All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia

Mirfakhraie, Reza; Dehaghi, Bentolhoda Kuhestani; Ghorbi, Mahmoud Dehghani; Ghaffari-Nazari, Haniyeh; Mohammadian, Mozhdeh; Salimi, Maryam; Ardakani, Maria Tavakoli; Parkhideh, Sayeh

doi:10.1016/j.htct.2023.06.006

Reza Mirfakhraie

conception and design and acquisition of data

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Bentolhoda Kuhestani Dehaghi

conception and design and acquisition of data

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Mahmoud Dehghani Ghorbi

methodology (lead)

writing, review and editing

revised the final approval of the version to be submitted for publication

Department of Internal Medicine, Imam Hossein Hospital, School of Medicine Shahid Beheshti University of Medical Science, Tehran, Iran

Haniyeh Ghaffari-Nazari

drafting the article or revising it critically for important intellectual content

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Mozhdeh Mohammadian

drafting the article or revising it critically for important intellectual content

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Maryam Salimi

methodology (lead)

writing, review and editing

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Department of Biology and Anatomical Sciences, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Maria Tavakoli Ardakani

methodology (lead)

writing, review and editing

revised the final approval of the version to be submitted for publication

Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Sayeh Parkhideh ^** Corresponding author at: Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box: 1985711151, Iran. E-mail address: s.parkhideh@sbmu.ac.ir (S. Parkhideh).

conception and design and acquisition of data

revised the final approval of the version to be submitted for publication

Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

https://orcid.org/0000-0002-3140-3254

* Corresponding author at: Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box: 1985711151, Iran. E-mail address: s.parkhideh@sbmu.ac.ir (S. Parkhideh).

Conflicts of interest

The authors have no conflicts of interest to declare.

Study	Results	Ref
Phase II trial	• Blinatumomab was tolerable at the dosage of 5 - 15μg/m²/d.	²²22 Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. Phase II trial of the anti-CD19 bispecific T cell–engager Blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–40.
Phase II trial	• Of 36 patients who received blinatumomab, 25 achieved CR and MRD became negative in 88% of responders.
Phase II trial	• 36% of patients achieved CR/CRh within the first two cycles.	²³23 Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, et al., editors. Complete Hematologic and Molecular Response in Adult Patients with Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment with Blinatumomab: Results from a Phase II, Single-Arm, Multicenter Study. American Society of Clinical Oncology; 2017.
	• 88% of CR/CRh responders achieved a complete MRD response.
	• Median RFS and OS were 6.7, and 7.1 months.
	• Of the 16 responders, 44% were alive without relapse, and 50% had relapsed with a median time of 6.7 months.
Phase Ib	• The maximum tolerable blinatumomab dose was 5μg/m2/day for week 1, followed by 15μg/ m2/day for weeks 2 to 4.	²⁴24 Horibe K, Morris JD, Tuglus CA, Dos Santos C, Kalabus J, Anderson A, et al. A phase lb study of Blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Int J Hematol. 2020;112(2):223–33.
	• Blinatumomab appeared to be safe, with preliminary evidence of efficacy in Japanese children with R/RBCP ALL.
	• All patients had at least one treatment-emergent adverse event.
	• The Ml remission rate within the first two treatment cycles was 56%, while 44% of M1 remission showed full bone marrow recovery.
	• The MRD response was detected in one patient who had M1 remission.
Phase II	• A total of 86% of the patients received dexamethasone within 30 days of blinatumomab therapy.	²⁵25 Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of Blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.
	• Of the 89 patients treated with blinatumomab, after two cycles, 81 patients had achieved a CR or CRh.
	• Median relapse-free survival was 5.9 months for the 82 patients in CR or CRh.
	• Median overall survival was 6.1 months for all 189 patients, with a median follow-up of 9.8 months.
	• The treatment-related mortality was low.
	• Of the 73 patients who achieved CR or CRh, 82% of them achieved an MRD response.
Phase II	• Of the 45 patients, 16 achieved CR/CRh within the first two cycles of blinatumomab.	²⁶26 Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Rambaldi A, et al. Long-term follow-up of Blinatumomab in patients with relapsed/refractory Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukaemia: final analysis of ALCANTARA study. Eur J Cancer. 2021;146:107–14
	• After a median follow-up of 25.1 months, the median OS was 9.0 months.
	• A total of 87.5% of CR/CRh patients achieved a complete MRD response with a 9.7-month median duration.
	• Patients with R/R PhÞ ALL revealed a long-term durable response to single-agent blinatumomab.
Phase III	• The OS for blinatumomab versus chemotherapy was higher, both in first salvage and in later salvage.	²⁷27 Dombret H, Topp MS, Schuh AC, Wei AH, Durrant S, Bacon CL, et al. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leuk Lym. 2019;60(9):2214–22.
	• Safety was similar between patients in first salvage and those in later salvage.
	• Blinatumomab was associated with greater remission or survival than chemotherapy, resulting in similar or higher transplantation rates.
	• Salvage therapy with blinatumomab, as the first salvage in adults with Ph-precursor BCP-ALL, may be particularly more beneficial than chemotherapy for overall survival; it may serve as a bridge to transplant in patients in later salvage.
Phase II	• The rate of CR or CRh was 36% for blinatumomab and 25% for SOC.	²⁸28 Rambaldi A, Ribera JM, Kantarjian HM, Dombret H, Ottmann OG, Stein AS, et al. Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia. Cancer. 2020;126(2):304–10.
Phase II	• Compared to external SOC, blinatumomab improves treatment outcomes in patients with r/r Ph + ALL.
Randomized phase III	• The MRD remission in the blinatumomab vs. consolidation chemotherapy groups was 90% vs. 54%.	²⁹29 Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of Blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial. Jama. 2021;325(9):843–54.
	• In the Blinatumomab vs. consolidation chemotherapy group, the death rate was 14.8% vs. 29.6%.
	• Using blinatumomab before allo-HSCT resulted in improved event-free survival, compared to standard chemotherapy.
Retrospective multicenter study	• A total of 75% of the patients became MRD negative following blinatumomab.	³⁰30 Badar T, Szabo A, Advani A, Wadleigh M, Arslan S, Khan MA, et al. Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with Blinatumomab. Blood Adv. 2020;4(10):2308–16.
	• The OS was 12.7 months using blinatumomab.
	• Blinatumomab provides a higher response rate, compared to conventional chemotherapy in RR ALL.
	• Combination therapy with blinatumomab and tyrosine kinase inhibitor combination is safe and effectively improves the long-term outcome of RR Ph1 B-cell ALL patients.

Type of Resistance	Mechanism	Ref
Loss of T cell activity	Up-regulation of PDL-1 expression on leukemic cells and PD-1 expression on T cells contributes to T cell exhaustion.	⁵¹51 Feucht J, Kayser S, Gorodezki D, Hamieh M, Döring M, Blaeschke F, et al. T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget. 2016;7 (47):76902.,⁵³53 Kobayashi T, Ubukawa K, Fujishima M, Takahashi N. Correlation between increased immune checkpoint molecule expression and refractoriness to Blinatumomab evaluated by longitudinal T cell analysis. Int J Hematol. 2021;113 (4):600–5.,⁵⁴54 Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, et al. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody Blinatumomab in patients with B-precursor ALL. Leukemia. 2017;31 (10):2181–90.
	Up-regulation of Tim-3, and TIGIT expression in CD8+ T cells of non-responder patients and elevated expression of Galectin-9 (Tim-3 ligand), PD-L2 (PD-1 ligand) and CD155 (TIGIT ligand) on tumor cells.
	High regulatory T cell (Treg) frequency leads to suppression of T cell proliferation and reduction of anti-leukemic cytotoxicity.
Modification of the target antigen	Down-regulation CD19 expression Suppressive microenvironment Disruption in CD19 membrane export	⁵⁵55 Aldoss I, Song J, Stiller T, Nguyen T, Palmer J, O’Donnell M, et al. Correlates of resistance and relapse during Blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. 2017;92(9):858–65.,⁵⁶56 Braig F, Brandt A, Goebeler M, Tony H-P, Kurze A-K, Nollau P. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129(1):100–4.

[1] * Corresponding author at: Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box: 1985711151, Iran. E-mail address: s.parkhideh@sbmu.ac.ir (S. Parkhideh).

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All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia

ABSTRACT

Introduction:

Method and results:

Conclusion: