Updated Results from a Phase II Study Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia
Authors: Nguyen Daniel , Kantarjian Hagop , Short Nicholas J. , Jain Nitin , Haddad Fadi G. , Yilmaz Musa , Ferrajoli Alessandra , Kadia Tapan M. , Alvarado Valero Yesid , Maiti Abhishek , Zoghbi Marianne , Senapati Jayastu , Garris Rebecca , Zhao Min , Konopleva Marina , Ravandi Farhad , Jabbour Elias 
Published: December 2024

Background
Blinatumomab improves overall survival (OS) in B-cell acute lymphoblastic leukemia (B-ALL) when combined with chemotherapy in the frontline setting. Inotuzumab ozogamicin (INO) improves OS in the relapsed/refractory setting, and we hypothesized that the addition of INO to hyper-CVAD plus blinatumomab would lead to deeper and more durable responses, reduce relapses, and improve survival. We present 30-month follow-up data since amendment of the protocol to include INO.
Methods
In this phase II study, pts age 14-59 with newly diagnosed Ph-negative B-ALL, including patients (pts) who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) 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). Initially, 8 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 cytomolecular features or persistent MRD-positivity by multiparameter flow cytometry (MFC) 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 (dose reduced to 500 mg/m2 of MTX and 1 g/m2 of Ara-C) and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). The protocol was also amended to increase the number of IT chemotherapy to 12.
Results
As of July 2024, 75 pts have been treated (38 without INO and 37 with INO). The median age across both cohorts was 33 (range, 18-59). 36 pts (48%) had high-risk (HR) cytomolecular features (defined as complex, low hypodiploidy, or near triploidy cytogenetics, KMT2Ar, Ph-like ALL, or TP53 mutation). Sixteen pts were in complete remission (CR) at enrollment after 1-2 cycles of off-protocol therapy, 10 of whom were MRD-negative by MFC.
All 59 pts (100%) with active disease upon study entry achieved CR, with 50 pts (84%) achieving CR after the first cycle. MRD negativity by MFC (sensitivity 10-4) was achieved in 62 of 65 evaluable pts (95%), with 43 pts (66%) achieving MFC MRD negativity after the first cycle. Overall, 40 of 56 tested pts (71%) achieved next-generation sequencing (NGS)-based MRD negativity (sensitivity of 10-6). Pts with HR features had comparable MFC MRD negativity rates (91%; 30/33) compared to pts with standard-risk features (100%; 32/32), but a trend towards lower rates of NGS MRD negativity (17/28 [61%] vs 23/28 [82%]; P=0.1).
The median duration of follow-up for the entire cohort is 38 months (range, 5-91 months). Overall, 8 pts (11%) relapsed in the absence of SCT, 23 pts (31%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 1 pt (1%) underwent CAR T-cell consolidation, 3 pts (4%) died in CR, and 40 pts (53%) remain in continuous remission without SCT or CAR T-cells. Among the 10 relapses, 3 were in the CNS, 2 of which were CNS-only. 7 of 10 pts (70%) who relapsed had HR features. Both pts who relapsed after SCT had a TP53 mutation.
Across both cohorts, the estimated 3-year relapse-free survival (RFS) was 82% and the 3-year OS was 90%. 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: 91% versus 94%; P=0.9). Outcomes of pts with HR features were comparable to standard-risk pts (3-year OS 86% vs 95%; P=0.3), and SCT also did not significantly improve outcomes in HR pts (landmark 3-year OS: 90% vs 81%; P=0.2).
With a median follow-up of 30 months in the INO group, 3 pts (8%) have relapsed, 2 with CNS-only relapses, and none have died. The 30-month RFS in the cohorts with and without INO were 91% vs 74% (P=0.05), and the OS was 100% vs 82% (p=0.008). Among HR pts, the 30-month RFS in the cohort with and without INO were 92% vs 67% (P=0.07) and the OS was 100% vs 76% (P=0.05).
One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and there were no cases of veno-occlusive disease.
Conclusion
In pts with newly diagnosed Ph-negative B-ALL, the addition of INO to the hyper-CVAD + blinatumomab appears to improve OS. To confirm these findings, this study now randomizes pts to hyper-CVAD + blinatumomab ± INO.