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2726 Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Biological therapies, adult, elderly, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Study Population, Human, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Giovanni Marconi, MD1, Alfonso Piciocchi, MS2*, Sabina Chiaretti, MD, PhD3, Cristina Papayannidis, MD, PhD4, Monia Lunghi, MD5*, Prassede Salutari, MD6*, Patrizia Zappasodi7*, Alessandro Rambaldi, MD8, Attilio Olivieri, MD9, Maurizio Cavallari, MD10*, Stefano Soddu2*, Nicola S Fracchiolla, MD11*, Federica Gigli, MD12*, Chiara Cattaneo, MD13*, Daniele Giovanni Mattei, MD14, Anna Candoni, MD15*, Giovanni Grillo, MD16*, Maria Chiara Abbenante, MD17*, Ernesta Audisio18*, Massimiliano Bonifacio, MD19*, Albana Lico, MD20*, Roberto Massimo Lemoli, MD21,22*, Paolo De Fabritiis, MD23*, Felicetto Ferrara, MD24*, Martina Rachele Marino25*, Monica Messina26*, Anna Ferrari, PhD27*, Valentina Robustelli, PhD28,29*, Jacopo Nanni, MD30*, Irene Della Starza, PhD31*, Giorgia Simonetti32*, Maria Stefania De Propris, PhD31*, Maria Teresa Bochicchio32*, Marco Vignetti33*, Paola Fazi, MD2* and Giovanni Martinelli, MD34

1IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori “Dino Amadori”(IRST),, Meldola, Italy
2GIMEMA Foundation, Rome, Italy
3Umberto I - Rome, AOU Policlinico, Rome, Italy
4IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy, Bologna, Italy
5Division of Hematology Department of Translational Medicine , AOU Maggiore della Carità, Università del Piemonte Orientale, Novara, ITA
6Dipartimento Oncologia Ematologia, Ospedale Civile Spirito Santo, Pescara, Italy
7Department of Hematology Oncology, Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
8Hematology, ASST Papa Giovanni XXIII, Bergamo, Italy
9Hematology, Università Politecnica Delle Marche-AOU Ospedali Riuniti, Ancona, Ancona, ITA
10Mestre, Ospedale serenissima, Mestre, Italy
11Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, MILANO, Italy
12European Institute of Oncology, Milan, Italy
13Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
14Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
15Division of Hematology and Bone Marrow Transplantation, Clinica Di Ematologia E Unità Di Terapie Cellulari 'carlo Melzi'-Azienda, Udine, Italy
16Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy, Italy
17university of Bologna, Istituto di Oncoematologia L. e A. Seragnoli, Bologna, Italy
19Department of Medicine, Section of Hematology, University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy
20Hematology and Clinical Immunology, Department of Medicine, AULSS 8 BERICA - OSPEDALE DI VICENZA, Vicenza, Italy
21IRCCS San Martino Hospital, Genoa, Italy
22University of Genoa, Clinic of Hematology, Department of Internal Medicine (DiMI), Genoa, Italy
23Department of Hematology S. Eugenio Hospital, Rome, Italy, Roma, Italy
24+390817472241, Napoli, Italy
25GIMEMA Foundation, ROMA, Italy
26Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
27Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
28Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
29Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy
30Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
31Hematology, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
32Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
33GIMEMA Foundation, Roma, ITA
34IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", Meldola, Italy

Background: Persistence of minimal residual disease (MRD) is associated with a high rate of treatment failure, relapse, and death in B-cell acute lymphoblastic leukemia (B-ALL). Particularly, patients who remain MRD positive before an allogeneic hematopoietic stem cell transplant (HSCT) have an expected disease-related death rate due to the disease of about 60%. The T cell-engager CD19-directed therapy blinatumomab demonstrated considerable efficacy in this setting, however resistant or unsuitable patients have no alternative therapy. Inotuzumab Ozogamicin (IO) is a CD22-directed antibody-drug conjugate with remarkable efficacy in B-ALL with overt disease. Furthermore, IO does not need a high effective immune system to exert activity.

Methods: In this multicenter phase 2 trial (NCT03610438), we are investigating the efficacy of IO in obtaining MRD negativity in two cohorts of 38 Ph+ and 38 Ph- B-ALL patients. IO was administered at the dose of 0.5 mg/sqm on days 1, 8, and 15 of a 28-days cycle. Patients who did not obtain MRD negativity after the 1st IO cycle had the option to receive the 2nd IO cycle maintaining the same dosage. Responding Ph- patients received short-term maintenance with low-dose chemotherapy (alternating vincristine, cyclophosphamide, prednisone, methotrexate, and 6-mercaptopurine), responding PH+ patients received tyrosine kinase inhibitor (TKI) for up to 12 weeks, allowing proper IO washout before HSCT. HSCT ineligible patients entered into low-dose chemotherapy or TKI maintenance for up to 2 years. For the primary endpoint, MRD was centrally assessed at baseline, after course 1, after course 2, and eventually before transplant with high sensitive molecular methods for BCR-ABL1 or V(d)J fusion transcripts. Here, we present the results of an unplanned interim analysis that was generated to evaluate the continuation of the study considering the slow accrual due to the Sars-COV2 pandemic.

Results: To date, 51 patients underwent screening procedures, and 43 were considered eligible. We report data from the first 39 patients treated in the study. Nineteen out of 39 patients had Ph- B-ALL and 20/39 Ph+ B-ALL. Eighteen out of 39 (46%) patients were male. The median age was 55 years (22-84), 15/39 patients (38%) were older than 65 years. Demographics were comparable between Ph+ and Ph- patients. Within Ph+, ALL 39% of patients harbored p190 and 61% p210 fusion transcript. Within Ph- B-ALL, 1 patient harbored ALL1/AF4 and 1 patient harbored ALL1/ENL fusion transcript. Most of the patients received 1 (16/39, 42%) or 2 (19/39, 50%) previous lines of therapy; 5 patients (13%) were resistant to blinatumomab, and all of them had Ph- B-ALL.

Twelve out of 19 (63%) Ph- B-ALL patients received only 1 IO cycle, 7/19 (37%) received 2 cycles; 5/20(25%) Ph+ B-ALL received only 1 IO cycle, and 15/20 (75%) received 2 cycles. To date, central MRD monitoring is available for 20 patients (12 Ph- and 8 Ph+ B-ALL, ongoing for the remaining cases). Overall, MRD negativity was obtained in 7/20 patients (35%); Particularly, in Ph- B-ALL cohort 5/12 (42%) patients achieved MRD negativity, 4/12 (38%) achieved disease reduction at low level MRD positivity (<10-4); in Ph+ B-ALL cohort, 2/8 (25%) patients achieved MRD negativity. One out of 5 (20%) blinatumomab pre-treated patients obtained MRD negative response.

IO was an effective bridge to HSCT for 10/39 patients (26%; in patients <65 years old, 9/24 patients, 37%); Specifically, all 7 patients who obtained MRD negativity after IO, a patient with low-positive MRD and 2 patients with non yet available MRD data were bridged to HSCT. Accordingly, with the caveat of a short median follow-up (2.8 months, range 0.6-20.0 months), overall survival in the study population seems promising (figure 1, median OS not reached).

Overall, adverse events collected during the study were limited in number and grading. Also, myelotoxicity was manageable. Out of 39 patients, we documented 1 veno-occlusive disease (2.5%) that occurred within 20 days from the last IO dose and before any HSCT.

Conclusions: IO administration demonstrated activity with a good safety profile in the setting of MRD positive B-ALL, including blinatumomab resistant patients. Importantly, IO was capable to bridge 37% of eligible patients to HSCT, augmenting the chance to achieve a cure. The continuation of the study will deliver mature efficacy and survival data for a proper evaluation of this promising strategy.

Disclosures: Marconi: pfizer: Honoraria, Research Funding, Speakers Bureau; servier: Honoraria; astellas: Honoraria; menarini/stemline: Honoraria, Speakers Bureau; abbvie: Research Funding. Chiaretti: Pfizer: Other: advisory board; Gilead: Other: advisory board; Abbvie: Other: advisory board; Incyte: Other: advisory board; Amgen: Other: advisory board. Papayannidis: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees. Rambaldi: Janssen: Honoraria; Roche: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Kite-Gilead: Honoraria; Jazz: Honoraria; ABBVIE: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene-BMS: Honoraria; Omeros: Honoraria. Fracchiolla: Amgen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Candoni: Celgene, Abbvie, Pfizer, Janssen, Astellas, Jazz, Gilead, Incyte, Amgen: Other: Speaker honoraria. Bochicchio: werfen, Imstrumentation Laboratory: Consultancy, Honoraria. Vignetti: Astrazeneca: Speakers Bureau; AbbVie: Speakers Bureau. Martinelli: Stemline: Consultancy; Pfizer: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Incyte: Consultancy; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Abbvie: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau.

OffLabel Disclosure: Inotuzumab is used for MRD positive ALL instead that in patient with overt disease

*signifies non-member of ASH