Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant

Michael Scordo; Trent P. Wang; Kwang W. Ahn; Yue Chen; Sairah Ahmed; Farrukh T. Awan; Amer Beitinjaneh; Andy Chen; Victor A. Chow; Bhagirathbhai Dholaria; Narendranath Epperla; Umar Farooq; Nilanjan Ghosh; Natalie Grover; Nada Hamad; Gerhard C. Hildebrandt; Leona Holmberg; Sanghee Hong; David J. Inwards; Antonio Jimenez-Jimenez; Reem Karmali; Vaishalee P. Kenkre; Farhad Khimani; Evgeny Klyuchnikov; Maxwell M. Krem; Pashna N. Munshi; Yago Nieto; Tim Prestidge; Praveen Ramakrishnan Geethakumari; Andrew R. Rezvani; Peter A. Riedell; Sachiko Seo; Nirav N. Shah; Melhem Solh; Jean A. Yared; Mohamed A. Kharfan-Dabaja; Alex Herrera; Mehdi Hamadani; Craig S. Sauter

doi:10.1001/jamaoncol.2021.1074

Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant

Michael Scordo, Trent P. Wang, Kwang W. Ahn, Yue Chen, Sairah Ahmed, Farrukh T. Awan, Amer Beitinjaneh, Andy Chen, Victor A. Chow, Bhagirathbhai Dholaria, Narendranath Epperla, Umar Farooq, Nilanjan Ghosh, Natalie Grover, Nada Hamad, Gerhard C. Hildebrandt, Leona Holmberg, Sanghee Hong, David J. Inwards, Antonio Jimenez-JimenezReem Karmali, Vaishalee P. Kenkre, Farhad Khimani, Evgeny Klyuchnikov, Maxwell M. Krem, Pashna N. Munshi, Yago Nieto, Tim Prestidge, Praveen Ramakrishnan Geethakumari, Andrew R. Rezvani, Peter A. Riedell, Sachiko Seo, Nirav N. Shah, Melhem Solh, Jean A. Yared, Mohamed A. Kharfan-Dabaja, Alex Herrera, Mehdi Hamadani, Craig S. Sauter

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

35 Scopus citations

Abstract

Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). Design, Setting, and Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Interventions: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). Main Outcomes and Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P =.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P <.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P =.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P =.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P =.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. Conclusions and Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics..

Original language	English
Pages (from-to)	993-1003
Number of pages	11
Journal	JAMA Oncology
Volume	7
Issue number	7
DOIs	https://doi.org/10.1001/jamaoncol.2021.1074
State	Published - Jul 2021

Bibliographical note

Funding Information:
reported personal fees from Angiocrine Bioscience, Inc. Consultancy and Research Support, personal fees from Omeros Corporation Consultancy and Research Support, personal fees from McKinsey & Company Consultancy, other from Kite - A Gilead Company Ad hoc advisory board, and personal fees from i3Health CME speaking engagement outside the submitted work. Dr Awan reported personal fees from AstraZeneca, personal fees from Genentech, personal fees from AbbVie, personal fees from Janssen, personal fees from Pharmacyclics, personal fees from Gilead Sciences, personal fees from Kite Pharma, personal fees from Celgene, personal fees from Karyopharm, personal fees from MEI Pharma, personal fees from Verastem, personal fees from Incyte, personal fees from Beigene, personal fees from ADCT Therapeutic, personal fees from Dava Oncology, personal fees from Bristol-Myers Squibb (BMS), personal fees from Merck, and personal fees from Johnson and Johnson Consultant outside the submitted work. Dr A. Chen reported personal fees from Morphosys, personal fees from Genentech, and personal fees from Mesoblast outside the submitted work. Dr Dholaria reported institutional research support from Takeda, Janssen, Angiocrine, Pfizer, and Poseida. Dr Epperla reported speaker’s bureau fees from Verastem, speaker’s bureau fees from Beigene, advisory board fees from Karyopharm, and consultancy fees from Genzyme outside the submitted work. Dr Farooq reported personal fees from Kite Pharma advisory board outside the submitted work. Dr Ghosh reported grants from Genen/Roche Research Funding, other from TG Therapeutics Research funding, consulting, other from Pharmacyclics Research funding, consulting, other from BMS Research funding, consulting, speakers bureau, personal fees from Seattle Genetics Consulting, personal fees from Gilead/Kite Research funding, consulting, speakers bureau, personal fees from AbbVie Consulting, Speakers bureau, personal fees from Astra Zeneca Consulting, Speakers Bureau, personal fees from Janssen Consulting, Speakers Bureau, personal fees from Karyopharm Consulting, personal fees from Genmab Consulting, personal fees from ADC Therapeutics Consulting, personal fees from Beigene Consulting, personal fees from Adaptive Biotech Consulting, and personal fees from Incyte Consulting outside the submitted work. Dr Grover reported grants from Genentech, grants from Tessa Therapeutics, personal fees from Kite, and nonfinancial support from Bellicum outside the submitted work. Dr Hamad reported honoraria from Novartis, AbbVie, Roche, and Janssen outside the submitted work. Dr Holmberg reported study funding from Seattle Genetics, Sanofi, Millennium-Takada, BMS, Merck, and Janssen outside the submitted work; in addition, Dr Holmberg had a patent for UpToDate with royalties paid. Dr Karmali reported personal fees from Janssen, personal fees from Karyopharm, personal fees from Gilead/Kite, personal fees from BMS/Celgene/Juno, personal fees from AstraZeneca, personal fees from BeiGene, personal fees from Morphosys, grants from Takeda, grants from Gilead/Kite, and grants from BMS/Celgene/ Juno outside the submitted work. Dr Khimani reported grants from BMS for GVHD prevention trial outside the submitted work. Dr Munshi reported other from Kite Speakers Bureau and other from Incyte Speakers Bureau outside the submitted work. Dr Rezvani reported grants from Pharmacyclics, other from Nohla One-time scientific advisory board, and scientific advisory board fees from Kaleido outside the submitted work. Dr Riedell reported personal fees from Kite/ Gilead, grants from MorphoSys, personal fees from BMS, personal fees from Novartis, personal fees from BeiGene, personal fees from Karyopharm Therapeutics, personal fees from Takeda, personal fees from Verastem, grants from Calibr, grants from Celgene, grants from Kite/Gilead, grants from Novartis, grants from BMS, and personal fees from Bayer outside the submitted work. Dr Seo reported personal fees from Janssen Pharmaceutical KK outside the submitted work. Dr Shah reported personal fees from Miltenyi, personal fees from Lilly, personal fees from TG Therapeutics, personal fees from Legend, and personal fees from Epizyme outside the submitted work. Dr Yared reported personal fees from Kite outside the submitted work. Dr Kharfan-Dabaja reported personal fees from Daiichi Sankyo outside the submitted work. Dr Herrera reported personal fees from BMS, personal fees from Merck, personal fees from Karyopharm, personal fees from Seattle Genetics, personal fees from Gilead/Kite Pharma, grants from Gilead Sciences, grants from BMS, grants from Merck, grants from Seattle Genetics, grants from Genentech, and personal fees from Genentech outside the submitted work. Dr Sauter reported grants from Juno Therapeutic, grants from Celgene, grants from BMS, grants from Precision Biosciences, personal fees from Precision Biosciences, grants from Sanofi Genzyme, personal fees from Sanofi Genzyme, personal fees from Juno Therapeutics, personal fees from Spectrum Pharmaceuticals, personal fees from Novartis, personal fees from Genmab, personal fees from Kite, a Gilead Company, personal fees from Celgene, personal fees from Gamida Cell, personal fees from Karyopharm Therapeutics, and personal fees from GlaxoSmithKline outside the submitted work. No other disclosures were reported.

Funding Information:
primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research; support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: Actinium Pharmaceuticals Inc; Adienne SA; Allovir Inc; Amgen Inc; Angiocrine Bioscience; Astellas Pharma US; bluebird bio Inc; Bristol-Myers Squibb; Celgene Corp; CSL Behring; CytoSen Therapeutics Inc; Daiichi Sankyo Co, Ltd; ExcellThera; Fate Therapeutics; Gamida-Cell Ltd; Genentech Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals Inc; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp; Millennium, the Takeda Oncology Co; Miltenyi Biotec Inc; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune Inc; Orca Biosystems Inc; Pfizer Inc; Pharmacyclics LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; Xenikos BV.

Publisher Copyright:
© 2021 American Medical Association. All rights reserved.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1001/jamaoncol.2021.1074

Cite this

Scordo, M., Wang, T. P., Ahn, K. W., Chen, Y., Ahmed, S., Awan, F. T., Beitinjaneh, A., Chen, A., Chow, V. A., Dholaria, B., Epperla, N., Farooq, U., Ghosh, N., Grover, N., Hamad, N., Hildebrandt, G. C., Holmberg, L., Hong, S., Inwards, D. J., ... Sauter, C. S. (2021). Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant. JAMA Oncology, 7(7), 993-1003. https://doi.org/10.1001/jamaoncol.2021.1074

@article{e09cedd04a5048439a27cf1685946a6e,

title = "Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant",

abstract = "Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). Design, Setting, and Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Interventions: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). Main Outcomes and Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P =.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P <.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P =.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P =.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P =.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. Conclusions and Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics..",

author = "Michael Scordo and Wang, {Trent P.} and Ahn, {Kwang W.} and Yue Chen and Sairah Ahmed and Awan, {Farrukh T.} and Amer Beitinjaneh and Andy Chen and Chow, {Victor A.} and Bhagirathbhai Dholaria and Narendranath Epperla and Umar Farooq and Nilanjan Ghosh and Natalie Grover and Nada Hamad and Hildebrandt, {Gerhard C.} and Leona Holmberg and Sanghee Hong and Inwards, {David J.} and Antonio Jimenez-Jimenez and Reem Karmali and Kenkre, {Vaishalee P.} and Farhad Khimani and Evgeny Klyuchnikov and Krem, {Maxwell M.} and Munshi, {Pashna N.} and Yago Nieto and Tim Prestidge and {Ramakrishnan Geethakumari}, Praveen and Rezvani, {Andrew R.} and Riedell, {Peter A.} and Sachiko Seo and Shah, {Nirav N.} and Melhem Solh and Yared, {Jean A.} and Kharfan-Dabaja, {Mohamed A.} and Alex Herrera and Mehdi Hamadani and Sauter, {Craig S.}",

note = "Funding Information: reported personal fees from Angiocrine Bioscience, Inc. Consultancy and Research Support, personal fees from Omeros Corporation Consultancy and Research Support, personal fees from McKinsey & Company Consultancy, other from Kite - A Gilead Company Ad hoc advisory board, and personal fees from i3Health CME speaking engagement outside the submitted work. Dr Awan reported personal fees from AstraZeneca, personal fees from Genentech, personal fees from AbbVie, personal fees from Janssen, personal fees from Pharmacyclics, personal fees from Gilead Sciences, personal fees from Kite Pharma, personal fees from Celgene, personal fees from Karyopharm, personal fees from MEI Pharma, personal fees from Verastem, personal fees from Incyte, personal fees from Beigene, personal fees from ADCT Therapeutic, personal fees from Dava Oncology, personal fees from Bristol-Myers Squibb (BMS), personal fees from Merck, and personal fees from Johnson and Johnson Consultant outside the submitted work. Dr A. Chen reported personal fees from Morphosys, personal fees from Genentech, and personal fees from Mesoblast outside the submitted work. Dr Dholaria reported institutional research support from Takeda, Janssen, Angiocrine, Pfizer, and Poseida. Dr Epperla reported speaker{\textquoteright}s bureau fees from Verastem, speaker{\textquoteright}s bureau fees from Beigene, advisory board fees from Karyopharm, and consultancy fees from Genzyme outside the submitted work. Dr Farooq reported personal fees from Kite Pharma advisory board outside the submitted work. Dr Ghosh reported grants from Genen/Roche Research Funding, other from TG Therapeutics Research funding, consulting, other from Pharmacyclics Research funding, consulting, other from BMS Research funding, consulting, speakers bureau, personal fees from Seattle Genetics Consulting, personal fees from Gilead/Kite Research funding, consulting, speakers bureau, personal fees from AbbVie Consulting, Speakers bureau, personal fees from Astra Zeneca Consulting, Speakers Bureau, personal fees from Janssen Consulting, Speakers Bureau, personal fees from Karyopharm Consulting, personal fees from Genmab Consulting, personal fees from ADC Therapeutics Consulting, personal fees from Beigene Consulting, personal fees from Adaptive Biotech Consulting, and personal fees from Incyte Consulting outside the submitted work. Dr Grover reported grants from Genentech, grants from Tessa Therapeutics, personal fees from Kite, and nonfinancial support from Bellicum outside the submitted work. Dr Hamad reported honoraria from Novartis, AbbVie, Roche, and Janssen outside the submitted work. Dr Holmberg reported study funding from Seattle Genetics, Sanofi, Millennium-Takada, BMS, Merck, and Janssen outside the submitted work; in addition, Dr Holmberg had a patent for UpToDate with royalties paid. Dr Karmali reported personal fees from Janssen, personal fees from Karyopharm, personal fees from Gilead/Kite, personal fees from BMS/Celgene/Juno, personal fees from AstraZeneca, personal fees from BeiGene, personal fees from Morphosys, grants from Takeda, grants from Gilead/Kite, and grants from BMS/Celgene/ Juno outside the submitted work. Dr Khimani reported grants from BMS for GVHD prevention trial outside the submitted work. Dr Munshi reported other from Kite Speakers Bureau and other from Incyte Speakers Bureau outside the submitted work. Dr Rezvani reported grants from Pharmacyclics, other from Nohla One-time scientific advisory board, and scientific advisory board fees from Kaleido outside the submitted work. Dr Riedell reported personal fees from Kite/ Gilead, grants from MorphoSys, personal fees from BMS, personal fees from Novartis, personal fees from BeiGene, personal fees from Karyopharm Therapeutics, personal fees from Takeda, personal fees from Verastem, grants from Calibr, grants from Celgene, grants from Kite/Gilead, grants from Novartis, grants from BMS, and personal fees from Bayer outside the submitted work. Dr Seo reported personal fees from Janssen Pharmaceutical KK outside the submitted work. Dr Shah reported personal fees from Miltenyi, personal fees from Lilly, personal fees from TG Therapeutics, personal fees from Legend, and personal fees from Epizyme outside the submitted work. Dr Yared reported personal fees from Kite outside the submitted work. Dr Kharfan-Dabaja reported personal fees from Daiichi Sankyo outside the submitted work. Dr Herrera reported personal fees from BMS, personal fees from Merck, personal fees from Karyopharm, personal fees from Seattle Genetics, personal fees from Gilead/Kite Pharma, grants from Gilead Sciences, grants from BMS, grants from Merck, grants from Seattle Genetics, grants from Genentech, and personal fees from Genentech outside the submitted work. Dr Sauter reported grants from Juno Therapeutic, grants from Celgene, grants from BMS, grants from Precision Biosciences, personal fees from Precision Biosciences, grants from Sanofi Genzyme, personal fees from Sanofi Genzyme, personal fees from Juno Therapeutics, personal fees from Spectrum Pharmaceuticals, personal fees from Novartis, personal fees from Genmab, personal fees from Kite, a Gilead Company, personal fees from Celgene, personal fees from Gamida Cell, personal fees from Karyopharm Therapeutics, and personal fees from GlaxoSmithKline outside the submitted work. No other disclosures were reported. Funding Information: primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research; support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: Actinium Pharmaceuticals Inc; Adienne SA; Allovir Inc; Amgen Inc; Angiocrine Bioscience; Astellas Pharma US; bluebird bio Inc; Bristol-Myers Squibb; Celgene Corp; CSL Behring; CytoSen Therapeutics Inc; Daiichi Sankyo Co, Ltd; ExcellThera; Fate Therapeutics; Gamida-Cell Ltd; Genentech Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals Inc; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp; Millennium, the Takeda Oncology Co; Miltenyi Biotec Inc; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune Inc; Orca Biosystems Inc; Pfizer Inc; Pharmacyclics LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; Xenikos BV. Publisher Copyright: {\textcopyright} 2021 American Medical Association. All rights reserved.",

year = "2021",

month = jul,

doi = "10.1001/jamaoncol.2021.1074",

language = "English",

volume = "7",

pages = "993--1003",

number = "7",

}

Scordo, M, Wang, TP, Ahn, KW, Chen, Y, Ahmed, S, Awan, FT, Beitinjaneh, A, Chen, A, Chow, VA, Dholaria, B, Epperla, N, Farooq, U, Ghosh, N, Grover, N, Hamad, N, Hildebrandt, GC, Holmberg, L, Hong, S, Inwards, DJ, Jimenez-Jimenez, A, Karmali, R, Kenkre, VP, Khimani, F, Klyuchnikov, E, Krem, MM, Munshi, PN, Nieto, Y, Prestidge, T, Ramakrishnan Geethakumari, P, Rezvani, AR, Riedell, PA, Seo, S, Shah, NN, Solh, M, Yared, JA, Kharfan-Dabaja, MA, Herrera, A, Hamadani, M & Sauter, CS 2021, 'Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant', JAMA Oncology, vol. 7, no. 7, pp. 993-1003. https://doi.org/10.1001/jamaoncol.2021.1074

TY - JOUR

T1 - Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant

AU - Scordo, Michael

AU - Wang, Trent P.

AU - Ahn, Kwang W.

AU - Chen, Yue

AU - Ahmed, Sairah

AU - Awan, Farrukh T.

AU - Beitinjaneh, Amer

AU - Chen, Andy

AU - Chow, Victor A.

AU - Dholaria, Bhagirathbhai

AU - Epperla, Narendranath

AU - Farooq, Umar

AU - Ghosh, Nilanjan

AU - Grover, Natalie

AU - Hamad, Nada

AU - Hildebrandt, Gerhard C.

AU - Holmberg, Leona

AU - Hong, Sanghee

AU - Inwards, David J.

AU - Jimenez-Jimenez, Antonio

AU - Karmali, Reem

AU - Kenkre, Vaishalee P.

AU - Khimani, Farhad

AU - Klyuchnikov, Evgeny

AU - Krem, Maxwell M.

AU - Munshi, Pashna N.

AU - Nieto, Yago

AU - Prestidge, Tim

AU - Ramakrishnan Geethakumari, Praveen

AU - Rezvani, Andrew R.

AU - Riedell, Peter A.

AU - Seo, Sachiko

AU - Shah, Nirav N.

AU - Solh, Melhem

AU - Yared, Jean A.

AU - Kharfan-Dabaja, Mohamed A.

AU - Herrera, Alex

AU - Hamadani, Mehdi

AU - Sauter, Craig S.

N1 - Funding Information: reported personal fees from Angiocrine Bioscience, Inc. Consultancy and Research Support, personal fees from Omeros Corporation Consultancy and Research Support, personal fees from McKinsey & Company Consultancy, other from Kite - A Gilead Company Ad hoc advisory board, and personal fees from i3Health CME speaking engagement outside the submitted work. Dr Awan reported personal fees from AstraZeneca, personal fees from Genentech, personal fees from AbbVie, personal fees from Janssen, personal fees from Pharmacyclics, personal fees from Gilead Sciences, personal fees from Kite Pharma, personal fees from Celgene, personal fees from Karyopharm, personal fees from MEI Pharma, personal fees from Verastem, personal fees from Incyte, personal fees from Beigene, personal fees from ADCT Therapeutic, personal fees from Dava Oncology, personal fees from Bristol-Myers Squibb (BMS), personal fees from Merck, and personal fees from Johnson and Johnson Consultant outside the submitted work. Dr A. Chen reported personal fees from Morphosys, personal fees from Genentech, and personal fees from Mesoblast outside the submitted work. Dr Dholaria reported institutional research support from Takeda, Janssen, Angiocrine, Pfizer, and Poseida. Dr Epperla reported speaker’s bureau fees from Verastem, speaker’s bureau fees from Beigene, advisory board fees from Karyopharm, and consultancy fees from Genzyme outside the submitted work. Dr Farooq reported personal fees from Kite Pharma advisory board outside the submitted work. Dr Ghosh reported grants from Genen/Roche Research Funding, other from TG Therapeutics Research funding, consulting, other from Pharmacyclics Research funding, consulting, other from BMS Research funding, consulting, speakers bureau, personal fees from Seattle Genetics Consulting, personal fees from Gilead/Kite Research funding, consulting, speakers bureau, personal fees from AbbVie Consulting, Speakers bureau, personal fees from Astra Zeneca Consulting, Speakers Bureau, personal fees from Janssen Consulting, Speakers Bureau, personal fees from Karyopharm Consulting, personal fees from Genmab Consulting, personal fees from ADC Therapeutics Consulting, personal fees from Beigene Consulting, personal fees from Adaptive Biotech Consulting, and personal fees from Incyte Consulting outside the submitted work. Dr Grover reported grants from Genentech, grants from Tessa Therapeutics, personal fees from Kite, and nonfinancial support from Bellicum outside the submitted work. Dr Hamad reported honoraria from Novartis, AbbVie, Roche, and Janssen outside the submitted work. Dr Holmberg reported study funding from Seattle Genetics, Sanofi, Millennium-Takada, BMS, Merck, and Janssen outside the submitted work; in addition, Dr Holmberg had a patent for UpToDate with royalties paid. Dr Karmali reported personal fees from Janssen, personal fees from Karyopharm, personal fees from Gilead/Kite, personal fees from BMS/Celgene/Juno, personal fees from AstraZeneca, personal fees from BeiGene, personal fees from Morphosys, grants from Takeda, grants from Gilead/Kite, and grants from BMS/Celgene/ Juno outside the submitted work. Dr Khimani reported grants from BMS for GVHD prevention trial outside the submitted work. Dr Munshi reported other from Kite Speakers Bureau and other from Incyte Speakers Bureau outside the submitted work. Dr Rezvani reported grants from Pharmacyclics, other from Nohla One-time scientific advisory board, and scientific advisory board fees from Kaleido outside the submitted work. Dr Riedell reported personal fees from Kite/ Gilead, grants from MorphoSys, personal fees from BMS, personal fees from Novartis, personal fees from BeiGene, personal fees from Karyopharm Therapeutics, personal fees from Takeda, personal fees from Verastem, grants from Calibr, grants from Celgene, grants from Kite/Gilead, grants from Novartis, grants from BMS, and personal fees from Bayer outside the submitted work. Dr Seo reported personal fees from Janssen Pharmaceutical KK outside the submitted work. Dr Shah reported personal fees from Miltenyi, personal fees from Lilly, personal fees from TG Therapeutics, personal fees from Legend, and personal fees from Epizyme outside the submitted work. Dr Yared reported personal fees from Kite outside the submitted work. Dr Kharfan-Dabaja reported personal fees from Daiichi Sankyo outside the submitted work. Dr Herrera reported personal fees from BMS, personal fees from Merck, personal fees from Karyopharm, personal fees from Seattle Genetics, personal fees from Gilead/Kite Pharma, grants from Gilead Sciences, grants from BMS, grants from Merck, grants from Seattle Genetics, grants from Genentech, and personal fees from Genentech outside the submitted work. Dr Sauter reported grants from Juno Therapeutic, grants from Celgene, grants from BMS, grants from Precision Biosciences, personal fees from Precision Biosciences, grants from Sanofi Genzyme, personal fees from Sanofi Genzyme, personal fees from Juno Therapeutics, personal fees from Spectrum Pharmaceuticals, personal fees from Novartis, personal fees from Genmab, personal fees from Kite, a Gilead Company, personal fees from Celgene, personal fees from Gamida Cell, personal fees from Karyopharm Therapeutics, and personal fees from GlaxoSmithKline outside the submitted work. No other disclosures were reported. Funding Information: primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research; support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: Actinium Pharmaceuticals Inc; Adienne SA; Allovir Inc; Amgen Inc; Angiocrine Bioscience; Astellas Pharma US; bluebird bio Inc; Bristol-Myers Squibb; Celgene Corp; CSL Behring; CytoSen Therapeutics Inc; Daiichi Sankyo Co, Ltd; ExcellThera; Fate Therapeutics; Gamida-Cell Ltd; Genentech Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals Inc; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp; Millennium, the Takeda Oncology Co; Miltenyi Biotec Inc; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune Inc; Orca Biosystems Inc; Pfizer Inc; Pharmacyclics LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; Xenikos BV. Publisher Copyright: © 2021 American Medical Association. All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). Design, Setting, and Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Interventions: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). Main Outcomes and Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P =.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P <.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P =.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P =.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P =.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. Conclusions and Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics..

AB - Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). Design, Setting, and Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Interventions: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). Main Outcomes and Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P =.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P <.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P =.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P =.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P =.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. Conclusions and Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics..

UR - http://www.scopus.com/inward/record.url?scp=85105866863&partnerID=8YFLogxK

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U2 - 10.1001/jamaoncol.2021.1074

DO - 10.1001/jamaoncol.2021.1074

M3 - Article

C2 - 33956047

AN - SCOPUS:85105866863

SN - 2374-2437

VL - 7

SP - 993

EP - 1003

JO - JAMA Oncology

JF - JAMA Oncology

IS - 7

ER -

Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant

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