Dasatinib-Blinatumomab Combination for the Front-Line Treatment of Adult Ph+ ALL Patients. Updated Results of the Gimema LAL2116 D-Alba Trial
Authors: Chiaretti Sabina , Bassan Renato , Vitale Antonella , Elia Loredana , Piciocchi Alfonso , Puzzolo Cristina , Canichella Martina , Ferrara Felicetto , Lunghi Monia , Fabbiano Francesco , Bonifacio Massimiliano , Fracchiolla Nicola , Salutari Prassede , Mancino Alessandra , Vignetti Marco , Guarini Anna , Rambaldi Alessandro , Foà Robin 
Published: February 2020

Background. The management of adult patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL), including the elderly, has changed since the introduction of tyrosine kinase inhibitors (TKI). A significantly better survival is observed in patients who become minimal residual disease (MRD)-negative.
Aims. To increase the rate of MRD-negative patients, we designed a front-line chemo-free induction-consolidation trial (D-ALBA, GIMEMA LAL2116) based on the combination of the second-generation TKI dasatinib with the bispecific monoclonal antibody blinatumomab. The primary endpoint of the study was the rate of patients who achieved a complete molecular remission (CMR) or a positive non-quantifiable (PNQ) disease after at least two cycles of blinatumomab. Secondary endpoints included disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR) and safety. We also sought to evaluate the prognostic impact of additional genomic lesions - performed on diagnostic samples - and the potential changes in the immunologic compartment, in terms of T cells and T-regulatory cells (Tregs), evaluated by flow cytometry (CD3+/CD4+, CD3+/CD8+ and CD3+/CD4+/CD25+/FOXp3+, respectively).
Methods. This multicenter phase II study enrolled Ph+ ALL patients aged 18 years or older, with no upper age limit. Prior to dasatinib, patients received a 7-day steroids pre-phase: steroids were continued for further 24 days and stopped at day 31. Dasatinib (140 mg/day) was administered as induction for 85 days. Thereafter, patients who obtained a complete hematologic response (CHR) received a post-induction consolidation treatment with blinatumomab at a flat dose of 28 μg/day. A minimum of 2 cycles was mandatory, while the administration of up to 3 additional cycles was allowed based on the response to blinatumomab and medical decision. Dasatinib was continued during treatment with blinatumomab. CNS prophylaxis was carried out during the whole treatment. Post-consolidation treatment was open.
Results. Between May 2017 and January 2019, 63 patients have been enrolled. Median age was 54.5 years (range: 24.1-81.7), 54% were female, the median white blood cell count (WBC) was 42 x109/l (range: 0.63-63.5) and 65.1% carried the p190 fusion. Copy number aberration analysis showed that the most frequent lesion was, as expected, IKZF1 deletion (54%): 23.9% of patients were thus classified as IKZF1plus (i.e. IKZF1 and/or PAX5 and/or CDKN2A/B deletions). The median follow-up is 10 months (range: 0.9-21.5). So far, 61 patients have completed induction, 55 the 1st cycle of blinatumomab, 47 the 2nd cycle, 33 the 3rd, 26 the 4th and 17 the 5th. Two patients have gone off protocol for medical decision and toxicity, and 1 died during induction. At the end of the induction with dasatonib, 17/58 pts (29.3%) had a molecular response (6 CMR and 11 PNQ). At the primary endpoint (end of the 2nd cycle of blinatumomab), 27/47 (56.3%) had a molecular response (17 CMR and 10 PNQ). The rates of molecular responses further increased after subsequent cycles of blinatumomab: 65.7% after the 3rd cycle and 80% after the 4th cycle. ABL1 mutational analysis was carried out in 15 patients with evidence of a MRD increase: 8 cases were WT, while mutations were detected in 7 (6 T315I, and 1 E255K). All mutations but 1 occurred prior to the start of blinatumomab and all were "cleared" by blinatumomab. The analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (19.8% before the start of blinatumomab and 29% after the 5th cycle, p=0.04) and a significant reduction in the rate of Tregs (11% before blinatumomab and 3.7% after the 5th cycle, p=0.02). Overall, 5 relapses have been recorded (2 hematologic, 2 isolated CNS and 1 nodal). The 12-month OS and DFS are 94.2% and 87.8%. A significantly inferior DFS (61.4%, p=0.01) was observed in IKZF1plus cases: these patients were prone to develop deleterious mutations. So far, 12 patients have been allografted and no transplant-related mortality has been recorded.
Conclusions. In the first chemo-free induction-consolidation protocol for adult Ph+ ALL patients of all ages based on a combination of a targeted and immunotherapeutic strategy, the rates of molecular responses and survival are highly promising; patients harboring IKZF1 plus represent, also in this setting, a clinical challenge.

Disclosures
Chiaretti: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Bassan:Amgen Inc.: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Bonifacio:BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Vignetti:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training. Rambaldi:Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.