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511 Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies II
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Clinical Research, Therapies, Monoclonal Antibody Therapy
Sunday, December 12, 2021: 4:30 PM

Patrice Chevallier, MD1, Thibault Leguay2*, Michael Doubek, MD, PhD3, Francoise Huguet, MD4*, Cyril Salek5*, Aurélie Cabannes, MD6*, Ulla Wartiovaara-Kautto, MD7, Colombe Saillard, MD8*, Emmanuel Raffoux, MD9*, Thomas Cluzeau, MD, PhD10, Stéphane Leprêtre, MD11*, Marie Balsat, MD12*, Anna Berceanu, MD13*, Nicolas Boissel, MD, PhD14, Emmanuelle Clappier, PhD, PharmD15*, Laure Morisset16*, Claude Gardin, MD17*, Hervé Dombret, MD, PhD18 and Philippe Rousselot19*

1Department of Clinical Hematology, Nantes University Hospital, Nantes, France
2Bordeaux University Hospital, Pessac, FRA
3Department of Internal Medicine - Hematology and Oncology, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
4Department of Hematology, Institut Universitaire du Cancer-Oncopole CHU de Toulouse, Toulouse, France
5Institute of Hematology and Blood Transfusion, Prague, CZE
6Hematology and Oncology department, Centre Hospitalier de Versailles, Le Chesnay, France
7Helsinki University Hospital, Helsinki University, Helsinki, Helsinki-Uusimaa, Finland
8Institut Paoli Calmettes, Marseille, France
9Hématologie clinique, Hôpital Saint-Louis, Paris, France
10Department of Clinical Hematology, CHU De Nice, Nice, France
11Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France
12Service Hematologie, Centre Hospitalier Lyon Sud, Lyon, France
13Department of Clinical Hematology, Besançon University Hospital, Besançon, France
14St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
15Hematology Laboratory and INSERM U944, Hopital Saint-Louis, Paris, France
16Clinical research department, Centre Hospitalier de Versailles, Le Chesnay, France
17Hematology, Avicenne Hospital, APHP, University Paris XIII, Bobigny, France, Bobigny, France
18Division of Hematology, EA3518 Saint-Louis Institute for Research, Hôpital Saint-Louis, APHP, University of Paris, Paris, France, Paris, France
19Department of Hematology and Oncology, Centre Hospitalier de Versailles, INSERM UMR 1184, Université Versailles Saint-Quentin-en-Yvelines, Université Paris Saclay, Le Chesnay, France

On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group.

Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL.

Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870.

Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation.

Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL.

Disclosures: Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Wartiovaara-Kautto: Sanofi: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding.

OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

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