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518 Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Progress Through Collaboration: Impactful Cooperative Efforts to Optimize Care for ALL
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, adult, Clinical Practice (Health Services and Quality), Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human
Sunday, December 10, 2023: 12:15 PM

Aurelie Cabannes-Hamy, MD1*, Lucien Courtois, PharmD2*, Marie Balsat, MD3*, Mathieu Simonin, MD, PhD4*, Françoise Huguet, M.D.5*, Martine Escoffre-Barbe6*, Florence Pasquier, MD, PhD7*, Caroline Bonmati, MD8*, Pascal Turlure, MD9*, Thomas Cluzeau, M.D.10*, Delphine Lebon11*, Eve Gehlkopf, MD12*, Eolia Brissot13*, Justine Decroocq, MD14*, Patrice Chevallier, MD15, Sylvain Chantepie, MD16*, Victoria Cacheux17*, Sebastien Maury18*, Safia Chebrek19*, Thibaut Leguay, MD20*, Melody Fort21*, Natacha Mauz22*, Mathlide Lamarque23*, Hunault-Berger Mathilde24,25*, Stefan Wickenhauser26*, Jamilé Frayfer27*, Anne Banos, MD28*, Emmanuelle Tavernier, MD29*, Denis Caillot, MD30*, Anne Marie Ronchetti31*, Celine Berthon, MD, PhD32*, Etienne Lengline33*, Véronique Lhéritier34*, Hervé Dombret35*, Ambroise Marçais, MD, PhD36*, Antoine Pinton37*, Guillaume P Andrieu, PhD38*, Nicolas Boissel, MD, PhD39*, Ludovic Lhermitte40*, Vahid Asnafi, MD, PhD41* and Philippe Rousselot, MD, PhD42*

1Department of Hematology, Versailles Hospital., Le Chesnay, France
2Laboratory of Onco-Hematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), PARIS, France
3Clinical Hematology Department, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France, Lyon, France
4Laboratory of Onco-Hematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
5Hematology department, Institut Universaitaire du Cancer, CHU de Toulouse, Toulouse, France
6Hematology Department, Hôpital de Pontchaillou, Rennes, France
7INSERM U790, PR1, IGR, Villejuif, FRA
8Hematology Department, CHU Nancy, Nancy, France
9Service d'Hématologie Clinique, CHU de Limoges, Limoges, France
10Centre Hospitalier Universitaire de Nice, Côte d’Azur University, Nice, France
11Hematology Department, CHU Amiens, Amiens, France
12Hematology, CHU Montpellier, Montpellier, FRA
13Hôpital Saint-Antoine, Sorbonne University, INSERM UMRs 938, Paris, France
14Clinical Hematology Department, Hopital Cochin, APHP, Paris, France, Paris, France
15Service d'hématologie, CHU de Nantes, Nantes, France
16Institut d'Hématologie, CHU de Caen, Caen, France
17CHU Estaing, Clermont Ferrand, FRA
18Hematology Department, Hôpitaux universitaires Henri Mondor AP-HP & Université Paris Est Créteil, Créteil, France
19CH d'Avignon, Avignon, FRA
20Hematology, CHU Bordeaux, Hôpital du Haut-Lévêque, Pessac, France
21Centre Hospitalier de Versailles, Le Chesnay, France
22Department of Hematology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
23Département d'Hématologie, Groupe Hospitalier de la région Mulhouse Sud Alsace, Mulhouse, France
24Hematology Department, CHU Angers, Angers, France
25Angers University Hospital, Angers, ML, France
26Hopital de Nîmes, Hematology Department, Nimes Cedex 9, France
27Hematology Department, Grand Hôpital de l'Est Francilien, Meaux, France
28Centre Hospitalier De Bayonne, Bayonne, FRA
29Département d'hématologie Clinique et de Thérapie Cellulaire, CHU Saint-Etienne, Saint-Etienne, France
30University Hospital INSERM UMR1231 and SAPHIIR-UMR 1231, University of Burgundy & France Comte, Dijon, France
31CH Sud Francilien, Hematology Department, Corbeil Essonne, France
32Centre Hospitalier Universitaire de Lille, Hematology Department, Lille, France
33Department of Hematology, Saint Louis University Hospital, AP-HP, PARIS, FRA
34Service d’Hématologie Coordination GRAALL, HCL, Hôpital Lyon Sud, Pierre Bénite, France
35Saint Louis Hospital, University of Paris, Paris, FRA
36Department of Hematology, Institut Imagine, Necker Hospital, Paris Descartes University, Paris, France
37Hôpital Necker Enfants-Malades, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Paris, France
38Assistance Publique-Hopitaux De Paris (AP-HP), Hopital Necker Enfants-Malades, Paris, France
39Hôpital Saint-Louis, Paris, France
40Laboratory of Onco-Hematology, Necker Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France
41Laboratory of Onco-Hematology, Necker Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France, Paris, France
42Hematology department, UMR1184, Centre Hospitalier de Versailles, University Paris-Saclay, Versailles, France

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations.

Objectives and methods

Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT).

The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy.

Results

Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7RALT were evidenced in 41 pts (48.2%), PI3KALT in 21 pts (24.7%), RAS pathway alterations (RASALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%). These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7RALT in 9 pts (37.5%), PI3KALT in 6 pts (25%), RASALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%).

Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2nd (40%), and 6 in 3rd/4th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy.

By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation.

Conclusion

Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

Disclosures: Cabannes-Hamy: Gilead Kite: Consultancy, Honoraria, Other: support attending meetings; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support attending meetings. Huguet: Clinign: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cluzeau: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support attending meetings/travel; BluePrint: Consultancy; Servier: Consultancy, Honoraria, Other: support attending meetings/travel; Agios: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support attending meetings/travel; Astellas: Honoraria; Incyte: Honoraria; Jazz Pharma: Consultancy, Honoraria; AbbVie: Consultancy, Other: support attending meetings/travel; Pfizer: Other: support attending meetings/travel; Syro: Honoraria; Takeda: Honoraria; Keros: Honoraria; Gilead: Other: support for attending meetings. Chevallier: Takeda: Honoraria; Incyte: Honoraria, Research Funding; Sanofi: Honoraria; Mallinckrodt Pharmaceuticals: Honoraria; Immedica Pharma: Honoraria; Servier: Honoraria. Mathilde: Clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Other: Support for attending meetings. Tavernier: Abbvie: Honoraria. Dombret: Incyte: Honoraria, Other: Support for attending meetings and/or travel, Advisory board; Jazz Pharmaceuticals: Other: Advisory board, Research Funding; Pfizer: Research Funding; Servier: Other: Advisory board, Research Funding; Celegene: Research Funding; Astellas: Research Funding. Boissel: Amgen: Consultancy, Honoraria, Other: Expert Testimony and advisory role, Research Funding; Astellas Pharma: Honoraria; Servier: Consultancy, Honoraria, Other: Advisory role; ARIAD/Incyte: Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory role, Research Funding. Rousselot: Incyte Biosciences: Honoraria, Research Funding.

*signifies non-member of ASH