Novel Therapies in the Treatment of Adult Acute Lymphoblastic Leukemia

Abstract

Purpose of Review

Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy. Advances in multi-agent chemotherapy have resulted in dramatic improvements in the number of pediatric cases that result in a cure; however, until recently, treatment options for older adults or patients with relapsed and refractory disease were extremely limited. This review seeks to describe in greater detail a number of emerging novel treatment modalities recently approved for this cancer.

Recent Findings

In this review, we discuss a number of recently approved novel therapies for ALL, including new approaches with targeted tyrosine kinase inhibitors, novel immune-based therapies including the bispecific antibody blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin, and the role of cellular therapeutics such as chimeric antigen receptor (CAR) T cells. We also discuss the impact that advances in diagnostics and disease classification and monitoring have had on treatment.

Summary

A number of advances in ALL have resulted in dramatic changes to the treatment landscape and therapeutic options both at the time of diagnosis and in salvage. These findings are reshaping our treatment paradigms throughout the course of disease.

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Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.

    NCI NCI. PDQ® Adult Treatment Editorial Board. PDQ Adult Acute Lymphoblastic Leukemia Treatment, Bethesda, MD. 2019; Available from: https://www.cancer.gov/types/leukemia/hp/adult-all-treatment-pdq. Accessed 24 Jan 2020.

  2. 2.

    National Cancer Institute B MD. SEER Cancer Stat Facts: Acute Lymphocytic Leukemia [Internet]. Available from: https://seer.cancer.gov/statfacts/html/alyl.html. Accessed 18 Feb 2020.

  3. 3.

    Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–52.

    CAS  PubMed  Google Scholar 

  4. 4.

    Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN, et al. Long term results of the Children’s Cancer group studies for childhood acute lymphoblastic leukemia 1983–2002: a Children’s oncology group report. Leukemia. 2010;24:285–97.

    CAS  PubMed  Google Scholar 

  5. 5.

    Pulte D, Jansen L, Gondos A, Katalinic A, Barnes B, Ressing M, et al. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS One. 2014;9:e85554.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101:2788–801.

    CAS  PubMed  Google Scholar 

  7. 7.

    Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7:e577–e577.

    Google Scholar 

  8. 8.

    Bassan R, Bourquin J-P, DeAngelo DJ, Chiaretti S. New approaches to the management of adult acute lymphoblastic leukemia. JCO. 2018;36:3504–19.

    CAS  Google Scholar 

  9. 9.

    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    CAS  Google Scholar 

  10. 10.

    SH Swerdlow, E Campo, NL Harris, ES Jaffe, SA Pileri, H Stein, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues [Internet]. 2020 [cited 2020 Feb 18]. Available from: https://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Who-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017

  11. 11.

    Wenzinger C, Williams E, Gru AA. Updates in the pathology of precursor lymphoid neoplasms in the revised fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues. Curr Hematol Malig Rep. 2018;13:275–88.

    PubMed  Google Scholar 

  12. 12.

    Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood. 1998;91:3995–4019.

    CAS  PubMed  Google Scholar 

  13. 13.

    • Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang Y-L, Pei D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia [Internet]. https://doi.org/10.1056/NEJMoa1403088. 2014 [cited 2020 Jan 16]. Available from: https://www.nejm.org/doi/10.1056/NEJMoa1403088?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov. This study illustrates the numerous fusions that may be present in Ph-like ALL and increasingly guide therapy decisions.

  14. 14.

    Siegele BJ, Nardi V. Laboratory testing in BCR-ABL1-like (Philadelphia-like) B-lymphoblastic leukemia/lymphoma. Am J Hematol. 2018;93:971–7.

    PubMed  Google Scholar 

  15. 15.

    Reckel S, Hantschel O. Bcr-Abl: one kinase, two isoforms, two diseases. Oncotarget. 2017;8:78257–8.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Yilmaz M, Kantarjian H, Ravandi-Kashani F, Short NJ, Jabbour E. Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: current treatments and future perspectives. Clin Adv Hematol Oncol. 2018;16:216–23.

    PubMed  Google Scholar 

  17. 17.

    Cimino G, Pane F, Elia L, Finolezzi E, Fazi P, Annino L, et al. The role of BCR/ABL isoforms in the presentation and outcome of patients with Philadelphia-positive acute lymphoblastic leukemia: a seven-year update of the GIMEMA 0496 trial. Haematologica. 2006;91:377–80.

    CAS  PubMed  Google Scholar 

  18. 18.

    Li S, Ilaria RL, Million RP, Daley GQ, Van Etten RA. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia–like syndrome in mice but have different lymphoid Leukemogenic activity. J Exp Med. 1999;189:1399–412.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lm S-W, Jm C, Jm H, Av H. Philadelphia positive acute lymphoblastic leukemia in adults: age distribution, BCR breakpoint and prognostic significance. Leukemia. 1991;5:196–9.

    Google Scholar 

  20. 20.

    Faderl S, Kantarjian HM, Thomas DA, Cortes J, Giles F, Pierce S, et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2000;36:263–73.

    CAS  PubMed  Google Scholar 

  21. 21.

    Preti HA, O’Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM. Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994;97:60–5.

    CAS  PubMed  Google Scholar 

  22. 22.

    Dombret H, Gabert J, Boiron J-M, Rigal-Huguet F, Blaise D, Thomas X, et al. Outcome of treatment in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial. Blood. 2002;100:2357–66.

    CAS  PubMed  Google Scholar 

  23. 23.

    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the Blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–42.

    CAS  PubMed  Google Scholar 

  24. 24.

    Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, 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 Am Soc Hematol. 2007;109:3676–8.

    CAS  Google Scholar 

  25. 25.

    Jones D, Thomas D, Yin CC, O’Brien S, Cortes JE, Jabbour E, et al. Kinase domain point mutations in Ph+ acute lymphoblastic leukemia (ALL) emerge following therapy with BCR-ABL kinase inhibitors. Cancer. 2008;113:985–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005–12.

    CAS  PubMed  Google Scholar 

  27. 27.

    • Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118:6521–8. This study established a TKI backbone as critical to Ph+ALL even in the absence of cytotoxic chemotherapy.

  28. 28.

    Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110:2309–15.

    CAS  PubMed  Google Scholar 

  29. 29.

    Caocci G, Vacca A, Ledda A, Murgia F, Piras E, Greco M, et al. Prophylactic and preemptive therapy with dasatinib after hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2012;18:652–4.

    PubMed  Google Scholar 

  30. 30.

    Cortes JE, Kim D-W, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of Ponatinib in Philadelphia chromosome–positive Leukemias. N Engl J Med. 2013;369:1783–96.

    CAS  PubMed  Google Scholar 

  31. 31.

    Papayannidis C, De Benedittis C, Soverini S, Iacobucci I, Abbenante MC, Sartor C, et al. Ponatinib is well tolerated and active in patients with relapsed/refractory Philadelphia positive acute lymphoblastic leukemia (PH+ ALL) and advanced phase of chronic myelogenous leukemia (CML) harbouring T315I mutation: the Bologna experience. Blood Am Soc Hematol. 2013;122:3911–3911.

    Google Scholar 

  32. 32.

    Martinelli G, Piciocchi A, Papayannidis C, Paolini S, Robustelli V, Soverini S, et al. First report of the Gimema LAL1811 phase II prospective study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130:99–99.

    Google Scholar 

  33. 33.

    Ravandi F, O’Brien S, Cortes J, Thomas D, Garris R, Faderl S, et al. Long-term follow-up of phase II study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia. Cancer. 2015;121:4158–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, et al. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a propensity score analysis. Cancer. 2016;122:3650–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM, et al. Treatment of Philadelphia chromosome–positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396–407.

    CAS  PubMed  Google Scholar 

  36. 36.

    Schultz K, Carroll A, Heerema N, Bowman W, Aledo A, Slayton W, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s oncology group study AALL0031. Leukemia. 2014;28:1467–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Slayton WB, Schultz KR, Kairalla JA, Devidas M, Mi X, Pulsipher MA, 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;36:2306–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Delannoy A, Delabesse E, Lhéritier V, Castaigne S, Rigal-Huguet F, Raffoux E, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia. 2006;20:1526–32.

    CAS  PubMed  Google Scholar 

  39. 39.

    Rousselot P, Coudé MM, Gokbuget N, Gambacorti Passerini C, Hayette S, Cayuela J-M, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL. Blood. 2016;128:774–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Litzow MR, Fielding AK, Luger SM, Paietta E, Ofran Y, Rowe JM, et al. The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults. Bone Marrow Transplant Nat Publish Group. 2017;52:1592–8.

    CAS  Google Scholar 

  41. 41.

    Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JGCAM, Peters STCJM, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10:125–34.

    Google Scholar 

  42. 42.

    Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Roberts KG, Gu Z, Payne-Turner D, McCastlain K, Harvey RC, Chen I-M, et al. High frequency and poor outcome of Philadelphia chromosome–like acute lymphoblastic leukemia in adults. JCO. 2016;35:394–401.

    Google Scholar 

  44. 44.

    Heatley SL, Sadras T, Kok CH, Nievergall E, Quek K, Dang P, et al. High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment. Haematologica 2017 [cited 2020 Apr 9]; Available from: http://www.haematologica.org/content/early/2017/09/15/haematol.2016.162925

  45. 45.

    O’Connor D, Enshaei A, Bartram J, Hancock J, Harrison CJ, Hough R, et al. Genotype-specific minimal residual disease interpretation improves stratification in pediatric acute lymphoblastic leukemia. JCO Am Soc Clin Oncol. 2017;36:34–43.

    Google Scholar 

  46. 46.

    Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for Cancer therapy. Cancer Res. 2009;69:4941–4.

    CAS  PubMed  Google Scholar 

  47. 47.

    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. JCO Am Soc Clin Oncol. 2014;32:4134–40.

    CAS  Google Scholar 

  48. 48.

    Jain T, Litzow MR. No free rides: management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv. 2018;2:3393–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Hathaway L, Sen JM, Keng M. Impact of blinatumomab on patient outcomes in relapsed/refractory acute lymphoblastic leukemia: evidence to date. Patient Relat Outcome Meas. 2018;9:329–37.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, 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;35:1795–802.

    CAS  PubMed  Google Scholar 

  51. 51.

    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;16:57–66.

    CAS  PubMed  Google Scholar 

  52. 52.

    Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia [Internet]. https://doi.org/10.1056/NEJMoa1609783. 2017 [cited 2020 Feb 19]. Available from: https://www.nejm.org/doi/10.1056/NEJMoa1609783?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov.

  53. 53.

    • Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131:1522–31. This study illustrates the particular efficacy of blinatumomab as a way to eliminate measurable residual disease.

  54. 54.

    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;92:858–65.

    CAS  PubMed  Google Scholar 

  55. 55.

    Köhnke T, Krupka C, Tischer J, Knösel T, Subklewe M. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J Hematol Oncol. 2015;8:111.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Braig F, Brandt A, Goebeler M, Tony H-P, Kurze A-K, Nollau P, et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood Am Soc Hematol. 2017;129:100–4.

    CAS  Google Scholar 

  57. 57.

    Shor B, Gerber H-P, Sapra P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol Immunol. 2015;67:107–16.

    CAS  PubMed  Google Scholar 

  58. 58.

    Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, et al. Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403–11.

    CAS  PubMed  Google Scholar 

  59. 59.

    Kantarjian H, Thomas D, Jorgensen J, Kebriaei P, Jabbour E, Rytting M, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119:2728–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Corbacioglu S, Jabbour EJ, Mohty M. Risk factors for development of and progression of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Biol Blood Transplant. 2019;25:1271–80.

    Google Scholar 

  61. 61.

    • Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53. Inotuzumab showed favorable response rates and duration compared to standard salvage chemotherapy approachesa.

  62. 62.

    Jabbour E, Ravandi F, Kebriaei P, Huang X, Short NJ, Thomas D, et al. Salvage Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase 2 clinical trial. JAMA Oncol. 2018;4:230–4.

    PubMed  Google Scholar 

  63. 63.

    Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer. 2003;3:666–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Sci Am Assoc Advance Sci. 2018;359:1361–5.

    CAS  Google Scholar 

  65. 65.

    Guedan S, Calderon H, Posey AD, Maus MV. Engineering and Design of Chimeric Antigen Receptors. Mol Ther Methods Clin Dev. 2019;12:145–56.

    CAS  PubMed  Google Scholar 

  66. 66.

    Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunol. 2019;8:e1049.

    Google Scholar 

  67. 67.

    Torikai H, Reik A, Liu P-Q, Zhou Y, Zhang L, Maiti S, et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood Am Soc Hematol. 2012;119:5697–705.

    CAS  Google Scholar 

  68. 68.

    Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev. 2016;30:157–67.

    CAS  PubMed  Google Scholar 

  69. 69.

    Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z car t cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25-224ra25.

    Google Scholar 

  70. 70.

    • Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18. Since the publication of this article, CAR-T cells in ALL have become a cornerstone of investigation and salvage options.

  71. 71.

    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of blood and marrow transplantation. Elsevier. 2019;25:625–38.

    CAS  Google Scholar 

  73. 73.

    Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Karschnia P, Jordan JT, Forst DA, Arrillaga-Romany IC, Batchelor TT, Baehring JM, et al. Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood Am Soc Hematol. 2019;133:2212–21.

    CAS  Google Scholar 

  75. 75.

    Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8:958–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 [cited 2020 Feb 19]; Available from: https://doi.org/10.1056/NEJMoa1709866*.

  77. 77.

    Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125:4017–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T-Cell therapy: Cytokine release syndrome, neurologic toxicity, and financial burden. American Society of Clinical Oncology Educational Book. Proc Am Soc Clin Oncol; 2019;433–444.

  80. 80.

    Cazzaniga G, Lorenzo PD, Alten J, Röttgers S, Hancock J, Saha V, et al. Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies. Haematol. 2018;103:107–15.

    CAS  Google Scholar 

  81. 81.

    Hovorkova L, Zaliova M, Venn NC, Bleckmann K, Trkova M, Potuckova E, et al. Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology. Blood. 2017;129:2771–81.

    CAS  PubMed  Google Scholar 

  82. 82.

    Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Della Starza I, Chiaretti S, De Propris MS, Elia L, Cavalli M, De Novi LA, et al. Minimal residual disease in acute lymphoblastic leukemia: Technical and clinical advances. Front Oncol. 2019 [cited 2020 Apr 13];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692455/

  84. 84.

    Short NJ, Jabbour E, Albitar M, de Lima M, Gore L, Jorgensen J, et al. Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: a consensus of north American experts. Am J Hematol. 2019;94:257–65.

    PubMed  Google Scholar 

  85. 85.

    Wu D, Emerson RO, Sherwood A, Loh ML, Angiolillo A, Howie B, et al. Detection of minimal residual disease in B lymphoblastic leukemia by high-throughput sequencing of IGH. Clin Cancer Res. 2014;20:4540–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the Dutch childhood oncology group. JCO Am Soc Clin Oncol. 2016;34:2591–601.

    Google Scholar 

  87. 87.

    Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood Am Soc Hematol. 2011;118:2077–84.

    CAS  Google Scholar 

  88. 88.

    Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209.

    CAS  PubMed  Google Scholar 

  89. 89.

    Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol Am Med Assoc. 2017;3:e170580–e170580.

    Google Scholar 

  90. 90.

    DeFilipp Z, Advani AS, Bachanova V, Cassaday RD, Deangelo DJ, Kebriaei P, et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25:2113–23.

    PubMed  Google Scholar 

  91. 91.

    Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood Am Soc Hematol. 2017;130:285–96.

    CAS  Google Scholar 

  92. 92.

    Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood Am Soc Hematol. 2020;135:987–95.

    Google Scholar 

  93. 93.

    Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol. 2010;150:345–51.

    CAS  PubMed  Google Scholar 

  94. 94.

    Ding YY, Stern JW, Jubelirer TF, Wertheim GB, Lin F, Chang F, et al. Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure. Haematologica. 2018;103:e427–31.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Nardi V, Ku N, Frigault MJ, Dubuc AM, Tsai HK, Amrein PC, et al. Clinical response to larotrectinib in adult Philadelphia chromosome–like ALL with cryptic ETV6-NTRK3 rearrangement. Blood Adv Am Soc Hematol. 2020;4:106–11.

    Google Scholar 

  96. 96.

    Jain N, Stevenson KE, Winer ES, Garcia JS, Stone RM, Jabbour E, et al. A multicenter phase I study combining Venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic leukemia. Blood Am Soc Hematol. 2019;134:3867–3867.

    Google Scholar 

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Correspondence to Andrew M. Brunner.

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Gavralidis, A., Brunner, A.M. Novel Therapies in the Treatment of Adult Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep 15, 294–304 (2020). https://doi.org/10.1007/s11899-020-00591-4

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Keywords

  • Acute lymphoblastic leukemia
  • CAR T cell therapy
  • BCR-ABL tyrosine kinase
  • Inotuzumab ozogamicin
  • Blinatumomab
  • Measurable residual disease