Efficacy and safety of nivolumab combined with brentuximab vedotin after nivolumab monotherapy failure in patients with relapsed and refractory classic Hodgkin lymphoma

Abstract Background: The fully human IgG4 anti-PD-1 monoclonal antibody, nivolumab, has shown to be highly efficacious in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL). Initial results of a single-arm nivolumab monotherapy in heavily pretreated young adults with RR cHL, previously treated with autologous hematopoetic stem cell transplantation (autoSCT) and brentuximab vedotin are promising. However, demonstrating similar results in real-life experience in patients not on Pharma clinical studies are of major clinical importance. Aim: The aim of the current study was to evaluate the efficacy and safety of nivolumab in previously heavily pretreated patients with RR cHL not on Pharma clinical studies. Methods: The records of patients with RR cHL who were treated with nivolumab in seven medical centers were reviewed. The regimen consisted of nivolumab 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity. Results: Between May 2015 and April 2016, 30 patients with RR cHL received nivolumab monotherapy. The median age was 35 years (range: 21 to 88). Patients were extremely heavily pretreated with median of 6 prior therapies (range: 3 to 11); 73% of them received ≥ 5 lines of therapy. Specifically, 29/30 (97%) received ABVD, 7/30 (23%) escBEACOPP, 20/30 (67%) gemcitabine based regimens, 30/30 (100%) brentuximab vedotin, 8/30 (27%) bendamustine, 3/30 (10%) lenalidomide, 28/30 (93%) other combinations of chemotherapy and 22/30 (73%) radiotherapy. Twenty patients (67%) previously underwent autoHSCT and 4/30 (13%) allogeneic transplantation (alloSCT), two before and two after receiving nivolumab. Median number of nivolumab doses received was 8 (range 1 to 29). Twenty three patients (77%) are still on treatment. Seven patients (23%) discontinued therapy due to disease progression 3/30 (10%), adverse events 2/30 (7%) and referral to alloSCT 2/30 (7%). Overall response rate among 25 evaluable patients was 76%, complete response (CR) - 7/25 (28%), partial response - 12/25 (48%), stable disease - 3/25 (12%) and only 3/25 (12%) progressed, one of them with cHL type of Richter's transformation. Two patients underwent alloSCT in remission following nivolumab treatment. One patient was transplanted from a matched sibling donor and the second patient from a T replete haploidentical donor with post transplantation cyclophosphamide as anti-graft versus host disease prophylaxis. Both patients are in CR, ten and three months post transplantation, respectively. The median overall survival (OS) and progression free survival (PFS) for the cohort were not reached (Figure 1). At 24 weeks the PFS was 74%. Adverse events reported in 9/30 patients (30%) were usually mild. Severe nivolumab related adverse events in 3/30 (10%) included immune related pneumonitis, myelitis and uveitis. No treatment related death occurred. Conclusions: The check point inhibitor nivolumab is a novel therapy for RR cHL patients, previously with unmet need following relapse or refractory to autoHSCT and brentuximab vedotin. Our real life experience confirms and highlights the efficacy and safety of nivolumab in very heavily pretreated young and elderly patients with cHL eligible as well as ineligible for autologous HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2016.72.1316 ◽

2017 ◽

Vol 35 (19) ◽

pp. 2125-2132 ◽

Cited By ~ 464

Author(s):

Robert Chen ◽

Pier Luigi Zinzani ◽

Michelle A. Fanale ◽

Philippe Armand ◽

Nathalie A. Johnson ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Phase Ii ◽

Safety Profile ◽

Response Rate ◽

Phase Ii Study ◽

Complete Response ◽

Salvage Chemotherapy ◽

Brentuximab Vedotin ◽

Classic Hodgkin Lymphoma ◽

Programmed Death

Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1–blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response ≥ 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.

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A Study of Retreatment With Brentuximab Vedotin in Subjects With Classic Hodgkin Lymphoma or CD30-expressing Peripheral T Cell Lymphoma

Case Medical Research ◽

10.31525/ct1-nct03947255 ◽

2019 ◽

Author(s):

Keyword(s):

T Cell ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Classic Hodgkin Lymphoma

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Salvage therapies in transplant-eligible relapsed classic Hodgkin lymphoma, are novel regimens better?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7530 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7530-7530

Author(s):

Sanjal Desai ◽

Yucai Wang ◽

Allison Claire Rosenthal ◽

Craig B. Reeder ◽

David James Inwards ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Progression Free Survival ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Multivariate Models ◽

Bulky Disease ◽

Classic Hodgkin Lymphoma ◽

Significant Difference

7530 Background: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) eligible for autologous stem cell transplant (ASCT). In this observational study, we report efficacies and outcomes of different ST in ASCT-eligible R/R cHL. Methods: Consecutive ASCT-eligible R/R cHL pts at 3 Mayo Clinic sites were included. Demographics and clinical variables at relapse were recorded by medical records review. Time to event endpoints were defined from relapse. Univariate associations were confirmed in multivariate models of age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year). Results: From Jan 2008 to May 2020, 207 ASCT-eligible pts with R/R cHL were included. Median age was 33 (24-43) years, 53% were male, 52% had advanced stage, 24% had BD, 36% had B symptoms, 41% had END, 11% had PRD and 43% had ER. All patients received ST and underwent ASCT; 43 (21%) received 2 ST, 14 (7%) 3 ST and 4 (0.5%) received 4 ST. 6 groups of ST were identified: ifosfamide, carboplatin and etoposide (ICE), bendamustine/brentuximab (BBV), brentuximab vedotin (BV), gemcitabine-based therapy (Gem), checkpoint inhibitor (CPI), and others. Table lists response to first line ST. BBV had significantly higher overall response rate (ORR) and complete response (CR) as first ST in univariate and multivariate models. 114 (79%) after ICE, 30 (97%) after BBV, 15 (56%) after BV, 25 (76%) after Gem, 8 (73%) after CPI and 15 (79%) after other ST underwent ASCT. Higher number of pts were bridged to ASCT after BBV than ICE (p<0.01). 110 (53%) went to ASCT in CR, 74 (36%) in partial response (PR) and 11% in progressive disease (PD). 43 received BV maintenance (BVm) after ASCT. Pts going to ASCT in PR or PD had significantly lower progression free survival (PFS) compared to pts in CR (2 yr PFS: 62%, 18% vs 77%, respectively, p<0.0001) in univariate and multivariate models. There was no difference in PFS and overall survival (OS) by type of ST. BVm was associated with higher PFS (HR 0.3 (CI95 0.2-0.8)) and higher number of ST was associated with lower OS (HR 2 (CI95 1.4-3)) in multivariate model (p<0.001). For pts transplanted in CR, there was no significant difference in PFS and OS by type of ST but higher number of ST predicted lower OS (HR 2.4 (CI95 1.2-3.5), p<0.01). Conclusions: Type of ST did not predict survival, response to and number of ST did. For pts with CR, number of ST not type of ST predicted survival. BBV had higher response rates, higher rates of bridge to ASCT, and may be a preferable ST than ICE. Large, randomized trials are needed to evaluate efficacy of BBV compared to ICE.[Table: see text]

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Brentuximab Vedotin in Combination with Donor Lymphocyte Infusion for Patients with Hodgkin Lymphoma Relapsing after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.4361.4361 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4361-4361

Author(s):

Panagiotis Tsirigotis ◽

Ronit Yerushalmi ◽

Kostantinos Gkirkas ◽

Noga Shentov ◽

Ivetta Danylesko ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Hodgkin Lymphoma ◽

Allogeneic Stem Cell Transplantation ◽

Low Dose ◽

Brentuximab Vedotin ◽

Donor Lymphocyte Infusion ◽

Efficacy And Safety

Abstract Introduction Brentuximab Vedotin (BV) has recently received approval for treatment of Hodgkin lymphoma (HL) relapse after auto-SCT. Although BV is very effective in treating relapse of HL post auto-SCT, response is usually transient. In contrast, there is a paucity of data regarding the efficacy and safety of BV, combined or not with donor lymphocyte infusion (DLI), for the treatment of relapse occurring after allo-SCT. Methods Search for patients (pts) with relapsed HL post allo-SCT was performed in our transplant data set with the aim to evaluate the efficacy and safety of BV in combination with DLI for the treatment of relapsing HL post allo-SCT. Eight pts with relapsed HL after allo-SCT that were treated with BV were included in this report. Results Patients and treatment: There were 6 males and 2 females, with a median age of 31 years (range, 23 - 40), who had previously failed an auto-SCT. Five pts had previously received BV after auto-SCT and all but one responded to treatment. All pts had chemosensitive disease before allo-SCT and were transplanted in a state of partial remission (PR). The graft source was unmanipulated peripheral blood stem cells from a matched related or an unrelated donor in 5 and 2 pts, respectively, while 1 pt received a double umbilical cord blood graft (DUCB). Five pts achieved complete remission (CR) and one PR after allo-SCT, while 2 pts had progressive disease (PD). Disease progression occurred in a median of 11 months (range, 4 - 17) after allo-SCT. All pts received BV at a dose of 1.8mg/kg every 3 weeks for a maximum of 16 doses, till disease progression or toxicity. In two pts chemotherapy was administered before BV. A median of 4.5 (range, 3 -12) BV cycles was administered. DLI was co-administered in 5 out of 7 pts (excluding one patient who received DUCB). Decision for DLI was at the discretion of the treating physician. One pt received 4 DLIs at escalating doses (5x106, 107, 5x107, 108/kg), while another one received 2 escalating DLIs (107, 108/kg) at 3 months interval. Three pts received a single DLI (107/kg). Treatment outcome: Three and two pts achieved CR and PR respectively after treatment with BV in combination with DLI. None of the pts treated only with BV responded. Four out of 5 pts developed GVHD (3 chronic, 1 acute) post DLI administration, that resolved in all cases after a short course of low dose steroids. Disease progression was observed in 3 out of 5 responders in 4, 7 and 9 months, while 2 pts remain progression free with a median follow up of 14,5 (range, 4 - 22) months. Six out of 8 pts are alive, while 2 pts died from HL. BV/DLI treatment was well tolerated and no serious adverse effects were observed in any of the patients. Conclusions In our study, we observed that administration of BV with DLI for HL relapsing post allo-SCT in pts with prior failure to auto-SCT was effective while toxicity was minimal. Notably, re-administration of BV to pts previously treated for post auto-SCT relapse did not result in additional toxicity or resistance. Furthermore, BV combined with DLI, but not BV alone, yielded anti-tumor response in 5/7 of these very high risk pts suggesting a possible synergistic effect. Of notice is the observation that one pt who was refractory to BV post auto-SCT, had a PR after re-administration of BV post allo-SCT. Our observations are in accordance with the results of a previous report, showing that BV plus DLI after allo-SCT creates a vaccination like-effect against HL [1]. Finally, in our study we observed lower than expected frequency of GVHD post DLI that was of transient duration and easily manageable with low dose steroids. We assume that this may be due to an immune-modulating effect produced by BV. Indeed previous studies have shown that CD30 is expressed on the surface of activated T-cells present in inflammatory infiltrates of GVHD lesions [2]. Administration of BV plus DLI should be tested in larger group of patients at high risk of relapse after allo-SCT. References Theurich S, Malcher J, Wennhold K, et al. Brentuximab Vedotin Combined With Donor Lymphocyte Infusions for Early Relapse of Hodgkin Lymphoma After Allogeneic Stem-Cell Transplantation Induces Tumor-Specific Immunity and Sustained Clinical Remission. J Clin Oncol. 2013; 31: 59-63. Chen Y, McDonough S, Hasserjian R, et al. Expression of CD30 in patients with acute graft-versus-host disease. Blood. 2012; 120: 691-696. Disclosures Tsirigotis: CELLTRION, Inc.: Research Funding.

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Brentuximab Vedotin with Chemotherapy in Frontline Treatment of Classic Hodgkin Lymphoma Nodular Sclerosis Syncytial Variant

Blood ◽

10.1182/blood-2020-138996 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-29

Author(s):

Raphael Eric Steiner ◽

Melody R. Becnel ◽

Branko Cuglievan ◽

Ranjit Nair ◽

Prachee Singh ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Brentuximab Vedotin ◽

Phase Iii ◽

Cytotoxic Therapy ◽

Bulky Disease ◽

Nodular Sclerosis ◽

Classic Hodgkin Lymphoma ◽

Pet Ct ◽

Frontline Treatment

BACKGROUND: Classic Hodgkin lymphoma (cHL) Nodular Sclerosis (NS) is the most common subtype of cHL and has a good prognosis. However, an uncommon variant of cHL NS, the syncytial variant (cHL NS-SV), represents an entity with a worse clinical outcome with conventional frontline cytotoxic therapy. Nevertheless, in the pivotal phase III study ECHELON-1, Brentuximab Vedotin (BV), doxorubicin, vinblastine, and dacarbazine (BV+AVD) while demonstrating a superior efficacy, unfortunately more febrile neutropenia (FN) and peripheral neuropathy (PN) were observed compared to bleomycin+AVD (ABVD) as frontline treatment of advanced-stage classical Hodgkin's lymphoma (cHL) (Straus et al Blood 2020). It is unknown whether BV combined with chemotherapy would improve the inferior prognosis of cHL NS-SV. METHODS: After obtaining institutional research approval, we retrospectively reviewed the characteristics and outcomes of adult cHL NS-SV patients, treated per physician preference with frontline BV combined with cytotoxic therapy, either as standard of care (SOC) or in a clinical trial (NCT01712490, NCT03646123 and NCT01060904) between 7/2010 and 7/2020. cHL NS-SV diagnosis was based on morphology and Immunophenotype. Bulky disease was defined as mass>10cm or mediastinal mass >1/3 of thoracic diameter at T5-T6. Lymph node regions were defined by the German Hodgkin Study Group (GHSG). Treatment consisted of 0.9 or 1.2 mg/kg of BV and standard dose ABVD or AVD or D, intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. All patients received support with pegfilgrastim. Response assessment was based on positron emission tomography/computerized tomography (PET/CT). Follow-up time was calculated from the date of pre-treatment baseline lab measurement to relapse date or death date, whichever happened first. Patients with no event were censored at the last follow-up date. RESULTS: Among the 11 patients included in the analysis, the median age was 29 (range 19-59 years), 27.2% were female, and 90.9% were Caucasian. All patients had Eastern Cooperative Oncology Group (ECOG) 0-1, 72.7% of patients had B-symptoms and 81.9% had stage III or IV disease. The median size of the largest lesion was 9.0 cm, 45.5% of patients had bulky disease, 63.6% had extranodal disease, 72.7% had >3 GHSG involved nodal sites and median International Prognostic Score was 4. Overall, all patients received 6 cycles of therapy, 63.6% received BV+AVD, 27.3% received BV+ABVD and 1 patient received SOC BV with dacarbazine because of previous anthracycline exposure. The interim PET/CT showed response in all patients with Deauville score (DS) of 2-3 in 45.5% and 4 in 54.4%. The end-of-therapy PET/CT showed DS of 1-3 in 90.1% and 4 in 8.9%. The latter patient had the most voluminous bulk of this study. To date, no patient received additional systemic therapy or consolidative radiotherapy after completion induction therapy. With a median follow-up time of 14 months (range 5-82 months), no patient had relapse and all were still alive (Progression-Free Survival and Overall Survival of 100%). CONCLUSIONS: BV combined with cytotoxic therapy such as BV+AVD is a highly effective treatment strategy for patients with cHL NS-SV. Further studies are required to evaluate whether frontline therapy of BV+AVD could improve the outcome of the higher-risk subgroup cHL NS-SV. Table Disclosures Lee: Oncternal Therapeutics:Research Funding;Guidepoint Blogal:Consultancy;Aptitude Health:Speakers Bureau;Takeda:Research Funding;Seattle Genetics:Research Funding;Celgene:Research Funding;Bristol-Myers Squibb:Consultancy, Research Funding.

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