First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients

Abstract Introduction. The outcome of adult Ph+ ALL has improved with the introduction of tyrosine kinase inhibitors (TKI) and, more recently, the addition of immunotherapy, i.e. blinatumomab, as shown by the GIMEMA LAL2116 trial (Foà et al, NEJM 2020 & JCO 2024). To improve the results and formally compare the efficacy and safety of a chemo-free approach to a strategy based on a TKI + chemotherapy, the GIMEMA phase III ALL2820 protocol (2:1 random) was designed for newly diagnosed adult Ph+ ALL (>18 years, no upper age limit). We report the first results of both treatment arms, in terms of complete hematologic remission (CHR), safety and toxicity, measurable residual disease (MRD, i.e. complete molecular response and positive non-quantifiable) after induction (day +70) and after 2 cycles of blinatumomab/therapy (day +133) by intention-to-treat, and event-free survival (EFS). Methods. The experimental (exp) arm was based on a steroid pre-phase followed by a 70-day induction with ponatinib at 45 or 30 mg according to age (< or >65 years) and at least 2 cycles (maximum 5) of i.v. blinatumomab. The control (cont) arm was based on imatinib 800 or 600 mg daily, depending on age (< or >65 years) + chemotherapy (6 or 4 cycles for patients < or >65 years). Response to induction was evaluated at day +70 after ponatinib or after 3 chemotherapy courses in the exp and cont arm, respectively. MRD response was set at day +133 (after 2 blinatumomab cycles or 4/6 chemotherapy cycles). A crossover to the exp arm was foreseen in MRD+ patients (pts) after cycle 4/6, or earlier in case of refractoriness or mutation development. Results. Between September 2021 and January 2025, 236 pts were enrolled, 158 in the exp and 78 in the cont arm. Features did not differ among the 2 arms (exp and cont arm): median age 57 (19-84) vs 55 (20-80) years (28% and 27% patients >65 years), male gender 50% vs 59%, median white blood count (WBC) 11x109/l (0.3-244) vs 18x109/l (1-231), p190 fusion protein 70% vs 63%, p210 and/or p190/p210 30% vs 37%, IKZF1 deletion 34% vs 49%, IKZF1plus34% vs 26%, no IKZF1 deletion 32% vs 26%. At the end of induction, there was a significantly higher CHR rate in the exp arm: 94.4% vs 79.4% (p=0.001). Non-CHR attainment in the exp arm were due to 6 (3.8%) deaths (pneumonia 4, paralyticus ileus 1, unknown cause 1), 1 early toxicity and subsequent relapse (0.6%), and 2 (1.2%) pts off study for cardiac toxicity while in CHR. In the cont arm, 8 (10.2%) pts died (septic shock 4, renal failure 1, cognitive deterioration 1, heart attack 1, pulmonary hemorrhage 1), 3 (3.8%) went off trial for toxicity, 2 withdrew consent (2.6%) and 3 (3.8%) were refractory. MRD response after induction was superimposable: 46.8% and 43.6% in the exp and cont arm. At day +133, MRD responses were higher in the exp arm: 111 (70.2%) compared to 41 (52.7%) (p=0.009). The % of pts becoming MRD- after further blinatumomab cycles rose to 80.3%. As per protocol, 29 (37.2%) pts in the cont arm crossed to the exp arm, 4 (13.8%) at very early time-points (1 refractoriness, 3 mutations). The crossover led to 18 (62.1%) pts becoming MRD-. So far, 10 relapses (4.2%) have occurred (median time to relapse 5 months), 7 (4.4%) in the exp and 3 (3.8%) in the cont arm. In both arms, 1 BCR::ABL1- relapse was detected, suggesting the presence of a Ph- subclone at diagnosis. In relapsed pts, the median WBC count was 22.4 x109/l (2.4-144) and 10.4 x109/l (2.7-11.7) in the exp and cont arm; the IKZF1plus signature was identified only in 4 cases of the exp arm.Three relapses of the exp arm occurred in pts who discontinued treatment. Three additional deaths in 1st CHR were recorded, 2 after allogeneic transplant and 1 for clinical deterioration. The 18-months EFS (median follow-up 19.6 months, range 0.1-44) showed a significant advantage for the exp arm: 89.9%, CI: 85.1-94.9% vs 76.8%, CI: 67.6-87.3% (p=0.011). Conclusions. The first results of the phase III GIMEMA ALL2820 trial show for the first time in a head-to-head comparison a significant advantage of a chemo-free targeted/immunotherapeutic strategy over a TKI/chemotherapy approach, with higher CHR and MRD responses, increasing further after additional blinatumomab cycles, fewer deaths and improved EFS. Compared to the GIMEMA LAL2116 trial, an increase in MRD negativity and less relapses were observed. A chemo-free approach should be the new standard for adult Ph+ ALL.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-439
Citations
2
Primary Topic
Acute Lymphoblastic Leukemia research
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article
Field-Weighted Citation Impact
3.76
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article

First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients

Vittorio Bellomarino, Monica Bocchia, Antonino Mulè, Daniela Pietrasanta et al.
2 citations
Blood
Acute Lymphoblastic Leukemia research
3.76
article

First results of the Phase III GIMEMA ALL2820 trial comparing ponatinib plus blinatumomab to imatinib and chemotherapy for newly diagnosed adult ph+ acute lymphoblastic leukemia patients

Vittorio Bellomarino, Monica Bocchia, Antonino Mulè, Daniela Pietrasanta, Daniele Giovanni Mattei, Michela Ansuinelli, Mario Luppi, Mariangela Di Trani, Robin Foà, Antonella Cucca, Prassede Salutari, Paola Fazi, Silvia Imbergamo, Elisabetta Todisco, Federico Mosna, Erika Borlenghi, Mario Annunziata, Barbara Scappini, Monica Messina, Francesco Di Raimondo, Cristina Skert, Francesco Zaja, Sabina Chiaretti, Alfonso Piciocchi, Patrizia Chiusolo, Marco Cerrano, Martina Rachele Marino, Daniele Vallisa, Matteo Della Porta, Valentina Mancini, Monia Lunghi, Claudio Romani, Alessandro Rambaldi, Patrizia Zappasodi, Martina Chiarucci, Irene Della Starza, Massimiliano Bonifacio, Fabio Giglio, Claudia Basilico, Crescenza Pasciolla, Catello Califano, Deborah Cardinali, Bianca Serio, Maria Paola Martelli, Stefano Soddu, Maurizio Musso, Nicola Stefano Fracchiolla, Giuseppe Rodolfo Nunziata, Caterina Alati, Maria Stefania De Propris, Loredana Elia, Giada Almici
article en
2 citations

Abstract

Abstract Introduction. The outcome of adult Ph+ ALL has improved with the introduction of tyrosine kinase inhibitors (TKI) and, more recently, the addition of immunotherapy, i.e. blinatumomab, as shown by the GIMEMA LAL2116 trial (Foà et al, NEJM 2020 & JCO 2024). To improve the results and formally compare the efficacy and safety of a chemo-free approach to a strategy based on a TKI + chemotherapy, the GIMEMA phase III ALL2820 protocol (2:1 random) was designed for newly diagnosed adult Ph+ ALL (>18 years, no upper age limit). We report the first results of both treatment arms, in terms of complete hematologic remission (CHR), safety and toxicity, measurable residual disease (MRD, i.e. complete molecular response and positive non-quantifiable) after induction (day +70) and after 2 cycles of blinatumomab/therapy (day +133) by intention-to-treat, and event-free survival (EFS). Methods. The experimental (exp) arm was based on a steroid pre-phase followed by a 70-day induction with ponatinib at 45 or 30 mg according to age (< or >65 years) and at least 2 cycles (maximum 5) of i.v. blinatumomab. The control (cont) arm was based on imatinib 800 or 600 mg daily, depending on age (< or >65 years) + chemotherapy (6 or 4 cycles for patients < or >65 years). Response to induction was evaluated at day +70 after ponatinib or after 3 chemotherapy courses in the exp and cont arm, respectively. MRD response was set at day +133 (after 2 blinatumomab cycles or 4/6 chemotherapy cycles). A crossover to the exp arm was foreseen in MRD+ patients (pts) after cycle 4/6, or earlier in case of refractoriness or mutation development. Results. Between September 2021 and January 2025, 236 pts were enrolled, 158 in the exp and 78 in the cont arm. Features did not differ among the 2 arms (exp and cont arm): median age 57 (19-84) vs 55 (20-80) years (28% and 27% patients >65 years), male gender 50% vs 59%, median white blood count (WBC) 11x109/l (0.3-244) vs 18x109/l (1-231), p190 fusion protein 70% vs 63%, p210 and/or p190/p210 30% vs 37%, IKZF1 deletion 34% vs 49%, IKZF1plus34% vs 26%, no IKZF1 deletion 32% vs 26%. At the end of induction, there was a significantly higher CHR rate in the exp arm: 94.4% vs 79.4% (p=0.001). Non-CHR attainment in the exp arm were due to 6 (3.8%) deaths (pneumonia 4, paralyticus ileus 1, unknown cause 1), 1 early toxicity and subsequent relapse (0.6%), and 2 (1.2%) pts off study for cardiac toxicity while in CHR. In the cont arm, 8 (10.2%) pts died (septic shock 4, renal failure 1, cognitive deterioration 1, heart attack 1, pulmonary hemorrhage 1), 3 (3.8%) went off trial for toxicity, 2 withdrew consent (2.6%) and 3 (3.8%) were refractory. MRD response after induction was superimposable: 46.8% and 43.6% in the exp and cont arm. At day +133, MRD responses were higher in the exp arm: 111 (70.2%) compared to 41 (52.7%) (p=0.009). The % of pts becoming MRD- after further blinatumomab cycles rose to 80.3%. As per protocol, 29 (37.2%) pts in the cont arm crossed to the exp arm, 4 (13.8%) at very early time-points (1 refractoriness, 3 mutations). The crossover led to 18 (62.1%) pts becoming MRD-. So far, 10 relapses (4.2%) have occurred (median time to relapse 5 months), 7 (4.4%) in the exp and 3 (3.8%) in the cont arm. In both arms, 1 BCR::ABL1- relapse was detected, suggesting the presence of a Ph- subclone at diagnosis. In relapsed pts, the median WBC count was 22.4 x109/l (2.4-144) and 10.4 x109/l (2.7-11.7) in the exp and cont arm; the IKZF1plus signature was identified only in 4 cases of the exp arm.Three relapses of the exp arm occurred in pts who discontinued treatment. Three additional deaths in 1st CHR were recorded, 2 after allogeneic transplant and 1 for clinical deterioration. The 18-months EFS (median follow-up 19.6 months, range 0.1-44) showed a significant advantage for the exp arm: 89.9%, CI: 85.1-94.9% vs 76.8%, CI: 67.6-87.3% (p=0.011). Conclusions. The first results of the phase III GIMEMA ALL2820 trial show for the first time in a head-to-head comparison a significant advantage of a chemo-free targeted/immunotherapeutic strategy over a TKI/chemotherapy approach, with higher CHR and MRD responses, increasing further after additional blinatumomab cycles, fewer deaths and improved EFS. Compared to the GIMEMA LAL2116 trial, an increase in MRD negativity and less relapses were observed. A chemo-free approach should be the new standard for adult Ph+ ALL.

BloodVol. 146(Supplement 1)
University of Verona (IT), University of Modena and Reggio Emilia (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Padua (IT), University of Trieste (IT), Ospedale di Circolo e Fondazione Macchi (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Ospedale Maggiore (IT), Ospedale Antonio Cardarelli (IT), International School of Trieste (IT), Azienda Ospedaliera di Perugia (IT), Azienda Unita' Sanitaria Locale Di Modena (IT), Ospedale di Bolzano (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Azienda Ospedaliera Universitaria Integrata Verona (IT), Azienda Ospedaliero Universitaria San Giovanni Battista (IT), Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT), Ospedale Vincenzo Cervello (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Istituto Nazionale di Fisica Nucleare, Sezione di Padova (IT), Ospedale Papa Giovanni XXIII (IT), Ospedale di Santo Spirito (IT), Azienda Ospedaliera S.Giuseppe Moscati (IT), Fondazione Gimema Onlus (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Ospedali Riuniti Marche Nord (IT), Azienda Ospedaliero Universitaria Maggiore della Carita (IT), Presidio Ospedaliero (IT), Ospedale di Circolo di Busto Arsizio (IT), Istituto Tumori Bari (IT), IRCCS Ospedale San Raffaele (IT), Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT), Azienda Ospedaliera Universitaria Senese (IT), Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo (IT), Guglielmo da Saliceto Hospital (IT), Ospedale dell' Angelo (IT), Azienda Ospedaliera Ospedale Maggiore (IT), Azienda di Rilievo Nazionale ed Alta Specializzazione (IT), Azienda USL di Pescara (IT), Policlinico San Matteo Fondazione (IT), Fondazione Humanitas per la Ricerca (IT), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco" (IT), Novamont (Italy) (IT), La Maddalena (IT), Azienda Ospedaliera G. Brotzu (IT), Sapienza University of Rome (IT)
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Acute Lymphoblastic Leukemia research
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