Abstract
A single-center retrospective study was performed with consecutive patients who received salvage therapy using ponatinib for the aim of allogeneic hematopoietic cell transplantation (HCT) for relapsed or refractory Ph-leukemia between January 2017 and July 2018. A total of ten patients—seven with Ph-acute lymphoblastic leukemia (ALL) and three with chronic phase (CP)/accelerated phase chronic myeloid leukemia (CML)—were eligible. Eight patients had a history of a single tyrosine kinase inhibitor (TKI) use prior to ponatinib. Any mutation of the tyrosine kinase domain was detected in eight patients, including seven of T315I. The median dose of ponatinib was 15 mg with a median duration of 7 weeks (range 4–23 weeks). The median duration from the start of ponatinib to HCT was 54 days (range 35–175 days). Hematological remission was obtained in five Ph-ALL patients. Maintenance therapy of ponatinib was applied to five patients. No vascular occlusion event has occurred over this series of treatments. Salvage therapy with low-dose ponatinib appears to be safe and effective in patients with relapsed or refractory Ph-leukemia, which may immediately bridge to HCT.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. Phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96.
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.
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.
Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42.
Miller GD, Bruno BJ, Lim CS. Resistant mutations in CML and Ph(+)ALL—role of ponatinib. Biologics. 2014;8:243–54.
Tojo A, Kyo T, Yamamoto K, Nakamae H, Takahashi N, Kobayashi Y, et al. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol. 2017;106(3):385–97.
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.
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.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European Leukemia Net recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.
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(1):43–50.
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.
Robinson S, Levy Y, Maisel C, Tong AW. Haematological complete remission by ponatinib and bortezomib in a patient with relapsed, Ph+ pre-B acute lymphoblastic leukaemia. BMJ Case Rep. 2014;2014:bcr2014203894.
DeFilipp Z, Langston AA, Chen Z, Zhang C, Arellano ML, El Rassi F, et al. Does post-transplant maintenance therapy with tyrosine kinase inhibitors improve outcomes of patients with high-risk philadelphia chromosome-positive leukemia? Clin Lymphoma Myeloma Leuk. 2016;16(8):466–71.
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393–404.
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, et al. Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res. 2016;48:84–91.
Tefferi A. Upfront low-dose ponatinib (15 mg/day) for multi-TKI resistant chronic myeloid leukemia. Hematol Oncol. 2018;36(4):718–20.
Iurlo A, Cattaneo D, Orofino N, Bucelli C, Molica M, Breccia M. Low-dose ponatinib in intolerant chronic myeloid leukemia patients: a safe and effective option. Clin Drug Investig. 2018;38(5):475–6.
Abumiya M, Miura M, Takahashi N. Therapeutic drug monitoring of ponatinib using a simple high-performance liquid chromatography method in Japanese patients. Leuk Res. 2018;64:42–5.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest to declare.
About this article
Cite this article
Tachibana, T., Koyama, S., Andou, T. et al. Salvage and bridging to allogeneic hematopoietic cell transplantation with ponatinib in patients with relapsed or refractory Philadelphia chromosome-positive leukemia. Int J Hematol 109, 162–168 (2019). https://doi.org/10.1007/s12185-018-02571-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-018-02571-0