Phase I study of sorafenib in patients with refractory or relapsed acute leukemias

Gautam Borthakur, Hagop Kantarjian, Farhad Ravandi, Weiguo Zhang, Marina Konopleva, John J. Wright, Stefan Faderl, Srdan Verstovsek, Sheela Mathews, Michael Andreeff, Jorge E. Cortes

Research output: Contribution to journalArticle

Abstract

Background Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Design and Methods Fifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules. Results Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. Conclusions Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenibbased combinations.

Original languageEnglish (US)
Pages (from-to)62-68
Number of pages7
JournalHaematologica
Volume96
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

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fms-Like Tyrosine Kinase 3
Leukemia
Appointments and Schedules
Acute Myeloid Leukemia
raf Kinases
Mutation
Hyperbilirubinemia
Myelodysplastic Syndromes
Hematologic Neoplasms
Amylases
Phosphotransferases
Blood Platelets
Bone Marrow
sorafenib
Hypertension

Keywords

  • FLT3 mutation
  • Leukemia
  • Sorafenib

ASJC Scopus subject areas

  • Hematology

Cite this

Borthakur, G., Kantarjian, H., Ravandi, F., Zhang, W., Konopleva, M., Wright, J. J., ... Cortes, J. E. (2011). Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica, 96(1), 62-68. https://doi.org/10.3324/haematol.2010.030452

Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. / Borthakur, Gautam; Kantarjian, Hagop; Ravandi, Farhad; Zhang, Weiguo; Konopleva, Marina; Wright, John J.; Faderl, Stefan; Verstovsek, Srdan; Mathews, Sheela; Andreeff, Michael; Cortes, Jorge E.

In: Haematologica, Vol. 96, No. 1, 01.01.2011, p. 62-68.

Research output: Contribution to journalArticle

Borthakur, G, Kantarjian, H, Ravandi, F, Zhang, W, Konopleva, M, Wright, JJ, Faderl, S, Verstovsek, S, Mathews, S, Andreeff, M & Cortes, JE 2011, 'Phase I study of sorafenib in patients with refractory or relapsed acute leukemias', Haematologica, vol. 96, no. 1, pp. 62-68. https://doi.org/10.3324/haematol.2010.030452
Borthakur G, Kantarjian H, Ravandi F, Zhang W, Konopleva M, Wright JJ et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica. 2011 Jan 1;96(1):62-68. https://doi.org/10.3324/haematol.2010.030452
Borthakur, Gautam ; Kantarjian, Hagop ; Ravandi, Farhad ; Zhang, Weiguo ; Konopleva, Marina ; Wright, John J. ; Faderl, Stefan ; Verstovsek, Srdan ; Mathews, Sheela ; Andreeff, Michael ; Cortes, Jorge E. / Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. In: Haematologica. 2011 ; Vol. 96, No. 1. pp. 62-68.
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AU - Wright, John J.

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AB - Background Sorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Design and Methods Fifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules. Results Complete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation. Conclusions Additional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with fms-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenibbased combinations.

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