Brentuximab Vedotin in Combination with Lenalidomide and Rituximab in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (ECHELON-3, Trial in Progress)

Abstract Background The majority of patients with relapsed/refractory (R/R) DLBCL who relapse after hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy, or who are not candidates for HSCT or CAR-T, have poor outcomes and need novel therapies (Crump 2017). Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing cell cycle arrest and apoptosis (Sutherland 2006). Lenalidomide may enhance the activity of BV through immune-mediated mechanisms. In a phase 1 trial (NCT02086604) in which 37 patients with R/R DLBCL were treated with BV + lenalidomide, the objective response rate (ORR) was 56.7% (73.3% in CD30+ patients). The median duration of remission was 13.2 months in patients with a complete response (CR) or partial response (PR) and 11.7 months in patients with a CR, PR, or stable disease (SD) >6 months. The median progression-free survival (PFS) and overall survival (OS) were 10.2 months and 14.3 months, respectively, and results were similar in the CD30+ and CD30 <1% groups (manuscript submitted). The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents provide a strong rationale for this combination in multiple relapsed and heavily pretreated patients with R/R DLBCL. Study Design and Methods ECHELON-3 (NCT04404283) is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV versus placebo, in combination with lenalidomide and rituximab, in patients with R/R DLBCL. Key eligibility criteria will include patients ≥18 years of age with R/R DLBCL with an eligible subtype, ≥2 prior lines of systemic therapy and ineligible for stem cell transplant or CAR-T therapy, Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose-avid disease by positron emission tomography (PET), and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT). Patients with a history of another malignancy within the past 2 years, any uncontrolled Grade ≥3 infection, Grade ≥2 peripheral neuropathy, or previous exposure to BV or lenalidomide will not be eligible. After completing the safety run-in period, patients (n=400) will be randomized 1:1 to receive either BV (1.2 mg/kg intravenously every 3 weeks [Q3W]) or placebo (intravenously Q3W) in combination with lenalidomide (20 mg orally daily) and rituximab (1400 mg subcutaneously Q3W from Cycle 2, with 375 mg/m 2 intravenously on Cycle 1 Day 1). Treatment may continue while there is clinical benefit (SD or better) without progression or unacceptable toxicity. Patients will be stratified by CD30 expression (≥1% [positive] vs <1% [negative]), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (germinal center B-cell [GCB] or non-GCB). The dual primary endpoints are PFS per blinded independent central review (BICR) in the intention-to-treat (ITT) and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of objective response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2014). Radiographic disease evaluations, including contrast-enhanced CT and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks thereafter. PET is not required after CR is achieved For the analyses of PFS per BICR, the stratified log-rank test will be used to compare PFS between the 2 treatment groups. Hazard ratios will be estimated using the stratified Cox regression model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used to estimate OS and other time-to-event efficacy endpoints. The study is currently enrolling and will be open in 16 countries. Disclosures Bartlett: Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Harwin: Sarah Cannon Research Institute: Other: Grants, Research Funding. Sims: Seagen Inc.: Current Employment. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding.

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Brentuximab vedotin in combination with lenalidomide and rituximab in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Trials in Progress).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7571 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7571-TPS7571

Author(s):

Nancy L. Bartlett ◽

Christopher A. Yasenchak ◽

Khaleel K. Ashraf ◽

William N. Harwin ◽

Robert Brownell Sims ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Large B Cell Lymphoma ◽

Car T ◽

Secondary Endpoints ◽

Large B Cell

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

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Trial-in-Progress: Brentuximab Vedotin in Combination with Lenalidomide and Rituximab in Subjects with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood-2020-136400 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-14

Author(s):

Nancy L. Bartlett ◽

Christopher A. Yasenchak ◽

Robert B. Sims ◽

Grzegorz S. Nowakowski

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Cell Of Origin ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Car T

Background Majority of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Preclinical data provides a strong rationale for combining brentuximab vedotin, lenalidomide, and rituximab in the treatment of R/R DLBCL. In a phase 1 trial, 37 subjects with R/R DLBCL were treated with brentuximab vedotin in combination with lenalidomide. The objective response rate (ORR) (proportion of subjects with complete response [CR] or partial response [PR]) for all subjects was 56.7% (21 of 37 subjects). For the CD30-positive population, the ORR was 73.3% (11 of 15 subjects), whereas the ORR for the CD30 <1% population was 45.6% (10/22). The median follow-up time was 14.3 months (range: 1 to 56.7 months). The median duration of remission for subjects with CR or PR was 13.2 months (range: 3.2 to 55.2 months). For subjects with CR, PR, or stable disease (SD) >6 months, the median duration of remission was 11.70 months (range: 3.2 to 55.2 months). The progression-free survival (PFS) and overall survival (OS) results appear similar in both the CD30-positive and CD30 <1% groups. The PFS in the combined population is 10.2 months and the median OS is 14.2 months (manuscript in preparation). Study Design and Methods This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of brentuximab vedotin in combination with lenalidomide and rituximab versus placebo in combination with lenalidomide and rituximab for the treatment of subjects with R/R DLBCL (NCT04404283). Key eligibility criteria include the following: subjects aged 18 and older with R/R DLBCL with an eligible subtype; subjects must have ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; subjects must have an ECOG performance status score of 0 to 2; subjects must have a fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Subjects (n=400) will be randomized 1:1 to receive either brentuximab vedotin or placebo in combination with lenalidomide and rituximab and will be stratified by CD30 expression (positive [≥1%] versus <1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (germinal-center B-cell-like (GCB) or non-GCB). Cell of origin (GCB or non-GCB) will be histologically determined by local pathology assessment. Disease response will be assessed by a blinded independent central review (BICR) and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET/CT, will be assessed at baseline, then every 6 weeks from randomization for 12 months, then every 12 weeks (±3 days). PET/CTs will be discontinued if negative. For the primary efficacy analyses of PFS per BICR in the intent-to-treat population and in CD30-positive subjects, the stratified log-rank test will be used to compare PFS between the 2 treatment groups. The hazard ratio will be estimated using a stratified Cox regression model. PFS will also be summarized using the Kaplan-Meier method. Similar methods will be used for the secondary efficacy endpoint of OS, and other time-to-event efficacy endpoints. The trial will have sites open in the US and multiple countries in Europe and Asia, with enrollment planning to begin in the second half of 2020. Disclosures Bartlett: Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding. Yasenchak:Takeda: Honoraria; BeiGene: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Nowakowski:Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding.

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Outcome of autologous hematopoietic stem cell transplant in older patients with B cell lymphoma when selected for fitness and chemosensitive disease

Leukemia Research ◽

10.1016/j.leukres.2019.01.002 ◽

2019 ◽

Vol 79 ◽

pp. 75-80 ◽

Cited By ~ 2

Author(s):

Christopher Lemieux ◽

Imran Ahmad ◽

Nadia M. Bambace ◽

Léa Bernard ◽

Sandra Cohen ◽

...

Keyword(s):

Stem Cell ◽

B Cell ◽

Hematopoietic Stem Cell ◽

Older Patients ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Transplant ◽

Hematopoietic Stem

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Impact of age on outcome of autologous stem cell transplant for follicular and diffuse large B cell lymphoma

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2003.12.044 ◽

2004 ◽

Vol 10 ◽

pp. 65

Author(s):

A. Arora ◽

J.M. Vose ◽

J. Lynch ◽

J.O. Armitage ◽

P. Bierman ◽

...

Keyword(s):

Stem Cell ◽

B Cell ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Large B Cell Lymphoma ◽

Large B Cell

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Survival of Patients with Relapsed Diffuse Large B-Cell Lymphoma In a Community Hospital

Blood ◽

10.1182/blood.v116.21.4902.4902 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4902-4902

Author(s):

Jaclyn Mirault ◽

Arash Ghanbari Milani ◽

Ditina Ghetia ◽

Isaac Yeboah ◽

Puja Sharma ◽

...

Keyword(s):

Stem Cell ◽

B Cell ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Initial Diagnosis ◽

Hodgkin's Lymphoma ◽

Cell Transplant ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 4902 Introduction: Of the various subtypes of non-Hodgkin's lymphoma, Diffuse Large B-cell Lymphoma (DLBCL) is the most prevalent, making up 30 percent of all non-Hodgkin's lymphoma cases. Information from community hospitals regarding the treatment and survival of relapsed patients is scarce. The study was done to obtain the survival data of patients with a relapse of DLBCL, treated with and without transplant at our center. Patients and Methods: The tumor registry data at Jersey Shore University Medical Center between 2000–2008 was reviewed. 41 patients had been diagnosed with DLBCL. Of these, the diagnosis in 13 pts represented a relapse of DLBCL. Review of the hospital records showed that the treatments for these relapsed patients had been radiation, rituximab -based chemotherapy, and/or autologous stem cell transplant. Eight were female and five were male, with a median age of 66 years at initial diagnosis (range: 51 to 81 years). The median age was 68 at the time of relapse (range: 52 to 82 years). Survival was measured from the time of the diagnosis of relapse until death from any cause or the date when lost to follow up. Information on the duration of time from initial diagnosis to relapse was also obtained. Results: Of the 13 patients who relapsed, 3 underwent stem cell transplant, one of whom died at 43 weeks and two are alive after 70 and 336 weeks. Of the 10 who did not have transplant, 6 died at 2, 8, 15, 19, 19 and 38 weeks. The 4 remaining non-transplant patients are alive at 37, 61, 167, and 221 weeks. Of the 13 patients who relapsed, at primary diagnosis, one had been stage I, 3 had been stage II, 3 had been stage III, and 5 had been stage IV. One was of unknown stage. The average time from diagnosis to relapse was 80 weeks. Conclusion: Although our numbers are small, it does appear that there is a role for second-line treatments in those patients with a relapse of large cell lymphoma that are not undergoing stem cell transplant. Further study of the treatment of non-transplanted patients with relapsed DLBCL appears warranted. Disclosures: No relevant conflicts of interest to declare.

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FDG-PET Adapted Sequential Therapy With Brentuximab Vedotin and Augmented ICE Followed By Autologous Stem Cell Transplant For Relapsed and Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.2099.2099 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2099-2099 ◽

Cited By ~ 5

Author(s):

Alison Moskowitz ◽

Heiko Schoder ◽

John F. Gerecitano ◽

Paul Hamlin ◽

Steven M. Horwitz ◽

...

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Salvage Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Genetics Research ◽

Grade 3

Abstract Background Pre-transplant FDG-PET (PET) normalization is the strongest predictor of outcome following autologous stem cell transplant (ASCT) for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) (Moskowitz, AJ. Blood. 2010 Dec 2;116(23):4934-7). Due to its high efficacy in ASCT failures, we aimed to determine whether brentuximab vedotin (BV) can replace ICE (ifosfamide, carboplatin, etoposide) salvage therapy, increase rate of PET normalization, and enhance referral to ASCT for patients (pts) who fail front-line HL therapy. Here we present our phase II study evaluating a novel salvage strategy for rel/ref HL, an intent-to-treat study of PET-adapted sequential therapy with BV and augmented ICE (augICE) prior to ASCT. Methods Patients with rel/ref HL who have failed 1 prior regimen are enrolling on this phase II clinical trial. Patients receive weekly brentuximab vedotin (BV) administered at 1.2mg/Kg IV weekly for 3 weeks on and 1 week off for 2 cycles, followed by PET. Patients who achieve normalization of PET (Deauville 2 or less) proceed to ASCT. Patients with PET scores of Deauville 3 or higher receive 2 cycles of augICE prior to consideration for ASCT. Results 41 of planned 46 patients have enrolled; 34 pts completed salvage therapy, of whom 33 proceeded to ASCT. 28 pts are at least 90 days post-ASCT and represent the focus of this report. These 28 pts include 20 (71%) males, 21 (75%) pts with primary refractory or relapse within 1 year of initial treatment, 11 (39%) with B symptoms at enrollment and 11 (39%) with extranodal disease. Median number CD34+ cells/kg collected were 7.44x 10^6 (2.96 - 31.43x10^6). Disease status prior to ASCT was CR (Deauville 2) for 27 pts and PR (Deauville 3) for 1 pt. Salvage therapy for pts in CR prior to ASCT include BV alone (9), BV followed by augICE (16), and BV followed by augICE (with Deauville 4 response) followed by involved field radiation to achieve CR (2). The 1 patient in PR prior to ASCT received BV followed by augICE. Conditioning regimens included BEAM (9), CBV( 9), and high dose chemoradiotherapy (10). Early (within 90 days) transplant-related toxicities include grade 2 pneumonitis (3pts) and grade 3 acute kidney injury (1pt); late toxicities include grade 3 esophageal stenosis (1pt), grade 3 acute kidney injury (1pt), and 1 death (7 months post ASCT) due to progressive multifocal leukoencephalopathy. After a median follow-up of 9.5 months post-ASCT (range 3.3-15.6 months), 2 of 28 pts have progressed (at 2.7 and 4.3 months post ASCT respectively). One achieved a second CR with BV and proceeded to allogeneic stem cell transplant (alloSCT); the second achieved near CR following GND (gemcitabine, vinorelbine, Doxil) and proceeded to alloSCT. Conclusion PET-adapted sequential salvage therapy with BV followed by augICE produces high CR rates, adequate stem cell collection, and facilitates referral to ASCT for virtually all pts. Updated results will be presented at the meeting. Disclosures: Moskowitz: Seattle Genetics: Research Funding. Off Label Use: Brentuximab vedotin is approved for treatment of Hodgkin lymphoma following failure of 2 multi-agent regimens or autologous stem cell transplant. This study is evaluating the use of brentuximab vedotin in the pre-transplant setting for Hodgkin lymphoma. Schoder:Seattle Genetics: Research Funding. Hamlin:Seattle Genetics : Consultancy, Honoraria. Horwitz:Millennium: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Moskowitz:Seattle Genetics: Research Funding.

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