer Center, Houston, TX

Background Myelodysplastic syndromes (MDS) lie on a continuum of myeloid neoplastic progression between clonal hematopoiesis (CH) and acute myeloid leukemia (AML). Interleukin 1 beta (IL-1β)-induced inflammasome activation is a mechanism of cancer initiation and progression. Given that IL-1β upregulation induces aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs), we hypothesize that IL-1β plays a critical role in MDS pathogenesis, and targeting IL-1β signaling will overcome aberrant MDS HSPCs' myeloid skewing. Here, we report final results of a phase 2 study evaluating the safety and efficacy of canakinumab, an IL-1β inhibitor, in patients with lower-risk MDS or chronic myelomonocytic leukemia (CMML).

Methods We conducted a single center, open-label phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged ≥ 18 with IPSS-R ≤ 3.5 MDS/CMML who have previously been treated were included in the study. Patients received 300 mg of canakinumab on day 1 of a 4-week cycle. The primary objective was to determine the clinical activity of canakinumab in MDS/CMML patients. Response was assessed using the modified International Working Group 2006 criteria for MDS (Cheson et al. 2006). Secondary objectives were to evaluate the safety profile including rate of transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). All patients who received 1 dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov (NCT04239157).

Findings Between August 2020 and May 2023, 27 patients were enrolled in the phase 2 portion of this study, and 2 patients failed screening. The median age was 74 years with 15 (60%) male patients; 20 patients (80%) were post-hypomethylating agent failure with a median number of prior lines of therapy of 2 (1-5). Transfusion dependency was observed in 24 patients (96%) prior to canakinumab initiation. Fourteen (56%) patients showed normal karyotype. IPSS-R stratification revealed an intermediate-2 risk in 12 (48%) patients and a high risk in one (4%). The most common mutations were SF3B1 (40%), TET2 (32%), DNMT3A (28%), and RUNX1 (24%). IPSS-M risk score was calculated for 24 cases showing one (4%) very low (VL), four (16%) low (L), 14 (16%) moderate low (ML), eight (32%) moderate high (MH), five (20%) high (H), and two (8%) very high (VH) risk categories. Canakinumab was well tolerated and no drug-related toxicities were observed. One death due to sepsis, which was deemed not treatment-related, occurred on the study drug. Out of 23 evaluable patients, the overall response rate was 17·4%, with erythroid and platelet hematological improvement (HI-E and HI-P, respectively) confirmed in 3 (13.0%) patients and 1 (4.3%) patient, respectively. Thirteen patients had stable disease (56·5%) and 6 (26·1%) progressed during therapy, 1 of which transformed to AML (Fig. 1). TI was achieved in 3 patients (median DoR 8·53 months (95% CI 0·41-16·1) and 2 of them maintained TI for over 12 months. With a median follow-up time of 22·6 months (95% CI 15·0-29·4), median OS was 17·3 months (95% CI 14·3-not estimable). We performed separate univariate analyses to evaluate any associations between the IPSS-M and OS/PFS. The median OS in patients with higher-risk MDS by IPSS-M (MH, H, VH) was 15·0 months vs 29·4 months in the lower-risk disease by IPSS-M (VL, L, ML) group (p=0·12). Interestingly, statistically significant findings were observed with 1-year PFS when stratifying patients into higher vs lower risk MDS by IPSS-M (64·3% vs 100·0%, respectively; p=0·022, Fig. 2).

Conclusion In this cohort of MDS patients who had experienced multiple lines of prior therapy and exhibited high-molecular-complexity, canakinumab showed limited efficacy (HI 17.3%). Nevertheless, canakinumab showed a good safety profile and yielded sustained long-term responses in patients with single somatic driver mutation in TET2 or DNMT3A. This suggests that clonal complexity, and therefore disease burden, may be a determining factor in response to canakinumab. Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

Disclosures: Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Borthakur: Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Short: Takeda: Consultancy, Research Funding; Stemline therapeutics: Research Funding; Astellas: Research Funding; Amgen: Honoraria; Pfizer: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy. Issa: Syndax: Consultancy, Research Funding; NuProbe: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Merck: Research Funding; Kura Oncology: Consultancy, Research Funding; Celgene: Research Funding; Astex: Research Funding; Abbvie: Consultancy; Cullinan Oncology: Research Funding. Kadia: Cyclacel: Research Funding; Amgen, Inc.: Research Funding; Agios: Consultancy; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Servier: Consultancy; Genzyme: Honoraria; BMS: Consultancy, Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Pinotb-Bio: Consultancy; Liberum: Consultancy; Genentech: Consultancy, Research Funding; Janssen Research and Development: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Cure: Speakers Bureau; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; GenFleet Therapeutics: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Ascentage Pharma Group: Research Funding; Astellas Pharma Global Development: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Cellenkos Inc.: Research Funding; Glycomimetics: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Iterion: Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; SELLAS Life Sciences Group: Research Funding; Sanofi-Aventis: Consultancy; Astex: Honoraria. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding.

*signifies non-member of ASH