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536 Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients - Interim Analysis of the European Sintra-REV TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Personalized Clinical-Decision Tools and treatment of lower risk MDS
Hematology Disease Topics & Pathways:
Non-Biological, Elderly, Therapies, chemotherapy, Study Population, Clinically relevant
Monday, December 7, 2020: 7:00 AM

Félix López Cadenas, MD1*, Eva Lumbreras2*, Blanca Xicoy, MD3*, Joaquín Sánchez, MD4*, Rosa Coll, MD5*, Bohrane Slama, MD6*, Jose Angel Hernandez-Rivas, MD, PhD7*, Sylvain Thepot, MD8*, Teresa Bernal, MD, PhD9*, Beatriz Arrizabalaga, MD. PhD10*, Agnès Guerci-Bresler, MD, PhD11*, Guillermo F Sanz, MD, PhD12, Joan Bargay, MD13*, Maria Luz Amigo, MD14*, Raquel de Paz, MD15*, Benet Nomdedeu, MD16*, Aristoteles Giagounidis17, Uwe Platzbecker, MD18, Stefan Wickenhauser19*, Katharina S. Götze20, Ali Arar21*, Jesus María Hernández Rivas, MD, PhD22,23, Pierre Fenaux, MD, PhD24, Consuelo Del Cañizo, MD, PhD25 and Maria Diez-Campelo, MD, PhD26,27*

1Hematology Department, Hospital Clínico Universitario de Salamanca, Salamanca, SALAMANCA, Spain
2Department of Hematology, Hospital Universitario de Salamanca, Spain, Salamanca, Spain
3Hematology Department, Institut Català d'Oncologia-Hospital Germans Trias i Pujol; Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain
4Hematology, University Hospital Reina Sofía, Córdoba, Cordoba, Spain
5Hematology Department, ICO - Hospital Doctor Josep Trueta, Girona, Spain
6Oncologie Médicale-Hématologie Clinique, Centre Hospitalier Departemental, Avignon, France
7University Hospital Infanta Leonor, Madrid, Spain
8Clinical Hematology, Angers University Hospital, Angers, France
9Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
10Department of Hematology, Hospital Universitario Cruces, Vizcaya, Spain
11Service d'Hématologie, Centre Hospitalier Universtaire Brabois, Vandoeuvre-lès-Nancy, France
12Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
13Department of Hematology, Son Llatzer University Hospital/ IdISBa, Palma de Mallorca, Spain
14Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain, Murcia, ESP
15Hematology Department, Hospital Universitario La Paz-Idipaz, Madrid, Spain
16Hematology Department, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain
17Department of Oncology, Hematology and Palliative Care, Marienhospital Düsseldorf, Düsseldorf, Germany
18Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
19HôPital Caremeau, Nimes Cedex 9, FRA
20Department of Medicine III, Technical University of Munich, Munich, Germany
21Centre Hospitalier Régional d’Orléans, Orleans, FRA
22University of Salamanca, IBSAL, IBMCC, CSIC, Cancer Research Center, Salamanca, Spain
23Department of Hematology, University Hospital of Salamanca, Salamanca, Spain
24Hôpital Saint-Louis, Paris, France
25Departamento de Hematología, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
26Hematology Department, Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain
27Grupo Español de Síndromes Mielodisplásicos (GESMD), salamanca, salamanca, Spain

Background: Most IPSS low and int1 (lower) risk MDS patients with isolated del(5q) develop RBC TD or need treatment for symptomatic anemia early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). Lenalidomide (LEN) is a reference treatment in MDS-del(5q) but approved in many countries only when RBC-TD occurs. LEN directly targets the del(5q) clone improving anemia and quality of life. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015), but no randomized trial has assessed the efficacy and tolerance of early LEN treatment in this MDS subset.

Material: The Sintra-Rev clinical trial is a phase III European multicenter study in low-risk MDS-del(5q) patients with anemia (Hb<12g/dL), without TD. Patients were randomized in a double-blind design to LEN (5mg/day continuously) vs placebo (2:1 randomization) for 2 years of treatment and 2y of follow-up. The primary endpoint was the time to TD, secondary endpoints included erythroid (HI-E) and cytogenetic response (CyR) (all according to IWG 2006 criteria), overall survival (OS), event free survival (EFS), time to AML and mutational analysis (TP53 and other myeloid mutations). Here, we report results of the interim analysis after completion of the treatment phase in all patients (March 2020).

Results: Main clinical characteristics of the 61 patients (ITT population) included (Feb-2010 to Feb-2018) are summarized in Table 1: 82% females, median age 72 years (range 37-89), median time since diagnosis 3.6 months, median Hb at inclusion 9.8 g/dL (7.1 - 11.7) g/dL and 93% patients had isolated del(5q). Four patients were excluded due either to screening failure (1 pat) or failure to complete at least 12w of treatment (3 pat). Fifty-seven patients were included in the ITT evaluable population for efficacy and 59 for safety (2 patients did not receive any drug).

Median time on treatment was 66 weeks (3-121), 95w in the LEN arm and 42w in the placebo arm (p=0.392). Forty-seven percent patients in the LEN arm successfully completed the study compared to 33% in the placebo arm.

After a median follow up of 25.6 months (Q1 16-Q3 39), median OS was not achieved. Among the 57 patients evaluable for efficacy, median time to TD was 75.7 mo for the LEN patients and 25.9 mo for the placebo arm (HR 2.703, 95CI1.162-6.286, p=0.021, figure 1). HI-E response was observed in 72.5% of LEN patients compared to 0% in the placebo arm (p<0.001). Median Hb improvement in responders was 2.8 g/dL. Eighty percent of LEN patients achieved a cytogenetic response (CyR) compared to 4.8% of patients receiving placebo (p<0.001, complete CyR 70% in the LEN arm). OS was similar in both arms (not reached) while EFS was superior in the LEN arm (HR 2.274, 95CI 1.034-5.001, p=0.041). AML evolution was similar in both arms (5%). Mutational analysis will be presented at the meeting.

Fifty-eight patients developed at least one adverse event (AE) during the trial (no differences between the LEN and placebo arm), related to the drug 86.8% in the LEN and 33.3% in the placebo arm, respectively (p<0.001). Hematological toxicity occurred in 40 patients in the LEN arm (50% grades 3/4) and only 4 patients in the placebo arm (25% grade 3/4). At least one SAE was seen in 31.6% of the LEN patients compared to 4.8% in the placebo arm (p=0.022), not related to the drug. Nineteen serious AE were reported in 13 patients, 4 of them (2nd neoplasia, pulmonary embolism, febrile neutropenia and blurred vision) potentially related with the study drug, with no related deaths.

Conclusions: In this interim analysis we confirm that low dose LEN (5 mg) in anemic non-TD low risk MDS del(5q) patients prolongs the period of time to TD (75.7 mo vs 25.9 mo), improves Hb levels (72.5% of ER) and induces clonal responses (70% complete CyR), ie potentially more responses than in historical series of MDS del(5q) treated with LEN at time of TD, with a manageable safety profile, and no increased progression rate. Longer follow up will be required to assess the effect of early treatment with LEN, and particularly the effect of the early reduction of the del(5q) clone size, on long-term outcomes.

Disclosures: Hernandez-Rivas: Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Thepot: astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Sanz: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees. Giagounidis: AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bergenbio: Research Funding; JAZZ: Honoraria, Research Funding. Götze: Celgene: Research Funding. Fenaux: Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Diez-Campelo: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

OffLabel Disclosure: LEN IN ANEMIC BUT NOT TD PATIENTS WITH LOW RISK MDS AND DEL(5Q)

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