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. 2024 Apr;24(4):e168-e173.
doi: 10.1016/j.clml.2023.12.016. Epub 2023 Dec 30.

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

Nicholas J Short  1 , Elias Jabbour  2 , Trevor Jamison  2 , Shilpa Paul  3 , Branko Cuglievan  4 , David McCall  4 , Amber Gibson  4 , Nitin Jain  2 , Fadi G Haddad  2 , Lewis F Nasr  2 , Kayleigh R Marx  3 , Caitlin Rausch  3 , J Michael Savoy  3 , Rebecca Garris  2 , Farhad Ravandi  2 , Hagop Kantarjian  2
Affiliations

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

Nicholas J Short et al. Clin Lymphoma Myeloma Leuk. 2024 Apr.

Abstract

Background: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Antibody-drug conjugate; Bispecific antibody; CD19; CD22; Chemoimmunotherapy.

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Conflict of interest statement

Disclosure N.J.S, E.J., and H.K. have received research funding and honoraria from Amgen and Pfizer Inc. The rest of the authors have no relevant conflicts to disclose.

Figures

Figure 1.
Figure 1.. Example treatment schema of the dose-dense mini-hyper-CVD, inotuzumab ozogamicin and blinatumomab regimen.
Only the first 4 cycles are shown. Note that this is an example of the regimen used in this cohort, although variations to dosing and timing of some agents were implemented in some patients.
Figure 2.
Figure 2.
Overall survival of the frontline and MRD consolidation cohorts
See this image and copyright information in PMC

References

    1. Short NJ, Kantarjian H, Jabbour E. Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. Leukemia. 2021;35(11):3044–3058. - PubMed
    1. Jabbour E, Short NJ, Senapati J, et al. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial. Lancet Haematol. 2023;10(6):e433–e444. - PMC - PubMed
    1. Kantarjian H, Haddad FG, Jain N, et al. Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia. J Hematol Oncol. 2023;16(1):44. - PMC - PubMed
    1. Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116–1123. - PubMed
    1. Short NJ, Kantarjian H, Ravandi F, et al. High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse. Blood Adv. 2022;6(13):4006–4014. - PMC - PubMed

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