Background: The outcome of adult Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients greatly improved since the introduction of tyrosine kinase inhibitors (TKIs). A further improvement was achieved with a chemo-free induction/consolidation strategy based on the sequential administration of dasatinib followed by blinatumomab - the D-ALBA GIMEMA LAL2116 trial - with overall survival (OS) and disease-free survival (DFS) rates of 95% and 88% at 18 months (Foa et al, NEJM 2020). Aims: To provide an updated follow-up of the D-ALBA trial and to document the long-term management of previously enrolled patients. Methods: In the D-ALBA trial, after the primary endpoint, patients were followed for 12 months. Data on subsequent treatment and survival are being collected in the ancillary study GIMEMA LAL2217. Results: As reported, 63 patients were enrolled (median age 54 years, 24-82; no upper age limit); the median follow-up is 40 months (0.9-62.5). Since enrollment in the D-ALBA trial, 9 relapses have been documented: 4 hematologic (1 major protocol deviation and 1 in an 82-year old woman who rapidly went off study), 4 at CNS and 1 nodal; median time to relapse was 4.4 months (1.9-25.8). Six deaths were recorded (3 post-allogeneic transplant) in 1st complete hematologic remission (CHR). Of the 58 patients who started blinatumomab, 29 continued treatment with TKI: 21 with dasatinib (85% after receiving all 5 cycles of blinatumomab), 2 switched to imatinib due to intolerance (all after the 5 cycles of blinatumomab) and 5 switched to ponatinib for a molecular minimal residual disease increase or medical decision (66% had received all 5 cycles of blinatumomab). Twenty-nine patients were allografted, including 6 patients in 2nd CHR: 9 from a sibling, 13 from an unrelated donor, 6 from a haploidentical donor and 1 from a cord blood. Six transplants were performed in 2nd CHR. Before transplant, 8 patients received 2 and 3 cycles of blinatumomab, respectively, 5 4 cycles and 6 5 cycles (2 patients were allografted after 1 cycle). Among grafted patients, 6 deaths occurred, 3 of which in cases transplanted in 2nd CHR; thus, the transplant-related mortality in 1st CHR is 10%. When considered in a covariate model, transplant did not impact on both OS and DFS; similar results were obtained also considering allograft only in 1st CHR. It must, however, be underlined that the allografted population was enriched in cases who did not achieve a molecular response (23 pts). Further investigation is ongoing on this aspect. In the updated follow-up, the estimated 48 months OS is 78% (95% CI: 66-92%) and the DFS is 75% (95% CI: 64-87%). DFS was significantly better in patients achieving a molecular response upon induction than in those who did not (100% vs 67%, p=0.016, Fig. 1A), with no events recorded in the group of complete molecular responders and positive-not-quantifiable cases. Furthermore, we confirmed the inferior DFS for patients carrying an IKZF1plus genotype compared to that of cases with no IKZF1 deletions/IKZF1 deletions alone (85% vs 47%, p=0.012, Fig. 1B). Image:Summary/Conclusion: In the updated analysis of the D-ALBA trial and the ancillary GIMEMA LAL2217 study, with a median OS of 40 months, we confirm the reported very favorable outcome. Among the few relapsed cases, we observed a rather high incidence of CNS involvements. These results represent the scientific rationale for the ongoing phase 3 GIMEMA LAL2820 trial, where dasatinib has been substituted by ponatinib, CNS prophylaxis has been increased, and transplant allocation is based on genomic features and minimal residual disease monitoring.