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1232 Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, Clinical Trials, ALL, Biological therapies, Adults, Bispecific Antibody Therapy, Workforce, Diseases, Therapies, Lymphoid Malignancies, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Nicolas Boissel, MD, PhD1, Francoise Huguet, MD2*, Carlos Graux3*, Yosr Hicheri4*, Patrice Chevallier, MD5, Rathana KIM, PharmD6*, Marie Balsat, MD7*, Thibaut Leguay, MD8*, Mathilde Hunault, MD PhD9*, Sébastien Maury10*, Anne Thiebaut-Bertrand11*, Martine Escoffre-Barbe, MD12*, Thomas Cluzeau, MD, PhD13, Alban Villate, MD14*, Florence Pasquier, MD, PhD15*, Laure Farnault, MD16*, Florence Van Obbergh17*, Philippe Rousselot18*, Yves Chalandon, MD19, Eric Delabesse, PharmD, PhD20*, Cedric Pastoret, MD21*, Emmanuelle Clappier, PhD, PharmD22*, Veronique Lheritier23* and Herve Dombret, MD, PhD24

1St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
2Department of Hematology, Institut Universitaire du Cancer-Oncopole CHU de Toulouse, Toulouse, France
3Université Catholique de Louvain, CHU UCL Namur (Godinne), Yvoir, Belgium
4Institut Paoli-Calmettes, MARSEILLE, France
5Hotel Dieu, CHU de Nantes, Service d'hématologie, Nantes, France
6Hematology Laboratory, Hopital Saint-Louis, Paris, France
7Service Hematologie, Centre Hospitalier Lyon Sud, Lyon, France
8Hematology Clinic, Bordeaux University Hospital, Pessac, France
9Clinical Hematology, Angers University Hospital, Angers, France
10AP-HP, Hôpital Henri Mondor, Service d’hématologie clinique, Créteil, France
11Department of Hematology, CHU-Grenoble Onco-Hematologie, Grenoble, France
12Hematology department, CHU Rennes, Rennes, France
13Department of Clinical Hematology, CHU De Nice, Nice, France
14Service d'hématologie et thérapie cellulaire, Hôpital Bretonneau, CHRU de Tours, Tours, France
15Gustave Roussy, Département clinique d'hématologie, INSERM UMR1170, Villejuif, FRA
16Service d'hématologie clinique et de thérapie cellulaire, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalier Universitaire La Conception, Marseille, France
17CH Jolimont, Hematology Department, La Louviere, BEL
18Hematology department, Hôpital André Mignot, Versailles, France
19Department of Hematology, Geneva University Hospital, Geneva, Switzerland
20Laboratoire d'hématologie, CHU de Toulouse - Institut Universitaire du Cancer De Toulouse-Oncopole, Toulouse cedex9, France
21Laboratoire d'Hematologie, INSERM U1236 /hematology laboratory/university hospital of Rennes, RENNES, FRA
22Hematology Laboratory, Hôpital Saint Louis, Paris, France
23Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), Centre Hospitalier Lyon Sud, Lyon, France
24Hematology, Hôpital Saint-Louis, Paris, France

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant.

Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here.

Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was <0.01% in 49/88 (56%) of evaluable patients. A total of 40 patients (42%) received an alloSCT. The median number of blinatumomab cycles received in patients not proceeding to alloSCT was 4 cycles (range, 1-5). Thirty-nine severe adverse events (SAEs) were reported: 1 CRS (grade 2), 8 neurotoxicities (1 grade 2, 3 grade 3, 3 grade 4, 1 grade 5), 19 infections, and 11 others. The only grade 5 SAE occurred after alloSCT (seizures). After blinatumomab, a complete MRD response (with at least 0.01% sensitivity) was achieved in 61/82 (74%) evaluable patients and in evaluable patients with pre-blinatumomab detectable MRD. MRD response to blinatumomab was lower in patients with high pre-blinatumomab MRD level, while not impacted by age, WBC, or oncogenic subgroup. With a median follow-up of 20 months, 18-month DFS and OS was 78.8% (95% CI [66.9-86.8]) and 92.1% (95% CI [83.2-96.4]) respectively (Figure 1). Patients with VHR diseases had a worse DFS (68.8%, 95% CI [51.1-81.2]) as compared to other patients (90.6%, 95% CI [72.1-97.1]); p=0.018). This difference of DFS was abrogated by censoring patients at transplant (VHR 88.1%, 95% CI [65.5-96.3] versus others 90.6%, 95% CI [72.1-97.1%], p=0.10). Other factors significantly associated with better DFS were DUX4/ERGdel subgroup, low pre-blinatumomab MRD, and complete MRD response after blinatumomab.

Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up.

Disclosures: Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria.

OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

*signifies non-member of ASH