scholarly journals Brentuximab Vedotin Alone and in Combination with Bendamustine As Salvage Therapy for Primary Refractory or Relapsed Hodgkin Lymphoma: Multicentre Experience of the Polish Lymphoma Research Group (PLRG)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5375-5375
Author(s):  
Anna Czyz ◽  
Anna Lojko-Dankowska ◽  
Monika Joks ◽  
Mieczyslaw Komarnicki ◽  
Monika Dlugosz-Danecka ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Salvage Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Metabolic Response ◽  
Therapeutic Option ◽  
Study Groups ◽  
Brentuximab Vedotin ◽  
European Medicines Agency ◽  
Cell Transplant

Abstract An optimal treatment for patients with primary refractory or relapsed (R/R) Hodgkin lymphoma (HL) who did not respond to standard salvage therapy has not been established. Brentuximab vedotin (BV) and bendamustine (B) used as monotherapy were shown to be active in R/R HL and both are recommended as a therapeutic option. It has been proposed that the combination of BV with B (BVB) may improve the outcome of R/R HL patients. To test this hypothesis, we compared retrospectively the efficacy and safety of BV and BVB regimen in R/R HL patients. Methods: Since March 2014 all patients with R/R HL treated at PLRG centers were offered either BV in monotherapy every 21 days or in combination with B (B 90 mg/m² on days 1 and 2 of treatment cycle) according to the policy in each center. Results: BV or BVB therapy was administered to 94 patients (median age 33 years, range 18-68) with primary refractory (n=54) or relapsed HL (n=40), including 34 patients after autologous stem cell transplant (ASCT). The patients were treated with the median of 3 (range, 2-12) prior chemotherapy lines. Fifty-seven patients received BV and 37 patients BVB regimen. In 16 of them, BVB was de-escalated to BV after the median of 2 cycles (range, 2-7). The patients' and disease characteristics did not differ between two groups. In the whole study group, the median number of applied cycles per patient was 4 (range, 2-16). Dose-limiting toxicities were observed in 8% of patients. No difference was found between BV and BVB group, with similar rate of grade 3-4 neutropenia (16% vs 13%) and thrombocytopenia (4% vs 3%). Lung infection occurred in 1 patient treated with BV (2%) and 3 treated with BVB (2% vs 8%, p ns), with 2 treatment-related deaths in the BVB group. The response rate after 2 cycles of BV and BVB treatment defined as complete (CMR) or partial metabolic response (PMR) assessed by positron emission tomography was 69% (26% of CMR and 43% of PMR) and 89% (46% of CMR and 43% of PMR), respectively (p=0.036). After 4-6 cycles of treatment, CMR, PMR and stable metabolic disease was documented in 59%, 19% and 13% in the BV group vs. 71%, 17% and 3%, respectively, in the BVB group (p ns). Finally, 36 patients (22 from BV and 14 from BVB group) proceeded to ASCT, and 17 (9 from BV and 8 from BVB group) to allogeneic SCT. The overall and progression-free survival at 24 months were 80% and 51%. The survival curves did not differ between two study groups. In conclusion, our results suggest that BVB is a feasible regimen that provides higher response rate after 2 cycles compared to BV monotherapy. However, the overall response rate achieved after 4-6 cycles of treatment are comparable between BV monotherapy and combined BVB treatment. Infectious complications, including serious lung infections, were observed in both study groups, with two treatment-related deaths in the BVB group. Disclosures Dlugosz-Danecka: Roche: Consultancy; Servier: Consultancy. Jurczak:Nordic Nanovector: Research Funding; Epizyme: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Merck: Research Funding; Servier: Consultancy, Honoraria, Research Funding; European Medicines Agency: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Roche: Research Funding; Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; TG therapeutics: Research Funding. Zaucha:Roche: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2099-2099 ◽  
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.

The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 673-673 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Auayporn Nadamanee ◽  
Tamas Masszi ◽  
Edward Agura ◽  
Jerzy Holowiecki ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Salvage Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Frontline Therapy

Abstract Background For the past 20 years, high-dose therapy plus autologous stem cell transplant (ASCT) has been the standard of care for patients (pts) with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), providing a cure for approximately 50% of pts (Sureda 2005). Despite optimization of salvage chemotherapy, supportive care, and pt selection, improvements in outcomes post-ASCT have plateaued, likely due to disease progression (PD) in pts with pre-salvage therapy risk factors. The majority of pts with multiple risk factors will progress post-ASCT and novel therapy is urgently needed. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), and has an objective response rate of 75% in relapsed or refractory HL. The AETHERA trial was initiated to evaluate whether early treatment with brentuximab vedotin post-ASCT can prevent progression in pts with HL (ClinicalTrials.gov #NCT01100502). Methods The AETHERA trial is a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Pts were enrolled in 1 of 3 high-risk categories: refractory to frontline therapy: 196 pts (60%), relapse <12 months after frontline therapy: 107 pts (33%), and relapse ≥12 months after frontline therapy with extranodal disease: 26 pts (8%). Pts were required to have obtained a CR, partial remission (PR), or stable disease (SD) to salvage therapy prior to ASCT. After ASCT, pts received brentuximab vedotin 1.8 mg/kg q3wk and best supportive care (BSC) or placebo and BSC for up to 16 cycles (approximately 12 months). Pts with PD were to discontinue study therapy and could request unblinding; these pts may have received subsequent brentuximab vedotin on another clinical trial or on-label in some regions. The primary endpoint is PFS per an independent review facility (IRF); additional endpoints include overall survival (OS) and safety/tolerability. Results A total of 329 pts were randomized at 78 sites in the United States and Europe. Of the 329 enrolled pts, 327 received study treatment. The median age was 32 years (range, 18–76) and 53% were male. The median number of prior systemic therapies (frontline and salvage) was 2 (range, 2–8); 47% of pts received more than 2 prior systemic therapies. Response to salvage therapy pre-ASCT was CR: 137 pts (42%), PR: 112 pts (34%), and stable disease (SD): 80 pts (24%). Prior to pre-ASCT salvage therapy, 106 pts (32%) had extranodal involvement and 87 pts (26%) had B symptoms. Prior to ASCT, 110 pts (33%) were PET negative, 116 pts (35%) were PET-positive and PET status was unknown for 103 pts (31%). Overall, 78% of pts had multiple risk factors for progression. All pts had completed or discontinued study treatment as of August 2013. The median number of treatment cycles was 15, and 159 pts (49%) received 16 cycles. Reasons for treatment discontinuation were: PD: 93 pts (28%), adverse event (AE): 61 pts (19%), patient decision: 15 pts (5%), and investigator decision: 1 pt (<1%). At the time of this analysis (June 2014), the median follow-up time from randomization was 24.4 mos (range, 0–43 mos). For the pooled study population at 24 mos, the Kaplan Meier estimates were 54% (95% CI: 47%, 60%) for PFS and 88% (95% CI: 84%, 91%) for OS. Of the 50 deaths, 8 occurred prior to PD. AEs of any grade in >15% of pts were peripheral sensory neuropathy (36%), upper respiratory tract infection (25%), neutropenia (24%), fatigue (21%), cough (19%), and pyrexia (17%). Grade 3 or higher AEs in ≥10 pts were neutropenia (20%), peripheral sensory neuropathy (6%), thrombocytopenia (3%), and peripheral motor neuropathy (3%). As assessed by a Standardised MedDRA Query, 144 pts (44%) had treatment-emergent events of peripheral neuropathy (PN). Grade 3 PN was reported for 23 pts (7%) and was mostly sensory; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in PN has occurred in 80% of pts with neuropathy events; the median time to resolution or improvement was 11.7 weeks (range, 0.1–128.0 weeks). Conclusions Based on analysis of blinded pooled efficacy data, the estimated 2-year PFS rate was 54% and the estimated 2 year OS rate was 88%. The most common reason for treatment discontinuation was disease progression. The primary analysis for the study will be performed in September 2014 and unblinded efficacy and safety data will be publicly presented for the first time at the conference. Figure 1 Figure 1. Disclosures Moskowitz: Genentech: Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Nadamanee:Gilead: Consultancy; Celgene: Consultancy; Spectrum: Research Funding; Seattle Genetics, Inc.: Research Funding. Masszi:Seattle Genetics, Inc.: Research Funding. Agura:Seattle Genetics, Inc.: Research Funding. Holowiecki:Seattle Genetics, Inc.: Research Funding. Abidi:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Chen:Seattle Genetics, Inc.: Research Funding. Stiff:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Gianni:Seattle Genetics, Inc.: Research Funding. Carella:Seattle Genetics, Inc.: Research Funding. Osmanov:Seattle Genetics, Inc.: Research Funding. Bachanova:Seattle Genetics, Inc.: Consultancy, Research Funding. Sweetenham:Seattle Genetics, Inc.: Honoraria, Research Funding, Speakers Bureau. Sureda:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Huebner:Takeda Pharmaceuticals International Co.: Employment, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Hunder:Seattle Genetics, Inc.: Employment, Equity Ownership. Walewski:Seattle Genetics, Inc.: Research Funding; Takeda Poland: Consultancy, Travel expenses, Travel expenses Other.

scholarly journals Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2994-2994
Author(s):  
Joseph M. Connors ◽  
Alina S Gerrie ◽  
Maryse M Power ◽  
Kerry J Savage
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Brentuximab Vedotin ◽  
Primary Objective ◽  
Initial Diagnosis ◽  
Cell Transplant ◽  
Free Survival

Abstract Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV. Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy. Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later. Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. Disclosures Connors: Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above: Interim Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4389-4389 ◽  
Author(s):  
Christopher A. Yasenchak ◽  
Robert Chen ◽  
Jeff P. Sharman ◽  
Ralph V. Boccia ◽  
Beata Holkova ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Stem Cell Transplant ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Treatment Naïve ◽  
Multi Agent ◽  
Grade 3

Abstract Introduction Hodgkin lymphoma (HL) in patients aged ≥60 years has disproportionately inferior outcomes as compared to HL in younger patients. This can be mostly attributed to treatment-related factors that compromise cure rates. Comorbidities in older patients are associated with higher rates of treatment-related toxicities and can prevent delivery of standard intensity and/or duration of chemotherapy. A retrospective multicenter analysis showed an increased incidence of bleomycin-associated pulmonary toxicity (32%; with a mortality rate of 25%) in HL patients aged ≥ 60 who received ABVD for frontline therapy (Evens 2012). Novel therapeutic approaches with improved efficacy and tolerability are needed for this population. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate that comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Robust antitumor activity and acceptable toxicity has been demonstrated in HL patients who relapse after conventional chemotherapy or autologous stem cell transplant. A retrospective analysis of patients aged ≥60 years with relapsed/refractory CD30+ lymphomas across 7 single-agent brentuximab vedotin studies showed antitumor activity and clinical response duration consistent with those observed in younger patients (Fanale 2012). Thus, this ongoing phase 2, single-arm, open-label study was initiated to evaluate the efficacy, safety, and tolerability of brentuximab vedotin as frontline monotherapy for HL patients aged ≥60 years (NCT01716806). Methods The population to be enrolled includes ∼30 treatment-naïve patients with classical HL (Stages I–IV). Eligible patients must be aged ≥60 years, have an ECOG status ≤3, and be ineligible for or have declined conventional chemotherapy. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks by IV infusion. Patients achieving stable disease (SD) or better can receive up to 16 cycles of treatment, after which therapy can be continued for those experiencing clinical benefit. The primary endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Response assessments are performed at Cycles 2, 4, 8, 12, and EOT (including PET at Cycles 2, 8, and EOT). Results Thirteen patients with treatment-naïve classical HL have been enrolled to date. Median age was 75 years (range, 64 to 92) and approximately half of the patients were male (54%). Seven patients (54%) had moderate age-related renal insufficiency at baseline (creatinine clearance ≥30 and<60). Thus far, patients have received a median of 5 cycles of brentuximab vedotin treatment (range, 1 to 11). Four patients discontinued treatment, 2 due to progressive disease, 1 due to a serious adverse event (Grade 3 orthostatic hypotension), and 1 due to patient decision. Of the 11 patients with a response assessment (see table), the ORR was 82% (n=9) and the complete remission (CR) rate was 64% (n=7). For the 10 patients who had interim PET scans after 2 cycles of therapy, the mean decrease in maximum standardized uptake value (SUVmax) between baseline and Cycle 2 was 83%. Cycle 2 PET scans were negative (Deauville Score 1-3) in 36% of patients, and the range of duration of response was 0.1+ to 20.6+ weeks thus far. Treatment-related adverse events (AEs) occurring in ≥15% of patients included neutrophil count decreased, peripheral sensory neuropathy, pruritus, and rash (n=2 each); most events were Grade 1 or 2. Grade 3 treatment-related AEs included neutrophil count decreased, rash, and orthostatic hypotension (n=1 each). No Grade 4 or 5 events have been observed to date. Conclusions In this interim analysis of patients aged ≥60 years with newly diagnosed HL, compelling antitumor activity with single-agent brentuximab vedotin has been demonstrated. To date, a response rate of 82% has been shown in this historically challenging population of patients who either declined or were not eligible for standard chemotherapy. Preliminary safety data demonstrate tolerability in this patient population and the data are consistent with the current safety profile of brentuximab vedotin. Disclosures: Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Boccia:Seattle Genetics, Inc.: Honoraria, Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Rosen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Honoraria, Research Funding. Friedberg:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau.

Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 292-292 ◽  
Author(s):  
Joseph M Connors ◽  
Stephen Ansell ◽  
Steven I. Park ◽  
Michelle A. Fanale ◽  
Anas Younes
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Brentuximab Vedotin ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Genetics Research

Background: The ABVD regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine is a common standard of care for the frontline treatment of advanced stage Hodgkin lymphoma (Santoro 1987; Duggan 2003) and is curative for the majority of patients; however, up to 30% of patients require a secondary therapy. Hodgkin Reed-Sternberg cells of classical HL (cHL) typically express CD30. In a pivotal phase 2 trial brentuximab vedotin (A, ADCETRIS®), comprised of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) induced an objective response rate (ORR) of 75% and complete response rate (CR) of 34% in highly treatment-refractory patients with cHL (Younes 2012). Methods: We conducted a phase 1, open-label, multicenter study to evaluate the safety and efficacy of A when administered in combination with standard therapy (ABVD) or the same regimen without bleomycin (AVD) (Younes 2013). Adult patients with newly diagnosed advanced stage (II bulky, II B, III or IV; 80% stage III or IV) received doses of 0.6, 0.9, or 1.2 mg/kg A with standard doses of ABVD or 1.2 mg/kg with AVD, depending on cohort assignment on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Previously we reported that among patients assessable for response 95% of patients given ABVD+A achieved a CR, as did 96% of patients given AVD+A. None of 26 patients given AVD+A but 11 of 25 (44%) given ABVD+A experienced pulmonary toxicity, including 2 deaths, establishing that A cannot be safely combined with bleomycin. In this current study we provide the long term survival and safety data on patients enrolled in the phase 1 trial. Results: In total 51 patients were assigned to either ABVD+A (n=25) or AVD+A (n=26). 1 patient who withdrew from the trial during the first cycle of ABVD+A is excluded from this analysis and 1 patient who received 3 cycles of ABVD+A, then withdrew, then received 3 cycles of ABVD alone and 2 patients who died during treatment (pulmonary toxicity) are included (total n=50). Median follow-up from diagnosis for the 24 patients treated with ABVD+A is 41 months (range 9-51 months) and for the 26 patients treated with AVD+A, 31 months (range 9-35 months). All 26 patients treated with AVD+A have been followed longer than the longest time to relapse (7 months). 45 patients remain in first CR and 5 treatment failures have occurred: 4 in the ABVD+A cohort (2 toxic deaths; 2 relapses (9 and 23 months from diagnosis)) and 1 after AVD+A (7 months from diagnosis). 3y-failure-free survival (3y-FFS) is 83% and 96% for ABVD+A and AVD+A, respectively, and 3y-overall survival (3y-OS), is 92% and 100%. No additional toxic deaths have occurred in follow-up. Conclusions: These updated outcomes reflecting the impact of adding brentuximab vedotin (1.2 mg/kg) to standard doses of AVD for classical Hodgkin lymphoma, demonstrating 96% 3y-FFS and 100% 3y-OS with no major unexpected toxicity, strongly support the current large international trial comparing AVD-A (AVD+1.2mg/kg brentuximab vedotin) to standard ABVD (ECHELON-1, clinicaltrials.gov NCT01712490), which may identify a new, less toxic gold standard treatment for advanced stage classical Hodgkin lymphoma. Disclosures Connors: Seattle Genetics: Research Funding. Off Label Use: brentuximab vedotin in phase 1 trial. Ansell:Seattle Genetics: Research Funding. Park:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding. Fanale:Seattle Genetics: Research Funding. Younes:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding.

scholarly journals PET-Adapted Nivolumab or Nivolumab Plus ICE As First Salvage Therapy in Relapsed or Refractory Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 239-239 ◽  
Author(s):  
Alex F. Herrera ◽  
Robert W. Chen ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Matthew Mei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Mental Status ◽  
Salvage Therapy ◽  
Research Funding ◽  
Design Research ◽  
Response Rate ◽  
Tumor Lysis Syndrome ◽  
Altered Mental Status ◽  
Equity Ownership

Introduction: Nivolumab (nivo) is an anti-PD-1 antibody that restores effective anti-tumor immune responses and is tolerable and effective in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL). Nivo combined with brentuximab vedotin (BV) as first salvage therapy (tx) yields high response rates and favorable progression-free survival (PFS) as a bridge to autologous stem cell transplantation (ASCT) in pts with RR HL. With the frontline approval of BV, it is necessary to evaluate the role of nivo as salvage tx separate from BV. We report interim results of a phase 2 trial evaluating PET-adapted nivo or nivo + ICE (NICE) chemotherapy as first salvage tx in RR HL. Methods: In this prospective, multicenter trial, pts with biopsy-proven RR HL after frontline tx received 3 mg/kg nivo every 2 weeks for up to 6 cycles (C). PET-CT was performed after C3 and C6. After C6, pts in CR proceeded to ASCT while pts not in CR received NICE for 2 cycles. The primary endpoint was complete response rate according to 2014 Lugano classification. PFS and overall survival (OS) were calculated using the Kaplan Meier method. Results: 39 pts were evaluable for toxicity; 37 were evaluable for response. Baseline characteristics are shown in Table 1. 32 pts received nivo alone and 7 pts received nivo/NICE. 32 pts completed study tx, 2 pts continue on protocol tx, 1 pt discontinued early in CR to undergo ASCT, 2 pts discontinued nivo early due to nivo-related adverse events (AE, 1 pt = Gr 4 altered mental status, 1 pt = Gr 2 pneumonitis), 1 pt discontinued due to unrelated death during nivo (Gr 5 sepsis due to untreated dental abscess), 1 pt withdrew due to refusal to receive NICE following nivo. After C3 of nivo, the overall response rate (ORR) was 89% (33/37), with a CR rate of 59% (22/37), partial response (PR) rate of 30% (11/37), and 2 pts each had stable disease (SD) and PD. After C6 of nivo (n=31), the ORR was 90%, with 24 CR (77%), 4 PR (13%), and 3 PD. Thus, including pts who stopped nivo early (due to toxicity or insufficient response and switch to NICE), at the end of nivo (n=37, not including 2 pts with ongoing tx) the ORR was 78%, with 26 CR (70%), 3 PR (8%), 1 pt with SD and 5 with PD. 7 pts were treated with NICE and all responded (100% ORR) with 6 CR (86%) and 1 PR (14%). At the end of protocol tx (nivo or nivo/NICE) including all pts (n=37) except the 2 who remain on ongoing tx, the ORR was 89% with 32 CR (86%) and 1 PR (3%). Among 35 evaluable pts, the ORR was 94% and CR rate was 91% (Figure). 27 pts proceeded to ASCT directly after protocol tx, 1 pt is awaiting ASCT, and 4 pts in CR refused ASCT. One pt with PR after NICE responded to subsequent salvage tx and underwent ASCT. In pts who had ASCT, a median of 2 (range 1-4) stem cell collections were required, a median of 4.7x106 CD34+ cells/kg (range 3.12 - 16.23) were collected, and the median time to neutrophil and platelet engraftment were 11 and 12 days, respectively. The median follow-up time in all pts (n=39) was 10.5 months (range 1.6-24.5 mo). The 1-year PFS was 79% (95 CI, 63-98%) and 1-year OS was 97% (95 CI, 92-100%). Two PD events occurred in pts who had CR but refused ASCT. There were 2 PD events in pts who completed therapy and proceeded to ASCT - both were in pts who required NICE. The most common AEs related to nivo alone (n=39) were fatigue (28%), rash (18%), fever (15%), thrombocytopenia (10%), and dyspnea (10%), and all were grade (gr) 1-2. Only 2 pts had gr 3-4 nivo-related AE, 1 pt had gr 3 thrombocytopenia and another pt had gr 4 altered mental status and gr 3 tumor lysis syndrome. Among 7 pts who received NICE, the most common AEs were nausea (71%), vomiting (57%), anemia (43%), fatigue (43%), hypertension (43%), and hyponatremia (29%) - all were gr 1-2. The only Gr 3-4 NICE-related AE was gr 4 neutropenia in 1 pt. Conclusion: PET-adapted nivo followed by NICE in patients without CR is a well-tolerated and effective first salvage approach in pts with RR HL. In our cohort, nivo alone was an effective bridge to ASCT in a majority of pts, sparing them the toxicity of traditional salvage chemotherapy. Pts who did not achieve CR with nivo were effectively salvaged by NIVO+ICE Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Chen:Autolus Therapeutics: Employment. Palmer:Gilead Sciences: Consultancy. Mei:Seattle Genetics, Inc.: Research Funding. Popplewell:City of Hope: Employment. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion, Inc.: Consultancy; Celltrion Healthcare: Consultancy. Lee:Seattle Genetics, Inc.: Research Funding.

Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 798-798 ◽  
Author(s):  
Stephen M. Ansell ◽  
Joseph M. Connors ◽  
Steven I. Park ◽  
Megan M. O'Meara ◽  
Anas Younes
Keyword(s):  
Hodgkin Lymphoma ◽  
Pulmonary Toxicity ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Multi Agent ◽  
Frontline Therapy

Abstract Abstract 798 Hodgkin lymphoma (HL) is a lymphoid neoplasm associated with the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells. The regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has become a common standard of care for the frontline treatment of HL. However, although ABVD is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a salvage therapy. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). This phase 1, open-label, multicenter study was conducted to evaluate the safety of brentuximab vedotin when administered in combination with standard therapy (ABVD) or a modified standard (AVD) (ClinicalTrials.gov NCT01060904). Patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of ≥ 7 days in standard ABVD or AVD therapy. Determination of antitumor activity was based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). FDG-PET interpretation for Cycle 2 was performed by a central review per Deauville criteria with uptake above liver background considered positive. Data are presented for the 51 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 26 patients received 1.2 mg/kg with AVD. Overall, 37 patients were male (73%) and the median age of all patients was 33 years (range, 18–59). At baseline, 45% of all patients had Stage IV HL, 25% had an IPS score ≥4, and all patients with available ECOG status had a score of 0 or 1. No DLT was observed up to 1.2 mg/kg in either regimen. Common AEs (≥20 patients overall) noted in the ABVD and AVD cohorts, respectively, were nausea (76%, 77%), neutropenia (80%, 69%), peripheral sensory neuropathy (72%, 65%), vomiting (60%, 38%), fatigue (44%, 46%), and constipation (48%, 31%). Common ≥Grade 3 AEs (>10% of patients overall) observed in the ABVD and AVD cohorts, respectively, were neutropenia (80%, 65%), anemia (20%, 12%), febrile neutropenia (20%, 8%), and pulmonary toxicity (24%, 0%). In the ABVD cohorts, 11/25 (44%) patients had AEs of pulmonary toxicity, interstitial lung disease, or pneumonitis that led to discontinuation of bleomycin; 2 of these events led to death. Of these 11 patients, 7 completed treatment with AVD and brentuximab vedotin. In general, these events occurred between Cycles 3 and 6. No pulmonary toxicity was observed in the AVD cohort. The incidence of neuropathy was similar between the ABVD (72%) and AVD (73%) regimens; none of these events were ≥Grade 4 in severity. Overall, 7 patients discontinued brentuximab vedotin due to an AE (5 ABVD patients and 2 AVD patients). At Cycle 2, 48 patients were evaluated by FDG-PET by central review; of these, all 22 ABVD and 24/26 AVD patients were PET negative. Of the 51 patients treated, 4 withdrew consent or were lost to follow-up prior to end of treatment (EOT) assessments. The remaining 47 patients had a 96% objective response rate: 21/22 ABVD patients (95%) and 23/25 AVD patients (92%) achieved CR at the end of frontline therapy, 1 AVD patient had PR (with further workup ongoing), 1 ABVD patient died of AEs (hyponatremia and pulmonary toxicity) prior to EOT, and 1 AVD patient had PD. In patients with newly diagnosed HL, the maximum tolerated dose of brentuximab vedotin combined with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg every 2 weeks, the maximum planned dose. The safety profile observed confirmed that brentuximab vedotin can be safely combined with AVD; however, combination with a bleomycin-containing regimen is not recommended due to the incidence of pulmonary toxicity. The very high CR rate seen in this cohort of advanced-stage HL patients compares favorably with historical controls and warrants comparison with standard therapy. A phase 3 study comparing brentuximab vedotin combined with AVD versus ABVD alone is planned. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding; Celgene Corporation: Consultancy. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Affimed: Research Funding; Gilead: Research Funding.

scholarly journals Salvage Therapy with Brentuximab-Vedotin and Bendamustine for Patients with Relapsed/Refractory T Cell Lymphoma. a Multicenter and Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 620-620
Author(s):  
Krimo Bouabdallah ◽  
Raphaëlle Aubrais ◽  
Loïc Chartier ◽  
Charles Herbaux ◽  
Anne Banos ◽  
...  
Keyword(s):  
Retrospective Study ◽  
T Cell ◽  
Salvage Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Multivariable Analysis ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity

Abstract Methods : This multicentric retrospective study aimed to evaluate the efficacy and the safety of the combination of BBV in patients with non-cutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was to evaluate the best overall response rate (ORR) (complete response (CR) and partial response (PR)). Secondary objectives were progression free survival (PFS), overall survival (OS), duration of response (DoR), impact of transplantation on outcome, and safety. Patients treated between January 2013 and October 2020 were reviewed and all the data were collected through an electronic questionnaire sent to all the physicians. Results : Eighty two patients with R/R PTCL (40 angioimmunoblastic lymphoma (AITL), 2 T-cell lymphoma with TFH phenotype ,13 PTCL not otherwise specified (PTCL NOS), 5 Alk+ anaplastic large cell lymphoma (ALCL), 17 Alk- ALCL, , 1 Extranodal NK-/T-cell lymphoma, 3 Enteropathy-associated T-cell lymphoma (EATL), 1 subcutaneous panniculitis) were included. Median age at beginning of BBV was 60 years, most of patients were male (61%), had advanced stage (88%) and an IPI ≥ 2 (79%). Half of patients were refractory to their last treatment. Median number of prior regimens was 1 (range 1 to 6). The best ORR was 71%, with 51% of patients in CR. In multivariable analysis, only the relapse status after the last regimen (relapse vs refractory) was associated with ORR, relapsed patients having a better ORR (83% vs 57% in refractory patients, p=.014, OR=3.70 (95%CI:1.3-10.5)). Median DoR was 15.4 months in patients with CR but differed significantly whether patients were transplanted or not (Not reached vs 8.4 months, p=.0055). Twenty-two patients (30% of patients ≤ 70 years of age) were transplanted (6 autologous and 16 allogenic). With a median follow-up of 9 months, the median PFS and OS were 8.3 and 26.3 months respectively. In multivariable analysis, only 2 factors had a significant impact on PFS and OS: best response (CR/PR vs SD/PD with a median PFS of 17.4 vs 1.9 months, p&lt;.0001, and a median OS Not Reached vs 5,9 months, p&lt;.0001) and transplantation (for patients in CR, median PFS was Not Reached in transplanted patients vs 13.1 months; p=.0410, and median OS was Not Reached vs 34, 6 months; p=.0304) (Fig1). Histological subgroups was also significantly associated with PFS (p=.012) but not with OS (p=.26) in multivariable analysis. Patients with PTCL NOS/Other subtypes had worse PFS than patients with TFH subtypes (HR=2.89 (95%CI: 1.4-5.8), p=.0029). Interestingly the CD30 status (positive vs negative) had no impact on ORR or survival. Fifty-nine percent of patients experienced a grade 3 to 4 adverse event which was mainly hematologic toxicity. Treatment had to be stopped in 11% of patients. Conclusion: To the best of our knowledge, this is the first study reporting on the combination of BBV in the treatment of R/R PTCL in such a large cohort. The results are very encouraging with a high response rate, long DoR in responding patients and a very good outcome. Furthermore, patients in CR who are eligible for transplant have the best outcome, making this combination a good candidate as salvage therapy before transplant consolidation in these high-risk lymphomas with limited treatment options. Figure 1 Figure 1. Disclosures Bouabdallah: Kite/Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Herbaux: Takeda: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Sibon: Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy; iQone: Consultancy; Takeda: Consultancy. Laribi: AstraZeneca: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Jansen: Research Funding. Damaj: roche: Consultancy, Honoraria; takeda: Consultancy, Honoraria. OffLabel Disclosure: Brentuximab Vedotin and Bendamustine

scholarly journals Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 234-234
Author(s):  
Alex F. Herrera ◽  
Lu Chen ◽  
L. Elizabeth Budde ◽  
Saro Armenian ◽  
Liana Nikolaenko ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Response Rate ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Cell Transplant ◽  
Pd1 Blockade ◽  
Privately Held

Abstract Introduction: Despite a high response rate to PD1 blockade in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL), the complete response (CR) rate is low and most patients will progress. Pts who are refractory to PD1 blockade have limited treatment options and poor outcomes. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study evaluating the safety and efficacy of pembrolizumab plus vorinostat, an HDACi, in pts with RR HL, diffuse large B-cell lymphoma, and follicular lymphoma. Here, we report the results of pts with RR HL. Methods: Adult pts with RR HL who had failed at least 1 prior line of therapy and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Prior anti-PD1 exposure was allowed. Anti-PD1 refractory was defined as stable disease (SD) or progressive disease (PD) as best response or PD during anti-PD1 therapy after objective response. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with treatment at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered orally at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg IV every 3 weeks in all DLs. Treatment could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification. Results: 32 HL pts were enrolled, including 2 at DL1 and 30 at DL2 (RP2D). At baseline, 69% were male, 72% were Caucasian, the median age was 35 years (range 18-79), and 75% had stage III-IV disease. The median number of prior therapies was 4 (range 2-12), 94% had prior brentuximab vedotin (BV), 66% were BV refractory, 78% had prior PD1 blockade and 56% were PD1 refractory. Baseline characteristics are shown in Table 1. The median number of cycles was 8.5 (range 1-36). The most common adverse events (AEs, any grade, Gr) were hypertension (72%), fatigue (63%), hyponatremia (63%), nausea (63%), diarrhea (47%), thrombocytopenia (44%), anemia (41%). The most common Gr 3+ AEs included hypertension (9%), neutropenia (6%), thrombocytopenia (6%), hypophosphatemia (6%), and lymphopenia (6%). Immune-related AEs included 4 pts with Gr 1-2 thyroiditis, 1 pt with Gr 1 rash, and 1 pt with Gr 3 esophagitis/duodenitis. 1 pt had vorinostat dose reduction for neutropenia. 20/32 pts discontinued treatment; treatment was discontinued for disease progression in 11 pts, stem cell transplant in 6 pts, patient preference in 2 pts, and completion of 2 years of therapy in 1 pt. Among 30 evaluable pts (2 too early), the best overall response rate (ORR) was 73% and the CR rate was 33% (Table 2). Among anti-PD1 naïve/sensitive pts (n=14), the ORR and CR rate were 93% and 64%. Among pts who were refractory to prior PD1 blockade (n=18), the ORR and CR rate were 56% and 6%. 10 evaluable anti-PD1 refractory pts had PD1 blockade as their most recent therapy (median 35 days between PD and study treatment start), and 6 (60%) had an objective response to pembro/vorinostat (all partial responses). The median follow-up time in 28 surviving pts was 18 months (mo, range 1-41). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all RR HL patients were 14 mo, 14.9 mo, and not reached. The 1-year PFS and OS were 52% and 93%. Conclusions: Pembrolizumab and vorinostat was tolerable and produced a high ORR and CR rate in pts with anti-PD1 naïve/sensitive RR HL. A majority of pts with anti-PD1 refractory RR HL had objective responses, including pts who had progressed while receiving PD1 blockade as their most recent therapy. Figure 1 Figure 1. Disclosures Herrera: ADC Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Chen: AstraZeneca: Current Employment; Autolus: Ended employment in the past 24 months. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Popplewell: Pfizer: Other: Travel; Hoffman La Roche: Other: Food; Novartis: Other: Travel. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Mei: TG Therapeutics: Research Funding; Epizyme: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; BMS: Research Funding; Beigene: Research Funding. OffLabel Disclosure: Vorinostat is not FDA-approved for use in patients with Hodgkin lymphoma

scholarly journals Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2836-2836
Author(s):  
Judah Friedman ◽  
Hun Ju Lee ◽  
Linda Ho ◽  
Ian W. Flinn
Keyword(s):  
Peripheral Neuropathy ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Performance Status ◽  
Laboratory Data ◽  
Brentuximab Vedotin ◽  
Stage Iii ◽  
Cell Transplant ◽  
Bulky Disease

Background For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study. The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant. BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Study Design SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate growth factor prophylaxis plus BV in combination with AVD in patients with stage III and IV cHL (Part A). A second cohort has been added to the study (Part B), which will evaluate the combination of AN + AD in this patient population. The primary objective of Part B is to estimate the CR rate at EOT with AN + AD in patients with previously untreated advanced cHL. All enrolled patients will be 12 years or older, with an ECOG performance status of ≤2. Patients in Part B will be treatment-naïve with Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky disease. Patients must have bidimensional measurable disease, as documented by radiographic technique, and qualifying baseline laboratory data. Patients will be excluded if they have nodular lymphocyte predominant HL or have symptomatic neurologic disease that compromises normal activities of daily living or requires medication. Patients with known cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy, will also be excluded. Approximately 50 patients will be enrolled in Part B. All patients will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. All study drugs will each be administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles of treatment. Efficacy will be assessed by PET and CT scans at Cycle 2 and EOT. Disease assessments will be performed during follow-up every 3 months for the first year, every 6 months for 2 additional years, and then per institutional standard of care. Disease response and progression will be assessed by investigators using the Lymphoma Response to Immunomodulatory Therapy Criteria modification of Lugano Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas (Cheson 2016). Disclosures Friedman: Amgen: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document