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1917 Gastrointestinal Events and Management Strategies for Patients with Acute Myeloid Leukemia (AML) in First Remission Receiving CC-486 in the Randomized, Placebo-Controlled, Phase III QUAZAR AML-001 Maintenance Trial

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster II
Hematology Disease Topics & Pathways:
AML, Adult, Diseases, Elderly, Adverse Events, Study Population, Myeloid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Farhad Ravandi, MBBS1, Christopher Pocock, MBBS2, Dominik Selleslag, MD3, Pau Montesinos, MD, PhD4*, Hamid Sayar, MD, MSc5, Maurizio Musso, MD6*, Angela Figuera Alvarez7*, Hana Safah, MD8, William Tse, MD, FACP9*, Sang Kyun Sohn, MD, PhD10*, Devendra Hiwase, MBBS, MD, FRACP, FRCPA, PhD11, Timothy Chevassut12*, Francesca Pierdomenico13*, Ignazia La Torre14*, Barry Skikne, MD15,16*, Keshava Kumar, PhD16*, Qian Dong, DrPH16*, C.L. Beach, PharmD16* and Hervé Dombret, MD17,18

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Kent & Canterbury Hospital, Canterbury, United Kingdom
3AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium
4Hospital Universitari i Politecnic la Fe, Valencia, and CIBERONC Instituto de Salud Carlos III, Madrid, Spain
5Indiana University Cancer Center, Indianapolis, IN
6La Maddalena - Casa di Cura, Palermo, Italy
7Hospital Universitario de La Princesa, Madrid, Spain
8Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, LA
9University of Louisville School of Medicine, Louisville, KY
10Kyungpook National University Hospital, Daegu, Korea, Republic of (South)
11Royal Adelaide Hospital, Adelaide, Australia
12Haematology Department, Brighton & Sussex University Hospitals NHS Trust, Brighton, United Kingdom
13Portuguese Institute of Oncology Lisbon, Lisbon, Portugal
14Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland
15Kansas University Medical Center, Kansas City, KS
16Bristol Myers Squibb, Princeton, NJ
17Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, France
18Institut de Recherche Saint Louis, Université de Paris, Paris, France

INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001.

METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory.

RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55–86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization.

Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1–2, 3–4, and 5–6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients.

DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes.

Disclosures: Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag: Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah: Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase: Novartis Australia: Research Funding. La Torre: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne: Bristol Myers Squibb: Current Employment. Kumar: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dombret: Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.

*signifies non-member of ASH