Long-term survival of sorafenib-treated FLT3-ITD–positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation

Published:October 18, 2017DOI:


      • Sorafenib induces long-term survival in Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)+ acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT).
      • Sorafenib cures a minority of FLT3-ITD+ AML relapsing after allo-SCT.
      • Achievement of molecular negativity is strongly associated with cure.



      Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available.


      We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD–positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy.


      With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years.


      Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD–positive AML relapsing after allo-SCT.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
        N Engl J Med. 2013; 368: 2059-2074
        • Grunwald M.R.
        • Levis M.J.
        FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance.
        Int J Hematol. 2013; 97: 683-694
        • Kottaridis P.D.
        • Gale R.E.
        • Frew M.E.
        • et al.
        The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.
        Blood. 2001; 98: 1752-1759
        • Fischer T.
        • Stone R.M.
        • DeAngelo D.J.
        • et al.
        Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3.
        J Clin Oncol – Off J Am Soc Clin Oncol. 2010; 28: 4339-4345
        • Levis M.
        Midostaurin approved for FLT3-mutated AML.
        Blood. 2017; 129: 3403-3406
        • Stone R.M.
        • DeAngelo D.J.
        • Klimek V.
        • et al.
        Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412.
        Blood. 2005; 105: 54-60
        • Stone R.M.
        • Mandrekar S.J.
        • Sanford B.L.
        • et al.
        Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation.
        N Engl J Med. 2017; 377: 454-464
        • Wilhelm S.M.
        • Carter C.
        • Tang L.
        • et al.
        BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.
        Cancer Res. 2004; 64: 7099-7109
        • Rollig C.
        • Serve H.
        • Huttmann A.
        • et al.
        Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial.
        Lancet Oncol. 2015; 16: 1691-1699
        • 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 (2264–2265;author reply 2265)
        • Brunet S.
        • Labopin M.
        • Esteve J.
        • 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 – Off J Am Soc Clin Oncol. 2012; 30: 735-741
        • Schlenk R.F.
        • Dohner K.
        • Krauter J.
        • et al.
        Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.
        N Engl J Med. 2008; 358: 1909-1918
        • Savani B.N.
        • Mielke S.
        • Reddy N.
        • Goodman S.
        • Jagasia M.
        • Rezvani K.
        Management of relapse after allo-SCT for AML and the role of second transplantation.
        Bone Marrow Transplant. 2009; 44: 769-777
        • Borthakur G.
        • Kantarjian H.
        • Ravandi F.
        • et al.
        Phase I study of sorafenib in patients with refractory or relapsed acute leukemias.
        Haematologica. 2011; 96: 62-68
        • Cortes J.E.
        • Kantarjian H.
        • Foran J.M.
        • et al.
        Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.
        J Clin Oncol – Off J Am Soc Clin Oncol. 2013; 31: 3681-3687
        • Levis M.J.
        • Perl A.E.
        • Altman J.K.
        • et al.
        Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML).
        J Clin Oncol – Off J Am Soc Clin Oncol. 2015; 33 (suppl; abstr 7003)
        • Metzelder S.
        • Wang Y.
        • Wollmer E.
        • 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: 6567-6571
        • Leung A.Y.H.
        • Man C.-H.
        • Kwong Y.-L.
        FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia.
        Leukemia. 2013; 27: 260-268
        • Thol F.
        • Schlenk R.F.
        • Heuser M.
        • Ganser A.
        How I treat refractory and early relapsed acute myeloid leukemia.
        Blood. 2015; 126: 319-327
        • Metzelder S.K.
        • Wollmer E.
        • Neubauer A.
        • Burchert A.
        Sorafenib bei rezidivierter und therapierefraktarer FLT3-ITD-positiver akuter myeloischer Leukamie: eine neue Behandlungsoption.
        Dtsch Med Wochenschr (1946). 2010; 135: 1852-1856
        • Metzelder S.K.
        • Schroeder T.
        • Finck A.
        • et al.
        High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses.
        Leukemia. 2012; 26: 2353-2359
        • Cheson B.D.
        • Bennett J.M.
        • Kopecky K.J.
        • et al.
        Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia.
        J Clin Oncol – Off J Am Soc Clin Oncol. 2003; 21: 4642-4649
        • Bacigalupo A.
        • Ballen K.
        • Rizzo D.
        • et al.
        Defining the intensity of conditioning regimens: working definitions.
        Biol Blood Marrow Transplant – J Am Soc Blood Marrow Transplant. 2009; 15: 1628-1633
        • Schmid C.
        • Labopin M.
        • Nagler A.
        • et al.
        Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party.
        J Clin Oncol – Off J Am Soc Clin Oncol. 2007; 25: 4938-4945
        • Yokoyama H.
        • Lundqvist A.
        • Su S.
        • Childs R.
        Toxic effects of sorafenib when given early after allogeneic hematopoietic stem cell transplantation.
        Blood. 2010; 116: 2858-2859
        • Randhawa J.K.
        • Kantarjian H.M.
        • Borthakur G.
        • et al.
        Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations.
        Blood. 2014; 124 (abstr 389)