A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408

Andrew M. Evens; Fangxin Hong; Thomas M. Habermann; Ranjana H. Advani; Randy D. Gascoyne; Thomas E. Witzig; Andrew Quon; Erik A. Ranheim; Stephen M. Ansell; Puneet Singh Cheema; Philip A. Dy; Timothy E. O'Brien; Jane N. Winter; Terrence P. Cescon; Julie E. Chang; Brad S. Kahl

doi:10.1158/1078-0432.CCR-20-1345

A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408

Andrew M. Evens^*, Fangxin Hong, Thomas M. Habermann, Ranjana H. Advani, Randy D. Gascoyne, Thomas E. Witzig, Andrew Quon, Erik A. Ranheim, Stephen M. Ansell, Puneet Singh Cheema, Philip A. Dy, Timothy E. O'Brien, Jane N. Winter, Terrence P. Cescon, Julie E. Chang, Brad S. Kahl

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

19 Scopus citations

Abstract

Purpose: We sought to improve upon frontline bendamustine/ rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P ¼ 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P ¼ 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3-4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P ¼ 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P ¼ 0.36) with OS rates of 87%, 90%, and 84%, respectively (P ¼ 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

Original language	English (US)
Pages (from-to)	4468-4477
Number of pages	10
Journal	Clinical Cancer Research
Volume	26
Issue number	17
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-1345
State	Published - Sep 2020

Funding

A.M. Evens reports nonfinancial support from ECOG-ACRIN Cancer Research Group (study coordination) during the conduct of the study; grants from ORIEN (Translational research grant), grants from Leukemia & Lymphoma Society (Translational research grant), grants from Tesaro (Translational research grant), personal fees from Seattle Genetics (Educational and research advisory board with honorarium), personal fees from MorphoSys (Research advisory board with honorarium), personal fees from Mylteni (Research advisory board with honorarium), personal fees from Epizyme (Research advisory board with honorarium), personal fees from Research to Practice (Educational speakers bureau with honorarium), personal fees from Physician Education Resource (Educational speakers bureau with honorarium), personal fees from OncLive (Educational speakers bureau with honorarium), personal fees from Cota (Research advisory board with honorarium), personal fees from Novartis (DSMB consultant), and personal fees from Pharmacyclics (DSMB consultant) outside the submitted work. T.M. Habermann reports grants from NCI ECOG-ACRIN (is the institutional principal investigator of this grant) during the conduct of the study. R.H. Advani reports other from Roche/Genetech (Consulting or Advisory Role; Institutional Research Support) and other from Celgene (Consulting or Advisory Role; Institutional Research Support) during the conduct of the study; other from Gilead (Consulting or Advisory Role) and other from Sanofi (Consulting or Advisory Role) outside the submitted work. T.E. Witzig reports other from Celgene (advisory board personally uncompensated; research support to Mayo) during the conduct of the study. E. Ranheim reports personal fees from ECOG (ECOG pays a reimbursement for pathology review of the cases involved in the trial to confirm diagnoses; this is in the form of monies to the institution that then are put in professional funds account for research related costs, not personal reimbursement) during the conduct of the study. S.M. Ansell reports other from Bristol Myers Squibb (Funding for clinical trials), other from Seattle Genetics (Funding for clinical trials), other from Affimed (Funding for clinical trials), other from Regeneron (Funding for This study was coordinated by the ECOG-ACRIN Cancer Research Group [Peter J. O'Dwyer (MD) and Mitchell D. Schnall (MD and PhD), Group Co-Chairs] and supported by the NCI of the NIH under the following award numbers: U10CA180820, U10CA180794, UG1CA189830, UG1CA189863, UG1CA232760, UG1CA233234, UG1CA233277, UG1CA233320, UG1CA233341, and UG1CA233339. We acknowledge Dr. Sandra Horning for insights into the initial study design.

ASJC Scopus subject areas

General Medicine

UN SDGs

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

Access to Document

10.1158/1078-0432.CCR-20-1345

Cite this

Evens, A. M., Hong, F., Habermann, T. M., Advani, R. H., Gascoyne, R. D., Witzig, T. E., Quon, A., Ranheim, E. A., Ansell, S. M., Cheema, P. S., Dy, P. A., O'Brien, T. E., Winter, J. N., Cescon, T. P., Chang, J. E., & Kahl, B. S. (2020). A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408. Clinical Cancer Research, 26(17), 4468-4477. https://doi.org/10.1158/1078-0432.CCR-20-1345

@article{1496b3d1f2a74fd089fa090629ff272f,

title = "A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408",

abstract = "Purpose: We sought to improve upon frontline bendamustine/ rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P ¼ 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P ¼ 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3-4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P ¼ 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P ¼ 0.36) with OS rates of 87%, 90%, and 84%, respectively (P ¼ 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.",

author = "Evens, {Andrew M.} and Fangxin Hong and Habermann, {Thomas M.} and Advani, {Ranjana H.} and Gascoyne, {Randy D.} and Witzig, {Thomas E.} and Andrew Quon and Ranheim, {Erik A.} and Ansell, {Stephen M.} and Cheema, {Puneet Singh} and Dy, {Philip A.} and O'Brien, {Timothy E.} and Winter, {Jane N.} and Cescon, {Terrence P.} and Chang, {Julie E.} and Kahl, {Brad S.}",

note = "Funding Information: A.M. Evens reports nonfinancial support from ECOG-ACRIN Cancer Research Group (study coordination) during the conduct of the study; grants from ORIEN (Translational research grant), grants from Leukemia & Lymphoma Society (Translational research grant), grants from Tesaro (Translational research grant), personal fees from Seattle Genetics (Educational and research advisory board with honorarium), personal fees from MorphoSys (Research advisory board with honorarium), personal fees from Mylteni (Research advisory board with honorarium), personal fees from Epizyme (Research advisory board with honorarium), personal fees from Research to Practice (Educational speakers bureau with honorarium), personal fees from Physician Education Resource (Educational speakers bureau with honorarium), personal fees from OncLive (Educational speakers bureau with honorarium), personal fees from Cota (Research advisory board with honorarium), personal fees from Novartis (DSMB consultant), and personal fees from Pharmacyclics (DSMB consultant) outside the submitted work. T.M. Habermann reports grants from NCI ECOG-ACRIN (is the institutional principal investigator of this grant) during the conduct of the study. R.H. Advani reports other from Roche/Genetech (Consulting or Advisory Role; Institutional Research Support) and other from Celgene (Consulting or Advisory Role; Institutional Research Support) during the conduct of the study; other from Gilead (Consulting or Advisory Role) and other from Sanofi (Consulting or Advisory Role) outside the submitted work. T.E. Witzig reports other from Celgene (advisory board personally uncompensated; research support to Mayo) during the conduct of the study. E. Ranheim reports personal fees from ECOG (ECOG pays a reimbursement for pathology review of the cases involved in the trial to confirm diagnoses; this is in the form of monies to the institution that then are put in professional funds account for research related costs, not personal reimbursement) during the conduct of the study. S.M. Ansell reports other from Bristol Myers Squibb (Funding for clinical trials), other from Seattle Genetics (Funding for clinical trials), other from Affimed (Funding for clinical trials), other from Regeneron (Funding for Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group [Peter J. O'Dwyer (MD) and Mitchell D. Schnall (MD and PhD), Group Co-Chairs] and supported by the NCI of the NIH under the following award numbers: U10CA180820, U10CA180794, UG1CA189830, UG1CA189863, UG1CA232760, UG1CA233234, UG1CA233277, UG1CA233320, UG1CA233341, and UG1CA233339. We acknowledge Dr. Sandra Horning for insights into the initial study design. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = sep,

doi = "10.1158/1078-0432.CCR-20-1345",

language = "English (US)",

volume = "26",

pages = "4468--4477",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "17",

}

Evens, AM, Hong, F, Habermann, TM, Advani, RH, Gascoyne, RD, Witzig, TE, Quon, A, Ranheim, EA, Ansell, SM, Cheema, PS, Dy, PA, O'Brien, TE, Winter, JN, Cescon, TP, Chang, JE & Kahl, BS 2020, 'A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408', Clinical Cancer Research, vol. 26, no. 17, pp. 4468-4477. https://doi.org/10.1158/1078-0432.CCR-20-1345

A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408. / Evens, Andrew M.; Hong, Fangxin; Habermann, Thomas M. et al.
In: Clinical Cancer Research, Vol. 26, No. 17, 09.2020, p. 4468-4477.

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

TY - JOUR

T1 - A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma

T2 - ECOG-ACRIN E2408

AU - Evens, Andrew M.

AU - Hong, Fangxin

AU - Habermann, Thomas M.

AU - Advani, Ranjana H.

AU - Gascoyne, Randy D.

AU - Witzig, Thomas E.

AU - Quon, Andrew

AU - Ranheim, Erik A.

AU - Ansell, Stephen M.

AU - Cheema, Puneet Singh

AU - Dy, Philip A.

AU - O'Brien, Timothy E.

AU - Winter, Jane N.

AU - Cescon, Terrence P.

AU - Chang, Julie E.

AU - Kahl, Brad S.

N1 - Funding Information: A.M. Evens reports nonfinancial support from ECOG-ACRIN Cancer Research Group (study coordination) during the conduct of the study; grants from ORIEN (Translational research grant), grants from Leukemia & Lymphoma Society (Translational research grant), grants from Tesaro (Translational research grant), personal fees from Seattle Genetics (Educational and research advisory board with honorarium), personal fees from MorphoSys (Research advisory board with honorarium), personal fees from Mylteni (Research advisory board with honorarium), personal fees from Epizyme (Research advisory board with honorarium), personal fees from Research to Practice (Educational speakers bureau with honorarium), personal fees from Physician Education Resource (Educational speakers bureau with honorarium), personal fees from OncLive (Educational speakers bureau with honorarium), personal fees from Cota (Research advisory board with honorarium), personal fees from Novartis (DSMB consultant), and personal fees from Pharmacyclics (DSMB consultant) outside the submitted work. T.M. Habermann reports grants from NCI ECOG-ACRIN (is the institutional principal investigator of this grant) during the conduct of the study. R.H. Advani reports other from Roche/Genetech (Consulting or Advisory Role; Institutional Research Support) and other from Celgene (Consulting or Advisory Role; Institutional Research Support) during the conduct of the study; other from Gilead (Consulting or Advisory Role) and other from Sanofi (Consulting or Advisory Role) outside the submitted work. T.E. Witzig reports other from Celgene (advisory board personally uncompensated; research support to Mayo) during the conduct of the study. E. Ranheim reports personal fees from ECOG (ECOG pays a reimbursement for pathology review of the cases involved in the trial to confirm diagnoses; this is in the form of monies to the institution that then are put in professional funds account for research related costs, not personal reimbursement) during the conduct of the study. S.M. Ansell reports other from Bristol Myers Squibb (Funding for clinical trials), other from Seattle Genetics (Funding for clinical trials), other from Affimed (Funding for clinical trials), other from Regeneron (Funding for Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group [Peter J. O'Dwyer (MD) and Mitchell D. Schnall (MD and PhD), Group Co-Chairs] and supported by the NCI of the NIH under the following award numbers: U10CA180820, U10CA180794, UG1CA189830, UG1CA189863, UG1CA232760, UG1CA233234, UG1CA233277, UG1CA233320, UG1CA233341, and UG1CA233339. We acknowledge Dr. Sandra Horning for insights into the initial study design. Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/9

Y1 - 2020/9

N2 - Purpose: We sought to improve upon frontline bendamustine/ rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P ¼ 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P ¼ 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3-4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P ¼ 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P ¼ 0.36) with OS rates of 87%, 90%, and 84%, respectively (P ¼ 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

AB - Purpose: We sought to improve upon frontline bendamustine/ rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P ¼ 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P ¼ 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3-4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3-4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P ¼ 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P ¼ 0.36) with OS rates of 87%, 90%, and 84%, respectively (P ¼ 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

UR - http://www.scopus.com/inward/record.url?scp=85099623352&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85099623352&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-1345

DO - 10.1158/1078-0432.CCR-20-1345

M3 - Article

C2 - 32532790

AN - SCOPUS:85099623352

SN - 1078-0432

VL - 26

SP - 4468

EP - 4477

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 17

ER -

A three-arm randomized Phase II study of bendamustine/rituximab with bortezomib induction or lenalidomide continuation in untreated follicular lymphoma: ECOG-ACRIN E2408

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this