S1617 A DASATINIB‐BLINATUMOMAB COMBINATION FOR THE FRONT‐LINE TREATMENT OF ADULT PH+ ALL PATIENTS. PRELIMINARY RESULTS OF THE GIMEMA LAL2116 D‐ALBA TRIAL; ON BEHALF OF GIMEMA ACUTE LEUKEMIA WORKING PARTY
Authors: Chiaretti S. , Bassan R. , Vitale A. , Elia L. , Piciocchi A. , Ferrara F. , Lunghi M. , Fabbiano F. , Bonifacio M. , Fracchiolla N. , Salutari P. , Mancino A. , Vignetti M. , Rambaldi A. , Foà R. 
Published: June 2019

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). Their use has led to overall survival (OS) rates approaching 50%. A significantly better survival is observed in patients who become minimal residual disease (MRD) negative. MRD negativity should be considered the primary endpoint of treatment.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.Methods:This multicenter phase II study enrolled Ph+ ALL patients aged 18 years or older (no upper age limit). Prior to dasatinib, patients received a 7‐days steroids pre‐phase: steroids were continued for 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. A minimum of 2 cycles was mandatory, while the administration of up to 3 additional cycles was dependent on the response to therapy with 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. 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), OS, cumulative incidence of relapse (CIR) and safety.Results:Between May 2017 and January 2019, 63 patients have been enrolled. Median age was 54.5 years (range: 24.1–81.7), 53% were female, the median white blood cell count (WBC) was 46.2x109/l (range: 8.61–355.2) and 66.1% carried the p190 fusion. The median follow‐up is 8.75 months (range: 0–19.5). So far, 50 patients have completed induction, 43 the 1st cycle of blinatumomab, 36 the 2nd, 24 the 3rd, 20 the 4th and 15 the 5th. Two patients went off protocol for medical decision and toxicity and 1 died during induction. At the end of induction, 13/50 pts (26%) had a molecular response (4 CMR and 9 PNQ). At the primary endpoint (end of 2nd cycle of blinatumomab), 19/35 (54%) had a molecular response (10 CMR and 9 PNQ) and the rate of molecular responses further increased after subsequent cycles (68% and 80% after the 3rd and 4th cycle, respectively). ABL1 mutational analysis, performed in cases with a MRD increase was performed in 11 patients: 6 cases were WT, while mutations were detected in 5 (4 T315I, and 1 E255K). All mutations but 1 occurred prior to the start of blinatumomab. Importantly, all of them were “cleared” by blinatumomab, confirming its efficacy also in ABL1 mutated cases. A single patient, still in CHR, re‐developed a T315I, Y253H, E255K after treatment completion. Overall, 2 relapses have been recorded (1 hematologic and 1 isolated CNS). So far, 8 patients have been allografted and no transplant‐related mortality have been recorded. The 12‐months OS and DFS are 96.2% and 91.6%, respectively.Summary/Conclusion:This is 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. Though preliminary, the rates of molecular responses and survival are highly promising.image