Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia

• Published in: Clinical lymphoma, myeloma and leukemia Vol. 24; no. 4; pp. e168 - e173
• Main Authors: Short, Nicholas J., Jabbour, Elias, Jamison, Trevor, Paul, Shilpa, Cuglievan, Branko, McCall, David, Gibson, Amber, Jain, Nitin, Haddad, Fadi G., Nasr, Lewis F., Marx, Kayleigh R., Rausch, Caitlin, Savoy, J. Michael, Garris, Rebecca, Ravandi, Farhad, Kantarjian, Hagop
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2024
• Subjects: Aged; Antibodies, Bispecific - adverse effects; Antibody-drug conjugate; Bispecific antibody; Cardiovascular Diseases - chemically induced; CD19; CD22; Chemoimmunotherapy; Humans; Inotuzumab Ozogamicin - pharmacology; Inotuzumab Ozogamicin - therapeutic use; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Retrospective Studies; Bispecific antibody; Chemoimmunotherapy; CD19; CD22; Antibody-drug conjugate
• ISSN: 2152-2650; 2152-2669
• DOI: 10.1016/j.clml.2023.12.016

The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, “dose-dense” administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10−6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings. We retrospectively analyzed the outcomes of patients with B-cell acute lymphoblastic leukemia (ALL) who received a dose-dense regimen of mini-hyper-CVD, inotuzumab ozogamicin and blinatumomab. In newly diagnosed or measurable residual disease (MRD)-positive ALL, 10/11 patients (91%) achieved next-generation sequencing (NGS) MRD negativity at a sensitivity of 10−6, and 6/10 patients (60%) achieved NGS MRD negativity after cycle 1. The regimen was safe and resulted in high rates of deep and rapid MRD negativity, warranting prospective evaluation.