The addition of inotuzumab ozogamicin to frontline hyper-CVAD and sequential blinatumomab leads to durable survival outcomes in adults with newly diagnosed B-cell acute lymphoblastic leukemia: Four-year follow-up of a phase 2 study

Abstract Background The combination of chemotherapy and blinatumomab (blina) in the frontline setting for Philadelphia-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL) leads to improved outcomes. Inotuzumab ozogamicin (InO) is a CD22 antibody drug conjugate that demonstrates efficacy in the relapsed setting and may further improve outcomes in the frontline. We present the updated results with a median follow-up of 48 months from the phase II study of Hyper-CVAD plus blina +/- InO for adults with newly diagnosed (ND) Ph-negative B-ALL. Methods This phase II study included patients (pts) between 14-59 years (yrs) with ND Ph-negative B-ALL. Pts may have received 1 prior cycle of chemotherapy. Pts received Hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blina. Blina was initiated after 2 cycles of Hyper-CVAD for pts with high-risk features or persistent measurable residual disease (MRD)-positivity by flow cytometry (MFC). Ofatumumab 2000 mg or rituximab 375 mg/m2 was administered in pts with CD20>1%. Starting with pt #39, InO 0.3 mg/m2 on days 1 and 8 was administered during the 2 MTX/Ara-C cycles and 2 blina cycles. Pts received 15 maintenance cycles with POMP and blina administered after every fourth cycle for a total of 7 cycles of blina. Pts received 12 IT chemotherapies and ursodiol. Results As of July 2025, 75 pts were treated (38 without InO [cohort 1] and 37 with InO [cohort 2]). The median age was 33 yrs (range, 18–59); 45% had high-risk cytomolecular features (KMT2Ar, CRLF2 overexpression, TP53mut, complex cytogenetics, low hypodiploidy/near triploidy); 55% in cohort 1 and 35% in cohort 2 (p=0.08). All other characteristics were similar. All patients (100%) achieved a complete remission (CR); 84% after induction (81% in cohort 1 and 89% in cohort 2). Ninety-five percent of pts achieved MRD-negativity by multiparameter flow cytometry (FCM) at any time (66% at CR): 97% (76%) in cohort 1 and 94% (56%) in cohort 2. Seventy-six percent of pts achieved MRD-negativity by next generation sequencing (NGS) at any time (26% at CR): 50% in cohort 1 and 79% in cohort 2. There were no early deaths. The median follow-up for cohort 1 and 2 was 73 months (28-104) and 40 months (24-53), respectively. Of the 38 pts in cohort 1, 14 pts (37%) proceeded to an allogeneic stem cell transplantation (ASCT); of these, 11 (79%) remain alive in remission, 1 (7%) died in CR and 2 relapsed (2/2 with high-risk cytomolecular features, 1/2 bone marrow relapse, 1/2 bone marrow/CNS relapse). Of these 2 relapsed pts, 1 died. Twenty-four pts (63%) did not proceed to ASCT; of these, 16 (67%) remain alive in CR, 3 (13%) died in CR, and 5 (20%) relapsed (4/5 had high-risk cytomolecular features, 3/5 with bone marrow only relapse, 1/5 with bone marrow/extramedullary relapse, 1/5 with extramedullary relapse only). Of these 5 relapsed pts, 4 died. Of the 37 pts in cohort 2, 10 (37%) proceed to ASCT; all remain alive in CR. Twenty-seven pts (65%) did not proceed to ASCT, of these, 24 (89%) remain alive in CR (with 1 receiving CAR T-cell therapy) and 3 (11%) relapsed (1/3 had high-risk cytomolecular features, 2/3 with extramedullary relapse, 1/3 with bone marrow relapse). The median overall survival (OS) and event-free survival (EFS) for the entire cohort have not been reached. The 4-year OS rates for the entire cohort, cohort 1 and cohort 2 are 91%, 82% and 100% (p=0.007), respectively, with 4-year EFS rates of 83%, 74%, and 91% (p=0.034), respectively. After a 6-month landmark, 4-year OS rates were as follows: high risk/no ASCT 79%, high risk/ASCT 90%, low risk/no ASCT 97%, low risk/ASCT 100% (p=0.15). With death as a competing risk, the 4-year cumulative incidence of relapse (CIR) rate was 18% for cohort 1 and 8% for cohort 2 (p = 0.177) and 4-year cumulative incidence of death without relapse rate was 2% and 0% (p = 0.083), respectively. MVA for OS and EFS demonstrates that the administration of InO was the only favorable predictive factor for OS (no InO HR 12.5; p=0.02) and borderline for EFS (no InO HR 3.15; p=0.06). There were no episodes of veno-occlusive disease. Conclusion For pts with ND Ph-negative B-ALL, the addition of InO to Hyper-CVAD plus blina leads to promising survival outcomes with the majority of pts remaining in long-term remission without ASCT. Pts are currently being randomized to Hyper-CVAD plus blina +/- InO.