Abstract
Acute myeloid leukemia (AML) harboring Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutation is associated with shorter remission and higher relapse risk. Several FLT3 inhibitors have been used in clinical trials, but their efficacy in extramedullary disease remains unclear. In the present case, a 56-year-old man was diagnosed with FLT3-ITD mutated AML. Due to bone marrow relapse during consolidation therapy, he underwent salvage therapy and a myeloablative conditioning regimen, followed by peripheral blood stem cell transplantation (PBSCT) from a HLA-matched related donor. Acute graft-versus-host disease (GVHD) did not develop, and complete donor chimerism was confirmed on days 27 and 96 after PBSCT. On day 180, he experienced extensive chronic GVHD and had several subcutaneous tumors in his body, which were diagnosed as myeloid sarcoma by pathological examination. We considered this to be a case of isolated extramedullary relapse, as his bone marrow had maintained complete donor chimerism. Treatment with etoposide and ranimustine produced no effect, and tumor progression continued. We started administration of gilteritinib, a FLT3/AXL inhibitor, after identifying the FLT3-ITD mutation in the tumor. Subsequently, there has been a remarkable regression of the tumors. Gilteritinib can be effective in isolated extramedullary relapse after allogeneic stem cell transplantation.
Similar content being viewed by others
References
Yuda S, Fuji S, Onishi A, Tanaka T, Inatomo Y, Kurosawa S, et al. Extramedullary relapse of acute myelogenous leukemia after allogenic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25:1152–7.
Ando T, Mitani N, Matusi K, Yamashita K, Nomiyama J, Tsuru M, et al. Recurrent extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation in a patient with the chromosomal abnormality t (8;21) and CD56-positivity. Int J Hematol. 2009;90:374–7.
Solh M, Solomon S, Morris L, Holland K, Bashey A. Extramedullary acute myelogenous leukemia. Blood Rev. 2016;30:333–9.
Lee JH, Choi SJ, Seol M, Lee YS, Ryu SG, Park CJ, et al. Anti-leukemic effect of graft-versus-host disease on bone marrow and extramedullary relapses in acute leukemia. Haematologica. 2005;90:1380–8.
Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioqlu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–28.
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.
Brunet S, Labopin M, Esteve J, Cornelissen J, Socie G, Iori A, et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol. 2012;30:735–41.
Fathi AT, Chen YB. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia. Eur J Haemal. 2017;98:330–6.
Takahashi T, Usuki K, Matsue K, Ohno H, Sakura T, Imanaka R, et al. Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study. Int J Hematol. 2019;110:665–74.
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutation in acute myeloid leukemia. Blood. 1999;93:3074–80.
Yamamoto C, Ito S, Mashima K, Umino K, Minakata D, Yamasaki R, et al. Dose-reduced combination of mitoxantrone, etoposide, and cytarabine (miniMEC) for relapsed and refractory acute leukemia. Leuk Lymphoma. 2016;57:2541–7.
Murphy KM, Levis M, Hafez MJ, Geiger T, Cooper LC, Smith BD, et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5:96–102.
Yoshihara S, Ando T, Ogawa H. Extramedullary relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: an easily overlooked but significant pattern of relapse. Biol Blood Marrow Transplant. 2012;18:1800–7.
Harris AC, Kitko CL, Couriel DR, Braun TM, Choi SW, Magenau J, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic stem cell transplantation: incidence, risk factors and outcomes. Haematologica. 2013;98:179–84.
Yoshihara S, Ikegame K, Kaida K, Taniguchi K, Kato R, Inoue T, et al. Incidence of extramedullary relapse after haploidentical SCT for advanced AML/myelodysplastic syndrome. Bone Marrow Transplant. 2012;47:669–76.
Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. 2007;109:2264–5.
Ando T, Mitani N, Matsunaga K, Nakazora T, Gondo T, Yujiri T, et al. Gemtuzumab ozogamicin therapy for isolated extramedullary AML relapse after allogeneic hematopoietic stem-cell transplantation. Tohoku J Exp Med. 2010;220:121–6.
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Bloomfield CD, Thiede C, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed/refractory acute myeloid leukemia: a multicenter, first-in-human, open-label, phase 1/2 study. Lancet Oncol. 2017;18:1061–75.
Gorcea CM, Burthem J, Tholouli E. ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial. Fut Oncol. 2018;14:1995–2004.
Perl AE, Martinelli G, Cortes JE, Naubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40.
Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichier S, Chaturvedi A, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113:6567–71.
Sora F, Chiusolo P, Metafuni E, Bellesi S, Giammarco S, Leurenti L, et al. Sorafenib for refractory FMS-like tyrosine kinase receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogeneic stem cell transplantation. Leuk Res. 2011;35:422–3.
Sharma M, Ravandi F, Bayraktar UD, Chiattone A, Bashir Q, Giralt S, et al. Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant. 2011;17:1874–7.
Tschan-Plessl A, Halter JP, Heim D, Medinger M, Passweg JR, Gerull S. Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation. Ann Hematol. 2015;94:1899–905.
Safaian NN, Czibere A, Bruns I, Fenk R, Reinnecke P, Dienst A, et al. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res. 2009;33:348–50.
Lee SH, Paietta E, Racevskis J, Wiernik PH. Complete resolution of leukemia cutis with sorafenib in an acute myeloid leukemia patient with FLT3-ITD mutation. Am J Hematol. 2009;84:701–2.
Takahashi N, Kawakami T, Sato H, Onoda T, Kanno M, Mitsui T, et al. Successful treatment with sorafenib for primary refractory acute monoblastic leukemia with FLT3-ITD. Rinsho Ketsueki. 2012;53:1932–6.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Kida, M., Kuroda, Y., Kido, M. et al. Successful treatment with gilteritinib for isolated extramedullary relapse of acute myeloid leukemia with FLT3-ITD mutation after allogeneic stem cell transplantation. Int J Hematol 112, 243–248 (2020). https://doi.org/10.1007/s12185-020-02855-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-020-02855-4