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512 The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 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, Clinical Research
Sunday, December 12, 2021: 4:45 PM

Philippe Rousselot1*, Yves Chalandon, MD2, Sylvie Chevret, MD, PhD3*, Jean-Michel Cayuela, PharmD, PhD4*, Francoise Huguet, MD5*, Patrice Chevallier, MD6, Carlos Graux7*, Anne Thiebaut-Bertrand8*, Sylvain Chantepie, MD9*, Xavier Thomas, MD, PhD10, Laure Vincent, MD11*, Celine Berthon, MD, PhD12*, Norbert Vey, MD13, Emmanuel Raffoux, MD14*, Martine Escoffre-Barbe, MD15*, Isabelle Plantier, MD16*, Jean Pierre Marolleau17, Pascal Turlure18*, Florence Pasquier, MD, PhD19*, Amine Belhabri20*, Gabrielle Roth Guepin21*, Olivier Spertini, MD22, Veronique Lheritier23*, Emmanuelle Clappier, PhD, PharmD24*, Nicolas Boissel, MD, PhD25 and Hervé Dombret, MD, PhD26

1Department of Hematology and Oncology, Centre Hospitalier de Versailles, INSERM UMR 1184, Université Versailles Saint-Quentin-en-Yvelines, Université Paris Saclay, Le Chesnay, France
2Geneva University Hospitals, Geneva, Switzerland
3APHP, Saint-Louis University Hospital, Department of Biostatistics, PARIS, France
4Laboratory of Hematology, University Hospital Saint-Louis, Paris, France
5Department of Hematology, Institut Universitaire du Cancer-Oncopole CHU de Toulouse, Toulouse, France
6D'Hematologie, Nantes University Hospital, Nantes, France
7Université Catholique de Louvain, CHU UCL Namur (Godinne), Yvoir, Belgium
8CHU de Grenoble, Grenoble, France
9Institut d'Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen Cedex 9, France
10Hematology Department, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre-Benite, France
11CHU de Montpellier / Département d'hématologie clinique, Hôpital Saint-Eloi, Montpellier, France
12Hematology Department, Lille University Hospital, Lille, France
13Institut Paoli Clamettes, Marseille, France
14Hématologie clinique, Hôpital Saint-Louis, Paris, France
15CHU de Rennes, Rennes, France
16Service d'hématologie clinique, CH Roubaix, Roubaix, France
17Hopital SUD, Amiens, Cedex 1, France
18Hematology Department, CHRU Limoges, Limoges, France
19Gustave Roussy, Département clinique d'hématologie, INSERM UMR1170, Villejuif, FRA
20Centre Leon Berard, Departement Oncologie Medicale, Lyon, France
21Hematology, Nancy University Hospital, Nancy, FRA
22CHUV de Lausanne, Lausanne, Switzerland
23Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), Centre Hospitalier Lyon Sud, Lyon, France
24Hematology, hopital saint louis, Paris, France
25St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
26Division of Hematology, EA3518 Saint-Louis Institute for Research, Hôpital Saint-Louis, APHP, University of Paris, Paris, France, Paris, France

On behalf of the GRAALL group.

Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4.

Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 <0.1%) was achieved. AlloSCT and autoSCT were followed by a 2-year imatinib maintenance. The randomization was stratified on age (40y, >40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44.

Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C).

Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4.

Disclosures: Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: JAZZ PHARMACEUTICALS: Honoraria; SERVIER: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; BIOKINESIS: Consultancy, Research Funding; BMS: Honoraria; Amgen: Honoraria; JANSSEN: Consultancy, Honoraria; Abbvie: Honoraria. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. 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.

OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

*signifies non-member of ASH