Cancer Treatment Today

Sorafenib (Nexavar,) has been approved for the treatment of metastatic renal cancer and advanced hepatocellular carcinoma. It inhibits the serine threonine kinase RAF-1, but also the FLT3-RTK and FLT3-ITD, suggesting that it may have a role in treating AML with FLT3 mutations. Sorafenib is a FLT3 tyrosine kinase inhibitor, and approximately 25 percent of patients with de novo AML have the FLT3 mutation. Sorafenib in a phase 1 clinical trial on 16 patients with AML was found to be active in 6 of the 7 Flt3-ITD–positive patients. Response in FLT negative patients was 15%. However, treatment duration was short (21-70 days), and no durable responses were reported. Notably, a complete molecular remission has recently been reported in a patient relapsing after stem cell transplantation (SCT). More recently, higher responses were reported in FLT3 negative patients.

There is a high degree of interest in the use of sorafenib with other drugs or alone for FLT+ AML and there are a number of recent publications corroborating its effectiveness. Although NCCN (AML-E) does not yet list this treatment, there is significant literature support and few other options in relapsed AML. However, its use front-line or for consolidation or maintenance is not literature supported.

Metzelder S, et al,  (2009) Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood113(26):6567–6571.

Metzelder SK1, Schroeder T, Finck A, Scholl S, Fey M, Götze K, Linn YC, Kröger M, Reiter A, Salih HR, Heinicke T, Stuhlmann R, Müller L, Giagounidis A, Meyer RG, Brugger W, Vöhringer M, Dreger P, Mori M, Basara N, Schäfer-Eckart K, Schultheis B, Baldus C, Neubauer A, Burchert A. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses.

Leukemia. 2012 Nov;26(11):2353-9.

R. H Carson. AML: Sorafenib May Hit More than FLT3

Oncology Times:10 February 2015 – Volume 37 – Issue 3 – p 32–33

Gail J. Roboz, Novel Approaches to the Treatment of Acute Myeloid Leukemia. ASH Education BookDecember 10, 2011 vol. 2011 no. 1 43-50

Delmonte J, Jr, Kantarjian HM, Andreeff M, Faderl S, Wright JJ, Zhang W, et al. Update of a Phase I Study of Sorafenib in Patients with Refractory/Relapsed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. ASH Annual Meeting Abstracts. 2007 November 16;110(11):893. 2007.

Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 2008;100:184-198

Mori S, Cortes J, Kantarjian H, Zhang W, Andreef M, Ravandi F. Potential role of sorafenib in thetreatment of acute myeloid leukemia. Leuk Lymphoma 2008;49:2246-2255.

S K Metzelder et al, High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia (16 April 2012)

Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar[registered]) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD(+) acute myeloid leukemia. Leuk Res 2009;33:348-350.

Stephan Metzelder et al, Compassionate use of sorafenib in FLT3-ITD–positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation Blood June 25, 2009 vol. 113 no. 26 6567-6571

Hu S, Niu H, Inaba H, Orwick S, Rose C, Panetta JC, Yang S, Pounds S, Fan Y, Calabrese C, Rehg JE, Campana D, Rubnitz JE, Baker SD. Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia.J Natl Cancer Inst. 2011 Jun 8;103(11):893-905.

Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP, Heym KM, Christensen R, Onciu M, Shurtleff SA, et al. Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol. 2011 Aug 20; 29(24):3293-300

Amir T Fathi and Yi-Bin Chen, Treatment of FLT3-ITD acute myeloid leukemia.Am J Blood Res. 2011; 1(2): 175–189.

Anders K. Vistisen et al, Compassionate Use of Sorafenib in Primary Resistant Severely Progressed FLT3-ITD Positive AML in a Young Woman – A Danish Case Report. Journal of Hematology. Volume 1, Number 2-3, June 2012, pages 58-60

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