General AML

Sorafenib as a salvage therapy following allogeneic stem cell transplantation in patients with acute myeloid leukemia

The prognosis for patients with fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) is poor, mainly due to early relapse and a lack of response to further treatment.1 Patients with FLT3-ITD AML in first complete remission often receive allogeneic stem cell transplantation (allo-SCT), however, relapse after allo-SCT has very low survival outcomes.2 The benefit of sorafenib as a monotherapy or in combination with other therapies in this setting remains unclear.

Professor Ali Bazarbachi, from the American University of Beirut, Beirut, LB, and colleagues published a report from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukaemia Working Party (ALWP), which assessed the safety and efficacy of sorafenib as a salvage therapy for adult patients with FLT3-ITD AML (n = 152) who relapsed or had disease progression following allo-SCT.3 This retrospective, registry-based, multicenter analysis examined the outcome of patients who received salvage therapy with sorafenib (n = 34; median age at allo-SCT = 48 years; range, 19–69) with patients who did not receive sorafenib salvage therapy (n = 118; median age = 51 years; range, 19–75). In addition, a pre-planned pair-matched analysis was also performed using data from 30 patients who had received sorafenib salvage compared to 30 patients who had not.  

All findings shown as sorafenib group versus control group, where applicable

Patient characteristics:
  • Patients were less likely to be CMV or MRD negative vs control
  • Patients were more likely to have received a matched related donor transplant and myeloablative conditioning vs control
  • All other disease, treatment, and patient characteristics were similar across groups
  • Patients receiving donor lymphocyte infusion (DLI): 33% vs 17%
  • Patients receiving a second allo-SCT: 13% vs 15%
Key findings:
  • Median time from allo-SCT to relapse: 2.8 months (range, 0.4–41.4) vs 3.7 months (range, 0.6–58.3)
  • Median time from relapse to start of treatment: 6 days (1–34) vs 8 days (1–245)
  • Median follow-up time after relapse: 22.69 months (range, 3.84–67.77) vs 19.74 months (range, 4.3–68.23)
  • Complete remission (CR) was induced by sorafenib in 39% (10/26) of patients
  • In the matched pair analysis, two-year overall survival (OS) rates: 38% vs 9%, HR = 0.28 (95% CI, 0.15–0.53), P = 0.0001

Multivariate analysis

  • OS was significantly improved by salvage therapy with sorafenib: HR = 0.44 (95% CI, 0.26–0.75), P = 0.001
  • OS was adversely affected by:
    • Older age: HR = 1.2 (95% CI, 1.01–1.43), P = 0.04
    • Active disease at transplant: HR = 2.4 (95% CI, 1.49–3.84), P = 0.001
    • Treatment with reduced intensity conditioning: HR = 1.76 (95% CI, 1.14–2.73), P = 0.01
  • Dose of sorafenib administered: 800 mg/day (n = 21, 62%), 400 mg/day (n = 12, 35%), or 200 mg/day (n = 1, 3%)
    • Patients requiring sorafenib dose modification: 35%
    • Main reason for dose modification: hematological toxicity

Based on this retrospective registry-based analysis the authors concluded that using sorafenib as a salvage therapy for patients with FLT3-ITD AML who relapsed or had disease progression following allo-SCT leads to improved survival. The administration of sorafenib as standard daily dose of 800 mg in two divided doses was safe, although dose modifications were frequently required.

References
  1. Schmid C. et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015 Oct 22; 126(17): 2062–2069. DOI: https://doi.org/10.1182/blood-2015-06-651562   
  2. Bejanyan N. et al. Survival of AML patients relapsing after allogeneic stem cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015 Mar; 21 (3): 454–459. DOI: 10.1016/j.bbmt.2014.11.007.
  3. Bazarbachi A. et al. Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of EBMT acute leukemia Working Party. Haematologica. 2019 Feb 21. DOI: 10.3324/haematol.2018.211615 [Epub ahead of print]
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!