Clinical Lymphoma, Myeloma & Leukemia, Vol.22, Suppl.2 - October 2022

Abstracts Clinical Lymphoma, Myeloma & Leukemia October 2022 S304 target characterized by overexpression of RARA has been identified (McKeown 201 7 ). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 201 7 ). Tamibarotene is an oral selective RAR  agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 201 7 ). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA- positive newly diagnosed (ND) unfit AML patients, including those with low blast count (  30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR- MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Objecti v e: To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/ azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. D esig n : Global, Phase 3, randomized, double-blind, placebo- controlled trial (NCT04 7 9 77 80). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. Patie n ts: The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. I n ter v e n tio n : Azacitidine will be administered at 7 5 mg/m 2 IV/SC daily on days 1– 7 (or 1–5, 8–9) followed by tamibarotene/placebo at 6 mg BID orally on days 8–28 of each 28-day cycle. Mai n Outco m e Measures: Response is assessed per the modified IWG MDS criteria (Cheson 2006). Keywords: MDS, myelodysplastic syndrome, retinoic acid receptor (RAR), clinical trial, Phase III MDS-111 Hemoglobin, Lactate Dehydrogenase, and FACIT-Fatigue Normalization in Pegcetacoplan-Treated Patients With Paroxysmal Nocturnal Hemoglobinuria from Two Phase 3 Clinical Trials Dharmik Desai PharmD 1 , Brian P. Mulherin MD 2,3 , Michael Yeh MD, MBA, MPH 1 , Mohammed Al- Adhami PhD 1 , Jessica Savage MD, MHS 1 , David Dingli MD, PhD 4 1 Apellis Pharmaceuticals Inc., Waltham, USA. 2 Hematology Oncology of Indiana, Indianapolis, USA. 3 Ascension St. Vincent Carmel, Carmel, USA. 4 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, USA Co n text: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease involving complement-mediated hemolysis. Pegcetacoplan is the first FDA/EMA-approved C3 complement- inhibitor for adults with PNH. Objecti v e: We report hemoglobin, lactate dehydrogenase (LDH), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization rates in the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. D esig n : The PEGASUS study (2018-2020) randomized patients with hemoglobin levels <10.5 g/dL at screening despite stable eculizumab treatment (  3-months) 1:1 to pegcetacoplan (n=41) or eculizumab (n=39) for the 16-week randomized controlled period (RCP). Eculizumab-treated patients switched to pegcetacoplan during the open-label period through Week 48. The 26-week PRINCE study (2019-2021) randomized complement- inhibitor naive patients 2:1 to pegcetacoplan (n=35) or control treatment ([n=18] without complement-inhibitors: eculizumab/ ravulizumab). Normalization was defined separately as hemoglobin  gender lower limit of normal, LDH  upper limit of normal, and FACIT-Fatigue scores  population norm (43.6). Transfusion recipients (hemoglobin/LDH endpoints only), patients withdrawn or lost to follow-up, or control-escape patients (PRINCE) were considered not normalized. Safety endpoints included incidences of adverse events (AEs). Results: Pegcetacoplan demonstrated rapid treatment effects in both studies; Week 2 hemoglobin normalization rates were 43.9% (PEGASUS, baseline 0%) and 22.9% (PRINCE, baseline 2.9%) and Week 2 LDH normalization rates were 8 7 .8% (PEGASUS, baseline 41.5%) and 51.4% (PRINCE, baseline 0%). At Week 16 (PEGASUS) and Week 26 (PRINCE), higher normalization rates were achieved with pegcetacoplan versus respective comparator treatments in hemoglobin (PEGASUS: 34.1% versus 0%; PRINCE: 45. 7 % versus 0%), LDH (PEGASUS: 7 0. 7 % versus 15.4%; PRINCE: 65. 7 % versus 0%), and FACIT-Fatigue (PEGASUS: 48.8% versus 10.3%; PRINCE: 60.0% versus 11.1%). Numerically similar results were observed at Week 48 in PEGASUS patients randomized to pegcetacoplan or switched from eculizumab to pegcetacoplan. Common AEs in pegcetacoplan-treated patients were injection site reactions (ISRs), diarrhea, abdominal pain, nasopharyngitis, upper respiratory tract infection, hemolysis, cough, and headache for PEGASUS, and ISRs, hypokalemia, and dizziness for PRINCE. Co n clusio n s: Pegcetacoplan rapidly enables higher rates of hemoglobin and LDH normalization, and improvements in FACIT-Fatigue scores compared to eculizumab and control treatment. This further supports the rapid treatment effect of pegcetacoplan in improving clinical parameters and health- related quality of life with a favorable safety profile. Keywords: MDS, paroxysmal nocturnal hemoglobinuria, PNH, pegcetacoplan, normalization, hemoglobin, complement-inhibitor, Phase III