Skip to main content

Advertisement

SpringerLink
Log in

Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1–42); median dose was 600 mg (range 100–1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01–0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Breems DA, Van Putten WL, De Greef GE et al (2008) Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 26:4791–4797

    Article  PubMed  Google Scholar 

  2. Burnett A, Wetzler M, Lowenberg B (2011) Therapeutic advances in acute myeloid leukemia. J Clin Oncol 29:487–494

    Article  PubMed  Google Scholar 

  3. Stirewalt DL, Radich JP (2003) The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3:650–665

    Article  CAS  PubMed  Google Scholar 

  4. Frohling S, Schlenk RF, Breitruck J et al (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372–4380

    Article  CAS  PubMed  Google Scholar 

  5. Knapper S, Burnett AK, Littlewood T et al (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108:3262–3270

    Article  CAS  PubMed  Google Scholar 

  6. Fischer T, Stone RM, Deangelo DJ et al (2010) 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 28:4339–4345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Swords R, Freeman C, Giles F (2012) Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia 26:2176–2185

    Article  CAS  PubMed  Google Scholar 

  8. Serve H, Krug U, Wagner R et al (2013) Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 31:3110–3118

    Article  CAS  PubMed  Google Scholar 

  9. Levis M, Ravandi F, Wang ES et al (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117:3294–3301

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Metzelder SK, Schroeder T, Finck A et al (2012) High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 26:2353–2359

    Article  CAS  PubMed  Google Scholar 

  11. Sora F, Chiusolo P, Metafuni E et al (2011) Sorafenib for refractory FMS-like tyrosine kinase receptor-3 (FLT3/ITD+) acute myeloid leukemia after allogenic stem cell transplantation. Leuk Res 35:422–423

    Article  PubMed  Google Scholar 

  12. Sharma M, Ravandi F, Bayraktar UD et al (2011) Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib. Biol Blood Marrow Transplant 17:1874–1877

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Slovak ML, Kopecky KJ, Cassileth PA et al (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083

    CAS  PubMed  Google Scholar 

  14. Bacigalupo A, Ballen K, Rizzo D et al (2009) Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15:1628–1633

    Article  PubMed Central  PubMed  Google Scholar 

  15. Filipovich AH, Weisdorf D, Pavletic S et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956

    Article  PubMed  Google Scholar 

  16. Glucksberg H, Storb R, Fefer A et al (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18:295–304

    Article  CAS  PubMed  Google Scholar 

  17. Cheson BD, Bennett JM, Kopecky KJ et al (2003) 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 21:4642–4649

    Article  PubMed  Google Scholar 

  18. Strumberg D, Richly H, Hilger RA et al (2005) Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 23:965–972

    Article  CAS  PubMed  Google Scholar 

  19. Fukudo M, Ito T, Mizuno T et al (2014) Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma. Clin Pharmacokinet 53:185–196

    Article  CAS  PubMed  Google Scholar 

  20. Chen YB, Li S, Lane AA et al (2014) Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant 20(12):2042–2048

    Article  CAS  PubMed  Google Scholar 

  21. Yokoyama H, Lundqvist A, Su S, Childs R (2010) Toxic effects of sorafenib when given early after allogeneic hematopoietic stem cell transplantation. Blood 116:2858–2859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Metzelder S, Wang Y, Wollmer E et al (2009) Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 113:6567–6571

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland

    A. Tschan-Plessl, J. P. Halter, D. Heim, M. Medinger, J. R. Passweg & S. Gerull

Authors
  1. A. Tschan-Plessl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. P. Halter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Heim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Medinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. R. Passweg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Gerull
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Tschan-Plessl.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tschan-Plessl, A., Halter, J.P., Heim, D. et al. Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation. Ann Hematol 94, 1899–1905 (2015). https://doi.org/10.1007/s00277-015-2461-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-015-2461-5

Keywords

Search

Navigation