The Addition of Inotuzumab Ozogamicin to Hyper-CVAD Plus Blinatumomab Further Improves Outcomes in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia: Updated Results from a Phase II Study

Background: Blinatumomab and inotuzumab ozogamicin (INO) both improve overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD) after initial ALL-directed therapy. We hypothesized that early incorporation of blinatumomab in pts with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. We subsequently amended this study to add INO in order to further improve outcomes.

Methods: We conducted a phase II study to evaluate the efficacy and safety of hyper-CVAD with sequential blinatumomab, with or without INO, in pts with newly diagnosed Ph-negative B-cell ALL. Pts 14-59 years of age with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m²). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO).

Results: As of June 2022, 62 pts have been treated (38 without INO and 24 with INO). Pt characteristics are summarized in Table 1. The median age was 34 years (range, 18-59 years). 32 pts (52%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 positivity by flow and/or TP53 mutation). 14 pts were in CR at enrollment, 7 of whom were MRD-negative by flow.

Among 48 pts with active disease at study entry, 100% achieved CR, with 81% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 37/53 evaluable pts (70%) after 1 cycle and 48/53 evaluable pts (91%) overall. Two of the 5 pts who did not achieve MRD negativity were later found to have a NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have received only 1 cycle.

The median duration of follow-up is 23 months (range, 1-63 months). Overall, 6 pts (10%) relapsed while on study, 20 pts (32%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 2 pts (3%) died in CR, and 34 pts (55%) remain in continuous remission without SCT. All relapses occurred in pts with ≥1 poor-risk feature(s), and no relapses have occurred beyond 2 years from the start of treatment.

For the entire cohort, the 3-year continuous remission duration (CRD) and OS rates were 83% and 84%, respectively (Figure 1). The 3-year OS rate for pts without a high-risk baseline feature was 90% and was 78% for pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 86% versus 88%). In the INO group, only 1 pt has relapsed and none has died. This pt had CNS disease at the time of enrollment and had a CNS-only relapse after 16 months of remission. The estimated 1-year CRD and OS rates in the INO cohort were both 100% (Figure 2).

Treatment was overall well-tolerated. One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

Conclusion: The addition of INO to hyper-CVAD with sequential blinatumomab is safe and highly effective as frontline treatment of Ph-negative B-cell ALL. This study shows the feasibility of incorporating both INO and blinatumomab into the frontline treatment of pts with B-cell ALL. Outcomes of the pts treated in the INO cohort are particularly promising.