Skip to main content

Advertisement

SpringerLink
Log in

Current Approaches to Philadelphia Chromosome–Positive B-Cell Lineage Acute Lymphoblastic Leukemia: Role of Tyrosine Kinase Inhibitor and Stem Cell Transplant

  • Pediatric Oncology (KL Davis, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the management of patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), and this has led to significant improvement in their outcome. In this review, we will provide an overview of the current understanding of treatment of Ph+ ALL focusing on TKIs, alloHSCT, and novel therapies.

Recent findings

The advent of more potent TKIs and the novel therapeutic options including blinatumomab, inotuzumab ozogamicin, and CD19 CAR-T therapy has changed the role of allogeneic hematopoietic stem cell transplant (alloHSCT) and intensive chemotherapy. To avoid toxicity from the historical treatment strategies, a more individualized, targeted approach to therapy including detection and monitoring of measurable residual disease (MRD) has become of interest.

Summary

The treatment of patients with Ph+ ALL has been rapidly evolving with a more individualized, targeted treatment and use of TKIs and novel therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85–109.

    CAS  PubMed  Google Scholar 

  2. Moorman AV, Chilton L, Wilkinson J, Ensor HM, Bown N, Proctor SJ. A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood. 2010;115(2):206–14.

    Article  CAS  PubMed  Google Scholar 

  3. Chao NJ, Blume KG, Forman SJ, Snyder DS. Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 1995;85(11):3353–4.

    Article  CAS  PubMed  Google Scholar 

  4. Pui CH, Crist WM, Look AT. Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia. Blood. 1990;76(8):1449–63.

    Article  CAS  PubMed  Google Scholar 

  5. Thomas X, Thiebaut A, Olteanu N, Danaila C, Charrin C, Archimbaud E, et al. Philadelphia chromosome positive adult acute lymphoblastic leukemia: characteristics, prognostic factors and treatment outcome. Hematol Cell Ther. 1998;40(3):119–28.

    CAS  PubMed  Google Scholar 

  6. Ravandi F. How I treat Philadelphia chromosome- positive acute lymphoblastic leukemia. Blood. 2019;133(2):130–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843–50.

  8. Ravandi F, Kebriaei P. Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23(5):1043–63 vi.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, 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):653–61.

  10. Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, 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):4158–64.

  11. 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(12):2788–801.

  12. Gleissner B, Gokbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood. 2002;99(5):1536–43.

    Article  CAS  PubMed  Google Scholar 

  13. Gotz G, Weh HJ, Walter TA, Kuse R, Kolbe K, Dolken G, et al. Clinical and prognostic significance of the Philadelphia chromosome in adult patients with acute lymphoblastic leukemia. Ann Hematol. 1992;64(2):97–100.

    Article  CAS  PubMed  Google Scholar 

  14. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995;85(8):2025–37.

  15. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008;111(5):2563–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, et al. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002;16(7):1259–66.

  17. Thomas X, Danaila C, Le QH, Sebban C, Troncy J, Charrin C, et al. Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: a single institution experience of 378 consecutive patients over a 21-year period. Leukemia. 2001;15(12):1811–22.

    Article  CAS  PubMed  Google Scholar 

  18. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.

  19. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100(6):1965–71.

  20. Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006;24(3):460–6.

  21. Hatta Y, Mizuta S, Matsuo K, Ohtake S, Iwanaga M, Sugiura I, et al. Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL. Ann Hematol. 2018;97(9):1535–45.

  22. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006;108(5):1469–77.

  23. Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Duhrsen U, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer. 2007;109(10):2068–76.

    Article  CAS  PubMed  Google Scholar 

  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. 2007;109(9):3676–8.

    Article  CAS  PubMed  Google Scholar 

  25. de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109(4):1408–13.

    Article  PubMed  CAS  Google Scholar 

  26. Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013;19(1):150–5.

  27. Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28(22):3644–52.

    Article  CAS  PubMed  Google Scholar 

  28. Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711–9.

  29. Lim SN, Joo YD, Lee KH, Kim DY, Lee JH, Lee JH, et al. Long-term follow-up of imatinib plus combination chemotherapy in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Am J Hematol. 2015;90(11):1013–20.

  30. Foa 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(25):6521–8.

    Article  CAS  PubMed  Google Scholar 

  31. Chiaretti S, Vitale A, Elia L, Albino S, Piciocchi A, Fazi P, et al. First results of the multicenter total therapy Gimema LAL 1509 Protocol for de novo adult Philadelphia chromosome positive (Ph plus) acute lymphoblastic leukemia (ALL) patients. Blood. 2014;124(21 Supplement_1):797.

    Article  Google Scholar 

  32. Ravandi F, Othus M, O'Brien SM, Forman SJ, Ha CS, Wong JYC, et al. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250–9.

  33. Rousselot P, Coude MM, Gokbuget N, Gambacorti Passerini C, Hayette S, Cayuela JM, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016;128(6):774–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ottmann OG, Pfeifer H, Cayuela JM, Spiekermann K, Beck J, Jung WE, et al. Nilotinib (Tasigna (R)) and chemotherapy for first-line treatment in elderly patients with de novo Philadelphia chromosome/BCR-ABL1 positive acute lymphoblastic leukemia (ALL): a trial of the European Working Group for Adult ALL (EWALL-PH-02). Blood. 2014;124(21).

  35. Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015;126(6):746–56.

  36. ••Jabbour E, Short NJ, Ravandi F, Huang X, Daver N, DiNardo CD, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5(12):e618–e27. This phase 2 study showed the combination of chemotherapy and ponatinib is highly effective and safe in newly diagnosed ALL patients in long term. The study opened the possibility of establishing novel standard of care in Ph+ ALL by combined regimen of chemotherapy and ponatinib.

  37. 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(Supplement_1):99.

    Article  Google Scholar 

  38. Hofmann WK, Komor M, Hoelzer D, Ottmann OG. Mechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia. Leuk Lymphoma. 2004;45(4):655–60.

    Article  CAS  PubMed  Google Scholar 

  39. Shah NP, Sawyers CL. Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene. 2003;22(47):7389–95.

    Article  CAS  PubMed  Google Scholar 

  40. Petzer AL, Gunsilius E, Hayes M, Stockhammer G, Duba HC, Schneller F, et al. Low concentrations of STI571 in the cerebrospinal fluid: a case report. Br J Haematol. 2002;117(3):623–5.

    Article  PubMed  Google Scholar 

  41. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96(3):1070–9.

    Article  CAS  PubMed  Google Scholar 

  42. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80.

  43. Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007;110(2):727–34.

  44. O'Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65(11):4500–5.

  45. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658–61.

  46. Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114(24):4944–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Daub H, Specht K, Ullrich A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov. 2004;3(12):1001–10.

    Article  CAS  PubMed  Google Scholar 

  48. 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(7):2309–15.

  49. Wieduwilt MJ, Yin J, Wetzler M, Uy GL, Powell BL, Kolitz JE, et al. A phase II study of dasatinib and dexamethasone as primary therapy followed by transplantation for adults with newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph plus ALL): final results of Alliance/CALGB Study 10701. Blood. 2018;132(Supplement_1):309.

    Article  Google Scholar 

  50. Can G, Ayvaz S, Can H, Karaboga I, Demirtas S, Aksit H, et al. The efficacy of tyrosine kinase inhibitor dasatinib on colonic mucosal damage in murine model of colitis. Clin Res Hepatol Gastroenterol. 2016;40(4):504–16.

    Article  CAS  PubMed  Google Scholar 

  51. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–41.

    Article  CAS  PubMed  Google Scholar 

  52. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A, et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome--positive acute lymphoblastic leukemia. Leukemia. 2013;27(6):1411–3.

  53. Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gruber FX, Ernst T, Porkka K, Engh RA, Mikkola I, Maier J, et al. Dynamics of the emergence of dasatinib and nilotinib resistance in imatinib-resistant CML patients. Leukemia. 2012;26(1):172–7.

  55. Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63(2):375–81.

  56. Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125(6):901–6.

    Article  CAS  PubMed  Google Scholar 

  57. Cortes JE, Jean Khoury H, Kantarjian H, Brummendorf TH, Mauro MJ, Matczak E, et al. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib. Am J Hematol. 2016;91(6):606–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Keller VAG, Brummendorf TH. Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther. 2012;12(9):1121–7.

    Article  CAS  Google Scholar 

  59. Soverini S, De Benedittis C, Papayannidis C, Paolini S, Venturi C, Iacobucci I, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: the main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014;120(7):1002–9.

    Article  CAS  PubMed  Google Scholar 

  60. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–12.

  61. Zhou T, Commodore L, Huang WS, Wang Y, Thomas M, Keats J, et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des. 2011;77(1):1–11.

  62. Cortes JE, Kim DW, 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(19):1783–96.

  63. 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(23):3650–6.

  64. Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, 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):1547–55.

  65. •Short NJ, Kantarjian HM, Ravandi F, Huang XL, Daver NG, DiNardo CD, et al. Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134(Supplement_1):283. The follow-up study after hyper-CVAD plus ponatinib in newly diagnosed Ph+ ALL patients demonstrated a high response and survival rates in long term. The study showed CMR rate at 84% and estimated 5-year OS rate at 73%.

  66. Nagorsen D, Baeuerle PA. Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab. Exp Cell Res. 2011;317(9):1255–60.

    Article  CAS  PubMed  Google Scholar 

  67. ••Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47. This study showed blinatumomab as a single agent has higher efficacy compared to chemotherapy in relapsed or refractory B-cell precursor ALL by large, randomized phase 3 trial. This study facilitated multiple studies using combined regimen to blinatumomab in ALL patients.

  68. •Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget 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(16):1795–802. This phase 2 study also confirmed the good efficacy and tolerability of single-agent blinatumomab in relapsed or refractory Ph+ ALL patients who failed TKI-based therapy.

  69. Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero G, 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.

  70. King AC, Pappacena JJ, Tallman MS, Park JH, Geyer MB. Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia. Leuk Res. 2019;79:27–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. •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. This recent phase 2 study showed favorable outcome in blinatumomab for patients with relapsed or refractory Ph+ ALL patients.

  72. ••Foa R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613–23. This phase 2 study published this year showed high efficacy of dasatinib and blinatumomab combination as a frontline treatment in relapsed or refractory Ph+ ALL patients with high molecular response rate and survival rate.

  73. 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(8):740–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gokbuget N, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474–87.

    Article  CAS  PubMed  Google Scholar 

  75. DeAngelo DJ, Stock W, Stein AS, Shustov A, Liedtke M, Schiffer CA, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv. 2017;1(15):1167–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Stock W, Martinelli G, Stelljes M, DeAngelo DJ, Gokbuget N, Advani AS, et al. Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer. 2020.

  77. Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, et al. Inotuzumab ozogamicin in combination with bosutinib for patients with relapsed or refractory Ph plus ALL or CML in lymphoid blast phase. Blood. 2017;130(Supplement_1):143.

    Google Scholar 

  78. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–28.

  81. 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(16):1507–17.

  82. ••Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59. This phase 1 trial showed favorable outcome in use of CD19-specific CAR T cells(median survival at 12.9 months) in relapsed or refractory ALL patients including Ph+ ALL patients. The study assessed long-term outcomes of ALL patients who were treated with 19-28z CAR-T cells with median follow-up of 29 months, and showed high rate of complete remission with MRD negativity in previously heavily treated patients.

  83. 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(224):224ra25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, 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):4489–96.

  85. Ravandi F. Current management of Philadelphia chromosome positive ALL and the role of stem cell transplantation. Hematology Am Soc Hematol Educ Program. 2017;2017(1):22–7.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Muffly L, Kebriaei P. Philadelphia chromosome positive acute lymphoblastic leukemia in adults: therapeutic options and dilemmas in 2020. Semin Hematol. 2020;57(3):137–41.

    Article  PubMed  Google Scholar 

  87. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhauser M, Stadler M, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Leukemia. 2013;27(6):1254–62.

    Article  CAS  PubMed  Google Scholar 

  88. •Saini N, Marin D, Ledesma C, Delgado R, Rondon G, Popat UR, et al. Impact of TKIs post-allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive ALL. Blood. 2020;136(15):1786–9. This is the largest retrospective study by date that demonstrated better outcome(longer PFS) in prophylactic use of TKIs and lower relapse rate in TKI use more than 24 months.

  89. Cai WZ, Cen JN, Chen J, Chen F, Fu CC, Han Y, et al. Major molecular response prior to allogeneic hematopoietic stem cell transplantation predicts better outcome in adult Philadelphia-positive acute lymphoblastic leukemia in first remission. Bone Marrow Transplant. 2017;52(3):470–2.

    Article  CAS  PubMed  Google Scholar 

  90. Lussana F, Intermesoli T, Gianni F, Boschini C, Masciulli A, Spinelli O, et al. Achieving molecular remission before allogeneic stem cell transplantation in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact on relapse and long-term outcome. Biol Blood Marrow Transplant. 2016;22(11):1983–7.

  91. Ravandi F, Jorgensen JL, O'Brien SM, Jabbour E, Thomas DA, Borthakur G, et al. Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol. 2016;172(3):392–400.

  92. Leonard JT, Rowley JS, Eide CA, Traer E, Hayes-Lattin B, Loriaux M, et al. Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Sci Transl Med. 2016;8(354):354ra114.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Kunhwa Kim, Elias Jabbour, Nicholas J. Short, Hagop Kantarjian & Farhad Ravandi

  2. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Partow Kebriaei

Authors
  1. Kunhwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elias Jabbour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas J. Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Partow Kebriaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hagop Kantarjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Farhad Ravandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farhad Ravandi.

Ethics declarations

Conflict of Interest

Kunhwa Kim declares that she has no conflict of interest. Elias Jabbour has received research funding and compensation for service as a consultant from Amgen, AbbVie, Adaptive Biotechnologies, Bristol-Myers Squibb, Genentech, Pfizer, Takeda, and Ascentage Pharma. Nicholas J. Short has received research funding from Takeda Oncology and Astellas; has received compensation for service as a consultant from Takeda Oncology and AstraZeneca; and has received honoraria from Amgen. Partow Kebriaei has received research funding from Amgen and Ziopharm; has received compensation for service as a consultant from Jazz Pharmaceuticals; and has participated on advisory boards for Pfizer, Kite Pharma, and Novartis. Hagop Kantarjian has received research funding from AbbVie, Amgen, Ascentage Pharma, Bristol-Myers Squibb, Daiichi Sankyo, ImmunoGen, Jazz Pharmaceuticals, Novartis, Pfizer, and Sanofi; has received honoraria from AbbVie, Amgen, Daiichi Sankyo, Novartis, Pfizer, Adaptive Biotechnologies, Aptitude Health, Bio Ascend, Delta-Fly Pharma, Janssen Global, Oxford Biomedical Technologies, and Takeda; and has served on an advisory board for Actinium Pharmaceuticals. Farhad Ravandi has received research funding from Bristol-Myers Squibb, and has received compensation for service as a consultant from Bristol-Myers Squibb, Novartis, Pfizer, and Takeda.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pediatric Oncology.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, K., Jabbour, E., Short, N.J. et al. Current Approaches to Philadelphia Chromosome–Positive B-Cell Lineage Acute Lymphoblastic Leukemia: Role of Tyrosine Kinase Inhibitor and Stem Cell Transplant. Curr Oncol Rep 23, 95 (2021). https://doi.org/10.1007/s11912-021-01086-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11912-021-01086-y

Keywords

Search

Navigation