Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia

Robert J Kreitman; Philippe Moreau; Farhad Ravandi; Martin Hutchings; Anas Gazzah; Anne-Sophie Michallet; Zev A Wainberg; Alexander Stein; Sascha Dietrich; Maja J A de Jonge; Wolfgang Willenbacher; Jacques De Grève; Evgeny Arons; Palanichamy Ilankumaran; Paul Burgess; Eduard Gasal; Vivek Subbiah

doi:10.1182/blood.2021013658

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia

Robert J Kreitman, Philippe Moreau, Farhad Ravandi, Martin Hutchings, Anas Gazzah, Anne-Sophie Michallet, Zev A Wainberg, Alexander Stein, Sascha Dietrich, Maja J A de Jonge, Wolfgang Willenbacher, Jacques De Grève, Evgeny Arons, Palanichamy Ilankumaran, Paul Burgess, Eduard Gasal, Vivek Subbiah

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Abstract

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

Original language	English
Pages (from-to)	996-1006
Number of pages	11
Journal	Blood
Volume	141
Issue number	9
Early online date	15 Sep 2022
DOIs	https://doi.org/10.1182/blood.2021013658
Publication status	Published - 2 Mar 2023

Bibliographical note

Funding Information:
The authors thank the patients participating in this clinical trial and their families, as well as the staff at each participating institution who assisted with the study. NIH patients were managed, in part, by several investigators, including Theresa Yu, Lacey James, and Dai Chihara. The authors also acknowledge Maurizio Voi (Novartis NPC) for contributions to this study. Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation. Contribution: The study was designed by the funder in collaboration with all the authors, and R.J.K. contributed to the conceptualization of the study; R.J.K. P.M. F.R. M.H. A.G. A.-S.M. Z.A.W. A.S. S.D. M.J.A.d.J. W.W. J.D.G, E.A. and V.S. evaluated patients on the study and contributed to data curation; P.B. performed statistical analysis; all authors had access to all the data reported in the study and contributed to data interpretation; R.J.K. P.I. E.G. and V.S. prepared the first draft of the manuscript, with editorial assistance from a medical writer paid for by the funder; and all authors reviewed and edited the manuscript and agreed to submit the manuscript for publication.

Funding Information:
Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation .

Publisher Copyright:
© 2022 The American Society of Hematology

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

Keywords

Dabrafenib
trametinib
relapsed/refractory BRAF V600E
positive hairy cell leukemia
BRAF V600E
oncogenic driver mutation
HCL

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Kreitman, R. J., Moreau, P., Ravandi, F., Hutchings, M., Gazzah, A., Michallet, A-S., Wainberg, Z. A., Stein, A., Dietrich, S., de Jonge, M. J. A., Willenbacher, W., De Grève, J., Arons, E., Ilankumaran, P., Burgess, P., Gasal, E., & Subbiah, V. (2023). Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. Blood, 141(9), 996-1006. https://doi.org/10.1182/blood.2021013658

Kreitman, Robert J ; Moreau, Philippe ; Ravandi, Farhad ; Hutchings, Martin ; Gazzah, Anas ; Michallet, Anne-Sophie ; Wainberg, Zev A ; Stein, Alexander ; Dietrich, Sascha ; de Jonge, Maja J A ; Willenbacher, Wolfgang ; De Grève, Jacques ; Arons, Evgeny ; Ilankumaran, Palanichamy ; Burgess, Paul ; Gasal, Eduard ; Subbiah, Vivek. / Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. In: Blood. 2023 ; Vol. 141, No. 9. pp. 996-1006.

@article{7b2e717130a44742a5b24bb3a6a58433,

title = "Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia",

abstract = "BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.",

keywords = "Dabrafenib, trametinib, relapsed/refractory BRAF V600E, positive hairy cell leukemia, BRAF V600E, oncogenic driver mutation, HCL",

author = "Kreitman, {Robert J} and Philippe Moreau and Farhad Ravandi and Martin Hutchings and Anas Gazzah and Anne-Sophie Michallet and Wainberg, {Zev A} and Alexander Stein and Sascha Dietrich and {de Jonge}, {Maja J A} and Wolfgang Willenbacher and {De Gr{\`e}ve}, Jacques and Evgeny Arons and Palanichamy Ilankumaran and Paul Burgess and Eduard Gasal and Vivek Subbiah",

note = "Funding Information: The authors thank the patients participating in this clinical trial and their families, as well as the staff at each participating institution who assisted with the study. NIH patients were managed, in part, by several investigators, including Theresa Yu, Lacey James, and Dai Chihara. The authors also acknowledge Maurizio Voi (Novartis NPC) for contributions to this study. Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation. Contribution: The study was designed by the funder in collaboration with all the authors, and R.J.K. contributed to the conceptualization of the study; R.J.K. P.M. F.R. M.H. A.G. A.-S.M. Z.A.W. A.S. S.D. M.J.A.d.J. W.W. J.D.G, E.A. and V.S. evaluated patients on the study and contributed to data curation; P.B. performed statistical analysis; all authors had access to all the data reported in the study and contributed to data interpretation; R.J.K. P.I. E.G. and V.S. prepared the first draft of the manuscript, with editorial assistance from a medical writer paid for by the funder; and all authors reviewed and edited the manuscript and agreed to submit the manuscript for publication. Funding Information: Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation . Publisher Copyright: {\textcopyright} 2022 The American Society of Hematology Copyright: Copyright 2023 Elsevier B.V., All rights reserved.",

year = "2023",

month = mar,

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doi = "10.1182/blood.2021013658",

language = "English",

volume = "141",

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Kreitman, RJ, Moreau, P, Ravandi, F, Hutchings, M, Gazzah, A, Michallet, A-S, Wainberg, ZA, Stein, A, Dietrich, S, de Jonge, MJA, Willenbacher, W, De Grève, J, Arons, E, Ilankumaran, P, Burgess, P, Gasal, E & Subbiah, V 2023, 'Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia', Blood, vol. 141, no. 9, pp. 996-1006. https://doi.org/10.1182/blood.2021013658

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia. / Kreitman, Robert J; Moreau, Philippe; Ravandi, Farhad; Hutchings, Martin; Gazzah, Anas; Michallet, Anne-Sophie; Wainberg, Zev A; Stein, Alexander; Dietrich, Sascha; de Jonge, Maja J A; Willenbacher, Wolfgang; De Grève, Jacques; Arons, Evgeny; Ilankumaran, Palanichamy; Burgess, Paul; Gasal, Eduard; Subbiah, Vivek.

In: Blood, Vol. 141, No. 9, 02.03.2023, p. 996-1006.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia

AU - Kreitman, Robert J

AU - Moreau, Philippe

AU - Ravandi, Farhad

AU - Hutchings, Martin

AU - Gazzah, Anas

AU - Michallet, Anne-Sophie

AU - Wainberg, Zev A

AU - Stein, Alexander

AU - Dietrich, Sascha

AU - de Jonge, Maja J A

AU - Willenbacher, Wolfgang

AU - De Grève, Jacques

AU - Arons, Evgeny

AU - Ilankumaran, Palanichamy

AU - Burgess, Paul

AU - Gasal, Eduard

AU - Subbiah, Vivek

N1 - Funding Information: The authors thank the patients participating in this clinical trial and their families, as well as the staff at each participating institution who assisted with the study. NIH patients were managed, in part, by several investigators, including Theresa Yu, Lacey James, and Dai Chihara. The authors also acknowledge Maurizio Voi (Novartis NPC) for contributions to this study. Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation. Contribution: The study was designed by the funder in collaboration with all the authors, and R.J.K. contributed to the conceptualization of the study; R.J.K. P.M. F.R. M.H. A.G. A.-S.M. Z.A.W. A.S. S.D. M.J.A.d.J. W.W. J.D.G, E.A. and V.S. evaluated patients on the study and contributed to data curation; P.B. performed statistical analysis; all authors had access to all the data reported in the study and contributed to data interpretation; R.J.K. P.I. E.G. and V.S. prepared the first draft of the manuscript, with editorial assistance from a medical writer paid for by the funder; and all authors reviewed and edited the manuscript and agreed to submit the manuscript for publication. Funding Information: Medical writing/editorial assistance was provided by Shruti Shah and Sharol Janice Rodrigues (Novartis Healthcare Pvt Ltd), as well as Michael Demars (ArticulateScience, LLC), and funded by Novartis Pharmaceuticals Corporation in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ). Support with the Bayesian study design and analysis was provided by Berry Consultants LLC. R.J.K. is supported in part by the Intramural Research Program of the US National Institutes of Health. V.S. is supported by National Institutes of Health (NIH), National Cancer Institute (NCI) grant R01CA242845, and University of Texas MD Anderson Cancer Center is supported by NIH, NCI support grant P30 CA016672. This study was supported by Novartis Pharmaceuticals Corporation . Publisher Copyright: © 2022 The American Society of Hematology Copyright: Copyright 2023 Elsevier B.V., All rights reserved.

PY - 2023/3/2

Y1 - 2023/3/2

N2 - BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

AB - BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

KW - Dabrafenib

KW - trametinib

KW - relapsed/refractory BRAF V600E

KW - positive hairy cell leukemia

KW - BRAF V600E

KW - oncogenic driver mutation

KW - HCL

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U2 - 10.1182/blood.2021013658

DO - 10.1182/blood.2021013658

M3 - Article

C2 - 36108341

VL - 141

SP - 996

EP - 1006

JO - Blood

JF - Blood

SN - 0006-4971

IS - 9

ER -

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia

Abstract

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Keywords

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