Therapy of Relapsed/Refractory Acute Lymphoblastic Leukemia Today and Tomorrow

Czech version

Authors: Š. Hrabovský ¹; F. Folber ¹; M. Doubek ^1,2
Authors‘ workplace: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; CEITEC – Středoevropský technologický institut, Masarykova univerzita, Brno ²
Published in: Klin Onkol 2019; 32(2): 90-96
Category: Review
doi: https://doi.org/10.14735/amko201990

Overview

Background:

New diagnostics and treatments, including the use of new drugs, have advanced considerably the treatment of acute lymphoplastic leukemia (ALL) in the past few years. Monoclonal antibodies and immunoconjugates targeting antigens CD19 and CD22 show greater efficacy and more favourable toxicity profiles than standard salvage chemotherapeutic protocols. Two of these drugs – blinatumomab and inotuzumab ozogamicin – have already made their way into clinical practice. Ponatinib and other new generation tyrosine kinase inhibitors allow dose reduction of intensive cytostatic regimens in Ph-positive ALL patients and slowly start to overshadow the importance of allogeneic hematopoietic cell transplants. For the time being, their use is reserved for relapsed/refractory ALL, but they are already available as a first line therapy in clinical trials. An entirely new group of living drugs is emerging for the treatment of ALL – chimeric antigen receptor T-cells produced by genetic modification of native human cells. Chimeric antigen receptor T-cells can be looked upon as in vitro trained professional blast killers. They show an efficacy never seen before for the treatment of relapsed/refractory ALL. On the other hand, this treatment still presents significant risks, mainly due to cytokine release syndrome. Ruxolitinib, mTOR inhibitors, bortezomib, and other drugs for targeted treatment of ALL are currently being evaluated in clinical trials.

Purpose:

The article focuses on current options and news in the field of relapsed and refractory ALL treatment.

This work was created at Masaryk University as part of the project “New Approaches in Research, Diagnostics and Therapy of Hematological Malignancies VI”, number MUNI/A/1105/2018, supported by Czech Ministry of Education, Youth and Sports in 2019.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 28. 8. 2018

Accepted: 10. 1. 2019

Keywords:

acute lymphoblastic leukemia – relapse – monoclonal antibodies – CAR T-cells – tyrosine kinase inhibitors – nelarabine

Sources

1. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol 2011; 29 (5): 532–543. doi: 10.1200/JCO.2010.30.

2. Ustwani OA, Gupta N, Bakhribah H et al. Clinical updates in adult acute lymphoblastic leukemia. Crit Rev Oncol Hematol 2016; 99: 189–199. doi: 10.1016/j.critrevonc.2015.12.007.

3. Cole, CH. Lessons from 50 years of curing childhood leukaemia. J Paediatr Child Health 2015; 51 (1): 78–81. doi: 10.1111/jpc.12803.

4. Šálek C, Šponerová D, Soukupová et al. Akutní lymfoblastová leukemie: historie a současnost. Vnitr Lek 2012; 58 (Suppl 2): 20–26.

5. Faderl S, O’Brien S, Pui CH et al. Adult acute lymphoblastic leukemia: concepts and strategies. Cancer 2010; 116 (5): 1165–1176. doi: 10.1002/cncr.24862.

6. O’Brien S, Thomas DA, Ravandi F et al. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer 2008; 113 (8): 2097–2101. doi: 10.1002/cncr.23819.

7. Folber F, Hadrabová M, Hrabovský Š et al. Acute lymphoblastic leukemia in the elderly: a tough one. Haematologica 2013; 98 (Suppl 1): 498–499.

8. 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): 6226–6233. doi: 10.1182/blood-2012-01-400515.

9. Kantarjian H, Stein A, Gökbuget N et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376 (9): 836–847. doi: 10.1056/NEJMoa1609783.

10. Martinelli G, Boissel N, Chevallier P et al. 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. J Clin Oncol 2017; 35 (16): 1795–1802. doi: 10.1200/JCO.2016.69.3531.

11. Raetz EA, Cairo MS, Borowitz MJ et al. Re-induction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL): phase II results from Children’s Oncology Group (COG) study ADVL04P2. Pediatr Blood Cancer 2015; 62 (7): 1171–1175. doi: 10.1002/pbc.25454.

12. Advani AS, McDonough S, Coutre S et al. SWOG S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukaemia. Br J Haematol 2014; 165 (4): 504–509. doi: 10.1111/bjh.12 778.

13. Poirot L, Philip B, Schiffer-Mannioui C et al. Multiplex genome-edited T-cell manufacturing platform for „off-the-shelf“ adoptive T-cell immunotherapies. Cancer Res 2015; 75 (18): 3853–3864. doi: 10.1158/0008-5472.CAN-14-3321.

14. Kantarjian HM, DeAngelo DJ, Stelljes M et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016; 375 (8): 740–753. doi: 10.1056/NEJMoa1509277.

15. Jabbour E, Sasaki K, Ravandi F et al. Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage. Cancer 2018; 124 (20): 4044–4055. doi: 10.1002/cncr.31 720.

16. Kantarjian H, Ravandi F, Short NJ et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2018; 19 (2): 240–248. doi: 10.1016/S1470-2045 (18) 30011-1.

17. Monjezi R, Miskey C, Gogishvili T et al. Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia 2017; 31 (1): 186–194. doi: 10.1038/leu.2016.180.

18. Zhao Y, Moon E, Carpenito C et al. Multiple injections of electroporated autologous T-cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 2010; 70 (22): 9053–9061. doi: 10.1158/0008-5472.CAN-10-2880.

19. Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 2016; 127 (26): 3312–3320. doi: 10.1182/blood-2016-02-629063.

20. Chmielewski M, Hombach AA, Abken H. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T-cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev 2014; 257 (1): 83–90. doi: 10.1111/imr.12125.

21. Kellner C, Günther A, Humpe A et al. Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30. Oncoimmunology 2015; 5 (1): e1058459. doi: 10.1080/2162402X.2015.1058459.

22. Maude SL, Frey N, Shaw PA et al. Chimeric antigen receptor T-cells for sustained remissions in leukemia. N Engl J Med 2014; 371 (16): 1507–1517. doi: 10.1056/NEJMoa1407222.

23. Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T-cell therapy in B-cell acute lymphoblastic leukemia. Sci Transl Med 2014; 6 (224): 224ra25. doi: 10.1126/scitranslmed.3008226.

24. Luskin MR, DeAngelo DJ. Chimeric antigen receptor therapy in acute lymphoblastic leukemia clinical practice. Curr Hematol Malig Rep 2017; 12 (4): 370–379. doi: 10.1007/s11899-017-0394-x.

25. Porter DL, Levine BL, Kalos M et al. Chimeric antigen receptor-modified T-cells in chronic lymphoid leukemia. N Engl J Med 2011; 365 (8): 725–733. doi: 10.1056/NEJMoa1103849.

26. Porter DL, Hwang WT, Frey NV et al. Chimeric antigen receptor T-cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7 (303): 303ra139. doi: 10.1126/scitranslmed.aac5415.

27. Neelapu SS, Locke FL, Bartlett NL et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377 (26): 2531–2544. doi: 10.1056/NEJMoa1707447.

28. Schuster SJ, Svoboda J, Chong EA et al. Chimeric antigen receptor T-cells in refractory B-cell lymphomas. N Engl J Med 2017; 377 (26): 2545–2554. doi: 10.1056/NEJMoa1708566.

29. Long KB, Young RM, Boesteanu AC et al. CAR T-cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front Immunol 2018; 9: 2740. doi: 10.3389/fimmu.2018.02740.

30. Short NJ, Kantarjian H, Jabbour E et al. Which tyrosine kinase inhibitor should we use to treat Philadelphia chromosome-positive acute lymphoblastic leukemia? Best Pract Res Clin Haematol 2017; 30 (3): 193–200. doi: 10.1016/j.beha.2017.05.001.

31. Fielding AK, Rowe JM, Richards SM et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009; 113 (19): 4489–4496. doi: 10.1182/blood-2009-01-199380.

32. Daver N, Thomas D, Ravandi F et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica 2015; 100 (5): 653–661. doi: 10.3324/haematol.2014.118588.

33. Jabbour E, Pui CH, Kantarjian H. Progress and innovations in the management of adult acute lymphoblastic leukemia. JAMA Oncol 2018; 4 (10): 1413–1420. doi: 10.1001/jamaoncol.2018.1915.

34. Vignetti M, Fazi P, Cimino G et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; 109 (9): 3676–3678. doi: 10.1182/blood-2006-10-052746.

35. Hu Y, Liu Y, Pelletier S et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004; 36 (5): 453–461. doi: 10.1038/ng1343.

36. Porkka K, Koskenvesa P, Lundan T et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008; 112 (4): 1005–1012. doi: 10.1182/blood-2008-02-140665.

37. Ravandi F, Othus M, O’Brien SM et al. US Intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv 2016; 1 (3): 250–259. doi: 10.1182/bloodadvances.2016001495.

38. Ravandi F, O’Brien SM, Cortes JE et al. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 2015; 121 (23): 4158–4164. doi: 10.1002/cncr.29646.

39. Slayton WB, Schultz KR, Kairalla JA et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group trial AALL0622. J Clin Oncol 2018; 36 (22): 2306–2314. doi: 10.1200/JCO.2017.76.7228.

40. Jabbour E, Kantarjian H, Ravandi F et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol 2015; 16 (15): 1547–1555. doi: 10.1016/S1470-2045 (15) 00207-7.

41. Nicolini FE, Basak GW, Kim DW et al. Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation. Cancer 2017; 123 (15): 2875–2880. doi: 10.1002/cncr.30558.

42. Jabbour E, DerSarkissian M, Duh MS et al. Efficacy of ponatinib versus earlier generation tyrosine kinase inhibitors for front-line treatment of newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk 2018; 18 (4): 257–265. doi: 10.1016/j.clml.2018.02.010.

43. Assi R, Kantarjian H, Short NJ et al. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk 2017; 17 (12): 897–901. doi: 10.1016/j.clml.2017.08.101.

44. Giles FJ, Swords RT, Nagler A et al. MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia. Leukemia 2013; 27 (1): 113–117. doi: 10.1038/leu.2012.186.

45. Borthakur G, Dombret H, Schafhausen P et al. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy. Haematologica 2015; 100 (7): 898–904. doi: 10.3324/haematol.2014.115279.

46. Weisberg E, Choi HG, Ray A et al. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. Blood 2010; 115 (21): 4206–4216. doi: 10.1182/blood-2009-11-251751.

47. Rossari F, Minutolo F, Orciuolo E. Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. J Hematol Oncol 2018; 11 (1): 84. doi: 10.1186/s13045-018-0624-2.

48. Wylie AA, Schoepfer J, Jahnke W et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 2017; 543 (7647): 733–737. doi: 10.1038/nature21702.

49. Roberts KG, Morin RD, Zhang J et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012; 22 (2): 153–166. doi: 10.1016/j.ccr.2012.06.005.

50. Zhao WL. Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways. Leukemia 2010; 24: 13–21. doi: 10.1038/leu.2009.223.

51. DeAngelo DJ, Yu D, Johnson JL et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007; 109 (12): 5136–5142. doi: 10.1182/blood-2006-11-056754.

52. Gökbuget N, Basara N, Baurmann H et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood 2011; 118 (13): 3504–3511. doi: 10.1182/blood-2011-01-329441.

53. Commander LA, Seif AE, Insogna IG et al. Salvage therapy with nelarabine etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 2010; 150 (3): 345–351. doi: 10.1111/j.1365-2141.2010.08236.x.