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2992 Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) – Updated Data from the Phase 2 ACE-536-MF-001 Study

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Diseases, Biological Processes, MPN, erythropoiesis, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Aaron T. Gerds, MD, MS1, Alessandro Vannucchi, MD2, Francesco Passamonti3*, Marina Kremyanskaya4, Jason Gotlib, MD MS5*, Jeanne M. Palmer, Md6, Kelly McCaul7*, Vincent Ribrag, MD8, Adam J. Mead, MD, PhD9, Claire Harrison, DM, FRCPath10, Ruben Mesa, MD11, Jean-Jacques Kiladjian12, Giovanni Barosi13, Torsten G. Gerike14*, Jeevan K. Shetty15*, Joseph Pariseau14*, Gabriel Miranda14*, Martin Schwickart14*, Ana Carolina Giuseppi14*, Jennie Zhang14*, Jay T. Backstrom16* and Srdan Verstovsek, MD, PhD17

1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
2Center for Research and Innovation of Myeloproliferative Neoplasms, AOU Careggi, Florence, Italy
3Department of Medicine and Surgery, University of Insubria, Varese, Italy
4Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY
5Stanford Cancer Institute, Stanford, CA
6Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ
7Avera Cancer Institute, Sioux Falls, SD
8Institut Gustave Roussy, Villejuif, France
9Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
10Guy's and Saint Thomas' NHS Foundation Trust, London, United Kingdom
11Mays Cancer Center, UT Health San Antonio Cancer Center, San Antonio, TX
12Hôpital Saint-Louis et Université Paris Diderot, Paris, France
13IRCCS Policlinico San Matteo Foundation, Pavia, Italy
14Bristol Myers Squibb, Princeton, NJ
15Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland
16Acceleron Pharma, Cambridge, MA
17Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: MF is a clonal stem cell disorder characterized by progressive bone marrow failure, extramedullary hematopoiesis, and debilitating constitutional symptoms. Approximately 60% of pts develop anemia within a year of diagnosis; pts who are transfusion dependent have worse survival and quality-of-life outcomes (Tefferi A, et al. Mayo Clin Proc 2012;87:25-33). Treatment for MF-associated anemia remains critically unaddressed, with no approved therapies available. Luspatercept is a first-in-class erythroid maturation agent that has been shown to increase hemoglobin and reduce transfusion burden in pts with myelodysplastic syndromes (Fenaux P, et al. N Engl J Med 2020;382:140-51) and β‑thalassemia (Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Pts have also achieved multiple response episodes with luspatercept (Fenaux P, et al. Blood 2019;134:841). We previously reported findings from the ongoing open-label, phase 2 ACE-536-MF-001 trial evaluating luspatercept in pts with MF-associated anemia (Gerds AT, et al. Blood 2019;134:557). Here we report updated study results, focusing on response in pts requiring RBC transfusions.

Methods: 79 pts with MF and anemia were enrolled (Figure). Of these, 43 were requiring RBC transfusions, defined as 6–12 U/84 d prior to treatment, or 4–12 U/84 d for the 3 expansion cohort pts. Pts in Cohort 3B received a stable ruxolitinib (RUX) dose for ≥ 16 wks (40 wks for expansion cohort pts), whereas Cohort 2 pts did not (Figure). Pts in Cohort 3B received a median RUX dose of 20 mg/d (range 5–40) for a median of 73 wks (range 29–359) prior to treatment.

Pts received luspatercept every 21 d at a starting dose of 1.0 mg/kg (1.33 mg/kg for 3 expansion cohort pts in Cohort 3B), with doses escalating up to 1.75 mg/kg; 81% and 50% of pts in Cohorts 2 and 3B escalated to 1.75 mg/kg. Primary endpoint for pts receiving transfusions was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks within the first 24 wks on study. However, as responses were observed that did not fall within the 24-wk response window, additional assessments were conducted for the entire treatment duration for RBC-TI and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease) from baseline. Intent-to-treat data were analyzed as of March 29, 2020.

Results: Pts in Cohorts 2 and 3B received a median of 8 cycles of luspatercept (range 1–39), for a median (mean) duration of 24 (31) and 23 (39) wks, respectively. Pts in Cohorts 2 and 3B received a median of 2.7 RBC U/28 d (range 1–5) and 2.7 RBC U/28 d (range 2–4), respectively. For the primary endpoint, 2/21 (10%) and 6/22 (27%) pts receiving transfusions in Cohorts 2 and 3B achieved RBC-TI over any consecutive 12 wks during the first 24 wks. Median time to start of first RBC-TI response period in Cohorts 2 and 3B was 1.5 days and 37 days; median duration of response was 49 wks (range 16–82) and 42 wks (range 12–111), respectively.

When assessing the entire treatment period, 4/21 (19%) and 8/22 (36%) pts in Cohorts 2 and 3B achieved RBC‑TI ≥ 12 wks, respectively. 25% of the RBC-TI responders in both cohorts experienced 2 separate episodes of RBC‑TI ≥ 12 wks.

Median cumulative duration of all individual ≥ 12-wk response episodes of RBC-TI was 59 wks (range 24–82) in Cohort 2 and 55 wks (range 12–116) in Cohort 3B.

8/21 (38%) and 10/22 (46%) pts in Cohorts 2 and 3B achieved a ≥ 50% reduction in RBC transfusion burden (minimum ≥ 4 U reduction) over 12 wks; of these, 38% and 20% of responders in Cohorts 2 and 3B experienced 2 separate ≥ 12-wk response episodes, and 1 pt (13%) in Cohort 2 experienced 3 separate responses.

4/15 (27%) and 8/14 (57%) pts in Cohorts 2 and 3B who reached 24 wks of treatment achieved clinical benefit and therefore continued luspatercept on an ongoing basis.

Safety is reported for all 79 pts on study. 5 (6%) pts had grade 3–4 treatment-related adverse events (AEs); these AEs were diarrhea (n = 2), dehydration (n = 1), and hypertension (n = 3). There were no treatment-related deaths. Treatment-related AEs (any grade) occurring in ≥ 5% of pts were hypertension (13%), bone pain (9%), and diarrhea (5%). 8 (10%) pts had ≥ 1 AE leading to discontinuation. 16 (20%) pts remain on treatment.

Conclusions: These longer-term findings suggest durable activity of luspatercept in pts with MF-associated anemia. In addition, a quarter of pts receiving transfusions achieved more than one ≥ 12-wk episode of RBC-TI response with luspatercept. The incidence of grade 3–4 AEs with luspatercept was low.

Disclosures: Gerds: Roche/Genentech: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Research Funding; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding. Vannucchi: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Passamonti: Novartis: Speakers Bureau; BMS: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Kremyanskaya: Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding. McCaul: BMS: Speakers Bureau; Seattle Genetics: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Speakers Bureau. Ribrag: argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; gustave roussy comprehensive cancer center: Current Employment; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding. Mead: Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Abbvie: Consultancy; CTI: Consultancy; Gilead: Consultancy. Harrison: Gilead Sciences: Honoraria, Speakers Bureau; Promedior: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Shire: Honoraria, Speakers Bureau; Roche: Honoraria; Sierra Oncology: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Incyte Corporation: Speakers Bureau. Mesa: Sierra Oncology: Consultancy; Novartis: Consultancy; CTI BioPharma: Research Funding; Incyte: Research Funding; LaJolla Pharmaceutical Company: Consultancy; AbbVie: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Promedior: Research Funding. Kiladjian: AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Barosi: Bristol Myers Squibb: Consultancy. Gerike: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Shetty: BMS: Current Employment, Current equity holder in publicly-traded company. Pariseau: Bristol Myers Squibb: Current Employment. Miranda: Bristol Myers Squibb: Current Employment. Schwickart: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Giuseppi: BMS: Current Employment, Current equity holder in publicly-traded company. Zhang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Backstrom: Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company. Verstovsek: AstraZeneca: Research Funding; Roche: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding.

*signifies non-member of ASH