Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial

LYMPHOID TUMORS ,

SN Bondarenko1, EN Parovichnikova2, AA Maschan3, OYu Baranova4, TV Shelekhova5, VA Doronin6, VYa Mel’nichenko7, KD Kaplanov8, OS Uspenskaya9, AN Sokolov2, NV Myakova3, IS Moiseev1, IV Markova1, EI Darskaya1, AG Smirnova1, TA Bykova1, BI Ayubova1, IA Samorodova1, EV Babenko1, IM Barkhatov1, TL Gindina1, AD Kulagin1, BV Afanas’ev1

1 RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

3 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

4 NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

5 VI Razumovskii Saratov State Medical University, 112 Bol’shaya Kazach’ya str., Saratov, Russian Federation, 410012

6 Municipal Clinical Hospital No. 40, 7 Kasatkina str., Moscow, Russian Federation, 129301

7 NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

8 Volgograd Regional Clinical Oncologic Dispensary, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

9 Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Sergei Nikolaevich Bondarenko, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-72; e-mail: dr.sergeybondarenko@gmail.com

For citation: Bondarenko SN, Parovichnikova EN, Maschan AA, et al. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial. Clinical oncohematology. 2019;12(2):145–53.

DOI: 10.21320/2500-2139-2019-12-2-145-153

ABSTRACT

Background. Recent advances in the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL) are attributed to the implementation of immunotherapy methods which include blinatumomab, the bispecific engager of a patient’s endogenous T-cells (Blincyto™, Amgen®) (BC).

Aim. To assess BC efficacy and toxicity in the treatment of R/R ALL patients with persistence of minimal tumor clone before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. The trial included 66 B-ALL patients with CD19+ aged 18 to 72 years, 23 (35 %) of them with measurable minimal residual disease (MRD+) and 43 (65 %) with R/R ALL. In 18 (27 %) patients BC was administered after prior allo-HSCT.

Results. In the overall group 2-year overall survival (OS) and disease-free survival (DFS) in patients with response to BC treatment were 53 % and 38 % respectively. In the R/R ALL group complete remission (CR) was achieved in 29 (67 %) patients including 24 (83 %) patients with negative MRD. CR rate was higher in standard cytogenetic risk group (73 %) in comparison with high-risk group (59 %). In patients with more or less than 50 % blast cells in bone marrow CR rate was 85 % and 61 %, respectively. When BC was administered after prior allo-HSCT and without it CR rate was 80 % and 60 %, respectively. In R/R ALL patients with response to BC 2-year OS and DFS were 40 % and 26 %, respectively, in the MRD+ group of ALL patients they were 66 % and 51 %, respectively. Relapse rate was lower in the group with allo-HSCT than in the group without it, i.e. 21 % vs. 55 %. Adverse events of grade 3–4 were observed in 25 (38 %) patients. In 11 (16 %) patients BC therapy had to be discontinued, in 5 (7 %) patients it was terminated prior to the scheduled date.

Conclusion. BC efficacy is higher in the MRD+ group and in R/R ALL patients with smaller tumor mass. BC treatment after allo-HSCT yields remissions in most patients and can be combined with immune-adoptive therapy.

Keywords: acute lymphoblastic leukemia, targeted therapy, blinatumomab.

Received: August 22, 2018

Accepted: January 18, 2019

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REFERENCES

  1. Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. 2012;120(10):2032–41. doi: 10.1182/blood-2011-12-399287.

  2. Faderl S, O’Brien S, Pui C-H, et al. Adult Acute Lymphoblastic Leukemia. Cancer. 2010;116(5):1165–76. doi: 10.1002/cncr.24862.

  3. Gokbuget N, Dombret H, Ribera J-M, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractor y acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524–33. doi: 10.3324/haematol.2016.144311.

  4. Pavlu J, Labopin M, Zoellner AK, et al. Allogeneic Hematopoietic Cell Transplantation for Primary Refractory Acute Lymphoblastic Leukemia: A Report From the Acute Leukemia Working Party of the EBMT. Cancer. 2017;123(11):1965–70. doi: 10.1002/cncr.30604.

  5. Bondarenko SN, Moiseev IS, Slesarchuk OA, et al. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cellular Therapy and Transplantation. 2016;5(2):12–20. doi: 10.18620/1866-8836-2016-5-2-12-20.

  6. Паровичникова Е.Н., Соколов А.Н., Троицкая В.В. и др. Острые Ph-негативные лимфобластные лейкозы взрослых: факторы риска при использовании протокола ОЛЛ-2009. Терапевтический архив. 2016;88(7):15–24.

    [Parovichnikova EN, Sokolov AN, Troitskaya VV, et al. Acute Ph-negative lymphoblastic leukemias in adults: Risk factors in the use of the ALL-2009 protocol. Terapevticheskii arkhiv. 2016;88(7):15–24. (In Russ)]

  7. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117(5):1137–46. doi: 10.1172/jci31405.

  8. Biagi E, Marin V, Attianese GM, et al. Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies. Haematologica. 2007;92(3):381–8. doi: 10.3324/haematol.10873.

  9. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226–33. doi: 10.1182/blood-2012-01-400515.

  10. Topp MS, Gokbuget N, Stein AS, 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. doi: 10.1016/s1470-2045(14)71170-2.

  11. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31. doi: 10.1182/blood-2017-08-798322.

  12. Kantarjian H, Stein AS, Gokbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836–47. doi: 10.1056/NEJMoa1609783.

  13. Zugmaier G, Gokbuget N, Klinger M, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015;126(24):2578–84. doi: 10.1182/blood-2015-06-649111.