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Stem cell transplantation

A new pre-emptive TKIs strategy for preventing relapse based on BCR/ABL monitoring for Ph+ALL undergoing allo-HCT: a prospective clinical cohort study

Leukemia volume 35, pages 2054–2063 (2021)Cite this article

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Abstract

Relapse is a major cause of treatment failure in Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to evaluate the effect of a new pre-emptive tyrosine kinase inhibitors (TKIs) strategy on relapse in Ph+ALL patients with complete remission undergoing allo-HCT. Pre-emptive TKIs initiation was based on BCR/ABL molecular monitoring. TKIs choice was based on BCR/ABL mutations. Donor lymphocyte infusion was recommended in those with poor response to TKIs. Prophylactic TKIs from historical data were as control. The primary endpoint was relapse. One hundred and sixty-seven Ph+ALL patients were enrolled in this study, including 103 in the pre-emptive group and 64 in the prophylactic group. The 3-year cumulative incidence of relapse was 11% and 31% in the pre-emptive and prophylactic groups (P = 0.001), respectively. The 3-year overall survival (OS) was 87% and 66% (P = 0.001), and leukemia-free survival (LFS) was 83% and 61% (P = 0.000), respectively, in the pre-emptive and prophylactic groups. Multivariate analysis showed that the pre-emptive strategy was the protective factor for relapse, OS, and LFS (P = 0.005, P = 0.005, and P = 0.003, respectively). Our data suggest that this new pre-emptive TKIs strategy based on BCR/ABL molecular monitoring might reduce relapse and improve survival for Ph+ALL patients undergoing allo-HCT. ClinicalTrials.Gov Identifier (NCT01883219).

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Fig. 1: Consolidated Standards of Reporting Trials (CONSORT) diagram.
Fig. 2: Relapse and survival after transplantation.
Fig. 3: The incidence of GVHD after transplantation.

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References

  1. 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 (Ph1 ALL). Blood. 2006;108:1469–77.

    Article  CAS  Google Scholar 

  2. Mizuta S, Matsuo K, Yagasaki F, Yujiri T, Hatta Y, Kimura Y, et al. Pre-transplant imatinib- based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR/ABL positive acute lymphoblastic leukemia. Leukemia. 2011;25:41–7.

    Article  CAS  Google Scholar 

  3. Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol. 2019;12:39.

    Article  Google Scholar 

  4. Gao L, Zhang C, Gao L, Liu Y, Su Y, Wang S, et al. Favorable outcome of haploidentical hematopoietic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia: a multicenter study in Southwest China. J Hematol Oncol. 2015;8:90.

    Article  Google Scholar 

  5. 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;125:3711–9.

    Article  CAS  Google Scholar 

  6. Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2016;122:2941–51.

    Article  CAS  Google Scholar 

  7. Zhu YM, Wu Z, Tan YP, Du YY, Liu Z, Ou RM, et al. Anti-CD19 chimeric antigen receptor T-cell therapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia: two case reports. Medicine. 2016;95:e5676.

    Article  CAS  Google Scholar 

  8. Zhang LN, Song Y, Liu D. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. J Hematol Oncol. 2018;11:41.

    Article  Google Scholar 

  9. Yoshimitsu M, Fujiwara H, Ozaki A, Hamada H, Matsushita K, Arima N, et al. Case of a patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia relapsed after myeloablative allogeneic hematopoietic stem cell transplantation treated successfully with imatinib and sequential donor lymphocyte infusions. Int J Hematol. 2008;88:331–5.

    Article  CAS  Google Scholar 

  10. Chen H, Liu KY, Xu LP, Chen YH, Han W, Zhang XH, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of philadelphia chromosome-positive acute lymphoblastic leukemia. Biol Blood Marrow Transpl. 2015;21:1110–6.

    Article  Google Scholar 

  11. 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 Transpl. 2012;18:652–4.

    Article  Google Scholar 

  12. Chen H, Liu KY, Xu LP, Liu DH, Chen YH, Zhao XY, et al. Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Hematol Oncol. 2012;5:29.

    Article  CAS  Google Scholar 

  13. Shimoni A, Volchek Y, Koren-Michowitz M, Varda-Bloom N, Somech R, Shem-Tov N, et al. Phase 1/2 study of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121:863–71.

    Article  CAS  Google Scholar 

  14. Brissot E, Labopin M, Beckers MM, Socié G, Rambaldi A, Volin L, et al. Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica. 2015;100:392–9.

    Article  CAS  Google Scholar 

  15. Warraich Z, Tenneti P, Thai T, Hubben A, Amin H, McBride A, et al. Relapse prevention with tyrosine kinase inhibitors after allogeneic transplantation for Philadelphia chromosome-positive acute lymphoblast leukemia: a systematic review. Biol Blood Marrow Transpl. 2020;26:e55–64.

    Article  CAS  Google Scholar 

  16. Nishiwaki S, Imai K, Mizuta S, Kanamori H, Ohashi K, Fukuda T, et al. Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT. Bone Marrow Transpl. 2016;51:43–50.

    Article  CAS  Google Scholar 

  17. Zhang FH, Ling YW, Zhai X, Zhang Y, Huang F, Fan ZP, et al. The effect of imatinib therapy on the outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology. 2013;18:151–7.

    Article  CAS  Google Scholar 

  18. Liew Elena, Ghosh Sunita, Saini Lalit. Use of tyrosine kinase inhibitors post-allogeneic stem cell transplant in patients with Philadelphia or BCR/ABL positive acute lymphoblastic leukemia: a systematic review and meta-analysis. Blood. 2016;128:2778.

    Article  Google Scholar 

  19. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhäuser 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;27:1254–62.

    Article  CAS  Google Scholar 

  20. Wassmann B, Pfeifer H, Stadler M, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD1 Philadelphia-positive acute lymphoblastic leukemia (Ph1 ALL). Blood. 2005;106:458–63.

    Article  CAS  Google Scholar 

  21. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Histopathology. 2000;36:69–86.

    Article  CAS  Google Scholar 

  22. Xuan L, Fan Z, Zhang Y, Zhou H, Huang F, Dai M, et al. Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT. Oncotarget. 2016;7:32579–91.

    Article  Google Scholar 

  23. O’Brien S, Berman E, Borghaei H, Deangelo DJ, Devetten MP, Devine S, et al. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. J Natl Compr Canc Netw. 2009;7:984–1023.

    Article  Google Scholar 

  24. O’Brien S, Radich JP, Abboud CN, Akhtari M, Altman JK, Berman E, et al. Chronic myelogenous leukemia, version 1.2015. J Natl Compr Canc Netw. 2014;12:1590–610.

    Article  Google Scholar 

  25. Yu G, Chen F, Yin C, Liu Q, Sun J, Xuan L, et al. Upfront treatment with the first and second-generation tyrosine kinase inhibitors in Ph-positive acute lymphoblastic leukemia. Oncotarget. 2017;8:107022–32.

    Article  Google Scholar 

  26. Fan Q, Liu H, Liang X, Yang T, Fan Z, Huang F, et al. Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia. J Hematol Oncol. 2017;10:135.

    Article  Google Scholar 

  27. Yu S, Huang F, Fan Z, Xuan L, Nie D, Xu Y, et al. Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data. J Hematol Oncol. 2020;13:18.

    Article  CAS  Google Scholar 

  28. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8.

    CAS  Google Scholar 

  29. Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev. 2006;20:15–27.

    Article  Google Scholar 

  30. Pfeifer H, Lange T, Wystub S, Wassmann B, Maier J, Binckebanck A, et al. Prevalence and dynamics of BCR/ABL kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent BCR/ABL positive acute lymphoblastic leukemia. Leukemia. 2012;26:1475–81.

    Article  CAS  Google Scholar 

  31. Jones D, Thomas D, Yin CC, O’Brien S, Cortes JE, Jabbour E, et al. Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR/ABL kinase inhibitors. Cancer. 2008;113:985–94.

    Article  CAS  Google Scholar 

  32. Kast RE, Focosi D. Three paths to better tyrosine kinase inhibition behind the blood-brain barrier in treating chronic myelogenous leukemia and glioblastoma with imatinib. Transl Oncol. 2010;3:13–5.

    Article  Google Scholar 

  33. Savani BN, Srinivasan R, Espinoza-Delgado I, Dorrance C, Takahashi Y, Igarashi T, et al. Treatment of relapsed blast-phase Philadelphia-chromosome-positive leukemia after non- myeloablative stem-cell transplantation with donor lymphocytes and imatinib. Lancet Oncol. 2005;6:809–12.

    Article  CAS  Google Scholar 

  34. Tiribelli M, Sperotto A, Candoni A, Simeone E, Buttignol S, Fanin R. Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib. Leuk Res. 2009;33:174–7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Pro. Robert Gale (Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College, London, UK) and Pro. Michael Andreeff (Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA) for offering expert advice. We thank all the faculty members that participated in these studies. This work was supported by the National Key Research and Development Programme of China (Grant Nos. 2017YFA105500, 2017YFA105504), the National Natural Science Foundation of China (Nos. 81770190, 81700176, 81500149, 81401315), Science and Technology Planning Project of Guangdong Province (2019B020236004), Project of the Zhujiang Science and Technology Star of Guangzhou City (No. 201806010029), Natural Science Foundation of Guangdong Province (No. 2019A1515011924), the Science and Technology Program of Guangzhou City (201707010213), and the Clinical Research Project of Nanfang Hospital, Southern Medical University (LC2016ZD009).

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  1. These authors contributed equally: Hui Liu, Li Xuan, Ren Lin, Lan Deng

Authors and Affiliations

  1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Hui Liu, Li Xuan, Ren Lin, Zhiping Fan, Dan Xu, Yu Zhang, Na Xu, Jieyu Ye, Hua Jin, Jing Sun, Fen Huang & Qifa Liu

  2. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Lan Deng

  3. Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Danian Nie & Liping Ma

  4. Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Xudong Li & Dongjun Lin

  5. Department of Hematology, First People’s Hospital of Chenzhou, Chenzhou, Hunan, China

    Xinquan Liang

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Liu, H., Xuan, L., Lin, R. et al. A new pre-emptive TKIs strategy for preventing relapse based on BCR/ABL monitoring for Ph+ALL undergoing allo-HCT: a prospective clinical cohort study. Leukemia 35, 2054–2063 (2021). https://doi.org/10.1038/s41375-020-01090-4

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