A Pilot Study of Brentuximab Vedotin, Rituximab and Dose Attenuated CHP in Patients 75 Years and Older with Diffuse Large B-Cell Lymphoma

Older patients with hematologic malignancies are underrepresented on prospective clinical trials relative to the incidence of disease in this group (Kanapuru et al, 2020). There are few studies in diffuse large B-cell lymphoma (DLBCL) focused specifically on older patients. Rituximab and dose attenuated cyclophosphamide, doxorubicin, vincristine, and prednisone (R-miniCHOP) has been studied on a prospective trial in fit patients aged 80 years and older. Seventy-two percent of patients on this study completed 6 cycles of R-miniCHOP. The overall response rate (ORR) was 73%, and the 2-year progression free survival (PFS) was 47% (Peyrade et al, 2011). Novel regimens are needed to improve upon the efficacy of therapy while preserving tolerability. Brentuximab vedotin (BV) has demonstrated activity in relapsed and refractory DLBCL (Jacobsen et al, 2015) as well as in combination with chemoimmunotherapy (Svoboda, 2020). This study evaluates the feasibility of BV with dose attenuated chemoimmunotherapy. Methods: Patients with both CD30 positive (cut off 1%) and CD30 negative DLBCL aged 75 years and older were enrolled on the study. Patients received six, 3-week cycles of BV 1.8 mg/kg, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg and prednisone 40 mg/m2 days 1-5 (BV R-miniCHP). For the first cycle patients received BV and prednisone as a prephase starting one week prior to cycle 1. All patients received pegfilgrastim. All patients underwent geriatric assessments at screening, following prephase and at the end of treatment. The primary endpoint was feasibility of this regimen in older patients. The regimen was considered feasible if 71% of patients completed 6 cycles of treatment with a 90% confidence interval (CI)=(58.0, 90.6%). Secondary endpoints included toxicity, ORR and complete response (CR) evaluated by positron emission tomography, PFS and overall survival (OS). Response assessments used the Lugano Criteria (Cheson et al, 2014). PFS and OS were estimated using the Kaplan-Meier method. Results: Twenty-two patients were enrolled and started prephase with BV and prednisone. Their baseline characteristics are summarized in the table. Seventy-seven percent (17/22) of patients completed 6 cycles of BV R-miniCHP. Reasons for not completing treatment included progressive disease in 2 patients, myocardial infarction, fatigue, and an unrelated injury in 1 patient each. Twenty-one patients were evaluable for response. ORR was 86% (18/21) in all patients, with 67% (14/21) achieving CR. In CD30 positive patients the ORR was 80% (8/10) and the CR rate was 70% (7/10). In CD30 negative patients the ORR was 91% (10/11) and the CR rate was 64% (7/11). With a median follow up of 23 months, median OS and PFS (figure) were not reached. The 2-year PFS was 60.6%, 90% CI=(40.0%, 76.1%), and the 2-year OS was 73.9%, 90% CI=(52.4%, 86.8%). The most common adverse events (AEs) were fatigue (82%), anemia (50%), diarrhea (50%), dysgeusia (45%) and peripheral sensory neuropathy (45%). Grade ≥3 AEs seen in more than 2 patients included neutropenia (23%), fatigue (18%), pneumonia (18%), hypoxia (14%), thrombocytopenia (9%) and thromboembolism (9%). Grade ≥3 peripheral sensory neuropathy was seen in 9% of patients. There were two deaths in patients receiving study treatment. These included a myocardial infarction related to treatment, and a bowel obstruction secondary to disease progression. Three other patients have died in follow up with 2 secondary to disease progression and 1 due to an unrelated event. Conclusions: The study met its primary feasibility endpoint with 77% of patients completing 6 cycles of therapy. This regimen was delivered safely in this population and toxicities were consistent with those reported in larger prospective studies with R-miniCHOP or ofatumumab and miniCHOP (Peyrade et al, 2011; Peyrade et al 2017). Peripheral neuropathy is a key AE of interest given the inclusion of BV and while nearly half of patients experienced some peripheral neuropathy, it was severe in only 9% of pts. The ORR and CR rate, as well as the 2-year PFS compare favorably to other prospective studies in a population that included patients with high clinical risk, histologic transformation, and double hit lymphoma. BV and R-miniCHP may be a feasible regimen in older patients, and warrants further study based on these preliminary data demonstrating clinical activity and tolerability. Figure 1 Disclosures Reagan: Seattle Genetics: Research Funding; Curis: Consultancy; Kite, a Gilead Company: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Barr:Gilead: Consultancy; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Merck: Consultancy. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Consultancy; Astellas: Consultancy; Bayer: Consultancy.

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Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood.v128.22.104.104 ◽

2016 ◽

Vol 128 (22) ◽

pp. 104-104 ◽

Cited By ~ 7

Author(s):

Lihua E. Budde ◽

Ahmad Halwani ◽

Christopher A. Yasenchak ◽

Charles Michael Farber ◽

John M Burke ◽

...

Keyword(s):

Peripheral Neuropathy ◽

High Risk ◽

Research Funding ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Peripheral Sensory Neuropathy ◽

Genetics Research ◽

Equity Ownership ◽

Grade 3 ◽

Peripheral Sensory

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

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Three-Year Follow-Up Data and Characterization Of Long-Term Remissions From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.4382.4382 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4382-4382 ◽

Cited By ~ 16

Author(s):

Ajay K. Gopal ◽

Robert Chen ◽

Scott E. Smith ◽

Stephen M Ansell ◽

Joseph D Rosenblatt ◽

...

Keyword(s):

Research Funding ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Observation Time ◽

Equity Ownership ◽

Time To Relapse ◽

Peripheral Sensory

Abstract Background Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory HL is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT). However, approximately 50% of pts experience relapse of HL after auto-SCT and this population represents a pronounced unmet need. In a 756-pt retrospective analysis, the median overall survival (OS) in HL pts who relapsed after auto-SCT was 2.4 years, as measured from the time of auto-SCT, with shorter time to relapse after auto-SCT being the most predictive factor for shortened survival (Arai 2013). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. A pivotal phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in 102 pts with relapsed or refractory HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Data representing approximately 3 years of follow up from this ongoing trial are described, including characterization of patients who experienced long-term remissions. Methods Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up assessments to determine survival and disease status occurred every 3 months (mos) for 2 years, every 6 mos during years 3 to 5, and annually thereafter. Results In this high-risk population with poor prognosis, the median time to relapse after auto-SCT was 6.7 mos (range, 0–131 mos). Pts received a median of 9 cycles of brentuximab vedotin and the ORR was 75% (76 of 102 pts), with complete remissions (CRs) in 33% of pts (n=34). As previously reported, the most common (≥15%) brentuximab vedotin-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At the time of this analysis (May 2013), the median observation time from first dose was 32.7 mos (range, 1.8 to 48.3 mos). Of the 102 pts enrolled, 51 (50%) were alive at the time of last follow up. The median OS was 40.5 mos (95% CI: 28.7, – [range, 1.8 to 48.3+ mos]) and the estimated 36-mo survival rate was 54% (95% CI: 44%, 64%). Median OS by best clinical response was CR (n=34): median not yet reached; partial remission (PR, n=42): 31.6 mos; stable disease (SD, n=22): 20.6 mos; and progressive disease (PD, n=3): 10.2 mos. Of the 51 pts who were alive at the time of this analysis, 14 remain in remission and have not started a new anti-cancer therapy other than 5 pts who received consolidative allo-SCT following brentuximab vedotin. Demographics/baseline characteristics of these 14 pts show that the majority are female (10/14; 71%) and white (12/14; 86%), with a median age of 26.5 years (range, 15–54). Eleven of the 14 pts had CRs and 3 had PRs following brentuximab vedotin; all 3 of the pts with PRs received subsequent allo-SCT. The observation time for the 14 pts who remain in remission ranges from 31.5 mos to 44.4 mos and their progression-free survival ranges from 27.2+ mos to 44.4+ mos. Additional characterization of the pts who achieved long-term remissions following brentuximab vedotin will be presented at the meeting. Conclusions After a median observation time of approximately 3 years from first dose of brentuximab vedotin, 50% of pts with relapsed or refractory HL were alive at the time of last follow up. The median OS was 40.5 mos. Fourteen patients remain in follow up with no evidence of lymphoma progression, providing early suggestion that a fraction of these patients may be cured. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for frontline treatment of HL (ClinicalTrials.gov #NCT01712490). Disclosures: Gopal: Biogen, Idec: Research Funding; Merck: Research Funding; BioMarin: Research Funding; Gilead: Research Funding; Emergent/Abbott: Research Funding; Pfizer: Research Funding; Cephalon/Teva: Research Funding; Janssen: Research Funding; Millennium: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; Piramal: Research Funding; Spectrum: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Trave expenses Other. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Cambridge US: Employment; Takeda: Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Millennium: Honoraria; Pharmacyclics: Honoraria; Curis: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Johnson and Johnson: Research Funding; Infinity: Research Funding.

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CD30 Expression in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1558.1558 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1558-1558 ◽

Cited By ~ 2

Author(s):

Graham W. Slack ◽

Christian Steidl ◽

Laurie H. Sehn ◽

Randy D. Gascoyne

Keyword(s):

B Cell ◽

Mrna Expression ◽

Research Funding ◽

Cell Lymphoma ◽

Independent Predictor ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 1558 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a variable clinical course. The addition of rituximab (R) to CHOP combination chemotherapy has improved overall (OS) and progression free survival (PFS) but some patients progress despite treatment and alternative therapies are needed. Brentuximab vedotin is an antibody-drug conjugate that targets CD30. It is efficacious in the treatment of relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma, two lymphomas associated with CD30 expression. The association between DLBCL and CD30 expression has not been well described. The aim of this study was to examine CD30 expression in DLBCL. Design: 395 cases of formalin-fixed paraffin-embedded DLBCL (excluding PMBCL) in a tissue microarray were independently evaluated by two pathologists for expression of CD30, CD10, BCL6, and MUM1 by immunohistochemistry (IHC) and EBV RNA (EBER) by in situ hybridization. CD30 expression was correlated with cell of origin (COO) phenotype, OS and PFS, EBV infection, International Prognostic Index (IPI) score and CD30 mRNA expression. The COO phenotype, germinal center B-cell like (GCB) or non-GCB, was determined by IHC using the Hans algorithm. CD30 mRNA expression and COO genotype by gene expression profiling (GEP) were determined using Affymetrix U133 2.0 Plus arrays (n=170). Outcome analysis only included patients treated with R-CHOP chemotherapy. CD30 was considered positive by IHC if any malignant cells exhibited membranous staining. The threshold for calling higher CD30 expression by GEP was determined using X-Tile software. Results: 25% (95/385) of DLBCL cases expressed CD30 by IHC with excellent concordance between two observers (r = 0.94). CD30 expression trended towards a non-GCB phenotype but was not significantly different (p=0.067). CD30 expression was not associated with PFS or OS in all R-CHOP treated cases (n=313); however, it was associated with a prolonged PFS in GCB-DLBCL (n=147) (p=0.019). In GCB-DLBCL CD30 expression remained an independent predictor of PFS in a multivariate analysis with IPI (p=0.038). CD30 expression by IHC was significantly associated with higher levels of CD30 mRNA (p=0.002). ABC-DLBCL exhibited significantly higher expression levels of CD30 mRNA (p=0.037). Higher CD30 mRNA expression was associated with a prolonged PFS in all R-CHOP treated DLBCL (p=0.012) as well as in DLBCL with a GCB-genotype (p=0.008), but not ABC or U-genotypes. Higher CD30 mRNA expression was also associated with a prolonged OS in the GCB-genotype (p=0.022). In the GCB-genotype higher CD30 mRNA expression remained an independent predictor of PFS, but not OS, in a multivariate analysis with IPI (p=0.037). EBV was identified in 3% of DLBCL (11/391), all of which exhibited a non-GCB phenotype (p=0.001) and were almost exclusively positive for CD30 expression (10/11)(p=<0.001). Conclusions: CD30 is expressed in approximately 25% of DLBCL and brentuximab vedotin could be considered for study in combination with traditional front-line therapies or as an alternative therapy in the relapsed or refractory disease. CD30 immunohistochemistry may be useful as a prognostic marker in R-CHOP treated GCB-DLBCL and the significant association of CD30 with EBV-positive non-GCB DLBCL suggests a distinct pathobiology for these cases. Disclosures: Slack: Seattle Genetics: Research Funding. Steidl:Seattle Genetics: Research Funding. Gascoyne:Seattle Genetics: Research Funding.

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Five-Year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v126.23.2736.2736 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2736-2736 ◽

Cited By ~ 5

Author(s):

Robert Chen ◽

Ajay K. Gopal ◽

Scott E. Smith ◽

Stephen Ansell ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Sensory Neuropathy ◽

Disease Status ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Pivotal Phase ◽

Genetics Research ◽

Equity Ownership

Abstract Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period. Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months. Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin. Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). Figure 1. Overall Survival Figure 1. Overall Survival Disclosures Chen: Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

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Pembrolizumab in Combination with Standard RCHOP Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-119129 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1686-1686

Author(s):

Stephen D. Smith ◽

Ryan C. Lynch ◽

Brian G. Till ◽

Andrew J. Cowan ◽

Qian V. Wu ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

Dose Intensity ◽

B Cell Lymphoma ◽

Response Assessment ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

History Of ◽

Grade 3 ◽

Anthracycline Dose

Abstract Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). However, a substantial proportion of patients (pts) will relapse. The anti-PD-1 monoclonal antibody pembrolizumab has shown modest efficacy in previously treated DLBCL. We postulated that the first-line setting, with relatively intact host immunity and coexistence of malignant cells with T-cells in the microenvironment, may represent an opportunity for effective immune checkpoint inhibition. We carried out the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma, to evaluate the safety of this combination. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3B follicular lymphoma with a plan for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. A 30-pt sample size permitted estimation of the rate of clinically relevant grade 3-5 toxicity, assumed to occur in 40% of pts with RCHOP alone. A stopping rule for more than 3 instances of non-relapse death or inability to complete 6 cycles of RCHOP for any reason was applied. Secondary endpoints included response rates, overall (OS) and progression-free survival (PFS). Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). Peripheral blood flow cytometry for changes in PD1, PDL-1, and PDL-2 subsets were performed. After PET-based response assessment, pts were followed for relapse and survival. Results: Since March 2016, 29 pts were treated on study; 28 have finished all therapy. One is currently on therapy, and 1 remains to be enrolled. Pt characteristics are in Table 1. In 29 pts to date, 18 grade 3-5 clinically significant AE's occurred in 13 unique pts (13/29, 45%). 16 SAE's occurred in 11 pts (11/29, 38%); none qualified as unanticipated events. Two deaths occurred: One in the first accured patient, who had extensive gastric involvement by DLBCL, and died during cycle 1 of bleeding from the responding tumor bed despite maximal inpatient intervention. The other death occurred due to steroid-refractory GVHD after haploidenticial allogeneic transplant for relapsed disease. Four immune-related adverse events (IRAE) occurred: grade 3 rash, resolving with oral steroids and not recurring with further pembrolizumab, grade 1 hyperthyroidism, grade 2 colitis, and 1 episode of grade 3 pneumonitis. This case of pneumonitis was the only immune-related SAE, occurring in a 78 yo with a history of tobacco use and COPD, and resulted in stopping therapy after cycle 3. Among 27 completing treatment (excluding the pt who died during cycle 1), average anthracycline dose was 95% of expected; anthracycline relative dose intensity (RDI: delivered dose intensity/standard dose intensity) was 94%. PET response assessment among 26 evaluable pts showed 18 CR (69%), 7 PR, and 1 primary refractory disease. Among 7 PR, 1 relapsed, 3 had negative biopsies, and 3 remain in remission. Median follow-up of survivors is 13 months and 2 relapses (1 primary progressive disease, 1 after PET PR) occurred. One-year PFS is 87% (Figure 1). Baseline PDL-1 staining available for 19 pts showed a median % tumor cell staining of 30% (moderate 2+ plus strong 3+ staining; range, 0-100%). Tumor PDL1 was ≤5% in 4, 10-29% in 5, 30-49% in 4, and ≥50% in 6 pts. Both EBV+ DLBCL had 60% tumor PDL1 expression. 1 relapsing pt had no detectable tumor PDL1, and the THRLBL failed for technical reasons. Conclusions: RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles is safe, with toxicity similar to RCHOP alone and only 4 IRAE's. Anthracycline dose intensity, CR rate, and PFS are favorable. PDL1 tumor cell expression of 10% or more was observed in 15/19 pts. These data support further study of pembrolizumab with chemotherapy in untreated lymphoid malignancies. Final response/progression, correlative studies, and survival data will be presented in December after final accrual. Disclosures Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Cowan:Sanofi: Research Funding; Juno Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Shadman:Acerta Pharma: Research Funding; Genentech: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy; Beigene: Research Funding; Pharmacyclics: Research Funding; AbbVie: Consultancy; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy. Shustov:Seattle Genetics: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding. Gopal:Pfizer: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Takeda: Research Funding; Incyte: Consultancy; Spectrum: Research Funding; Gilead: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Teva: Research Funding.

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Pembrolizumab with R-CHOP in Previously Untreated Diffuse Large B-Cell Lymphoma: Long Term Follow up and Analysis of the Mechanism of Pdl-1 Tumor Expression

Blood ◽

10.1182/blood-2020-137328 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

Stephen D. Smith ◽

Jonathan R. Fromm ◽

Min Fang ◽

Brian G. Till ◽

Mazyar Shadman ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

Genomic Array ◽

Tumor Expression ◽

Large B Cell

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). We previously reported that adding pembrolizumab to RCHOP (PR-CHOP), shows no significant additive toxicity and a promising 2-year progression free survival of 83% (Smith B J Haem 2019), with no progression events among 19 pts with known PDL-1+ tumors. In that analysis, we noted 83% of patients had tumor PDL-1 expression by IHC using a centralized standard assay, including 18/23 (78%) and 13/23 (56%) demonstrating positivity in ≥5% and ≥30% of lymphoma cells respectively. Herein we report long-term clinical follow up, as well as results of high-resolution molecular karyotyping using chromosome genomic array testing (CGAT), to assess whether 9p24.1 abnormalities explained the extent of PDL1 tumor expression. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma eligible for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. There was no maintenance or consolidation therapy. Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). CGAT was performed from DNA extracted from formalin-fixed, paraffin-embedded tissue sections using the OncoScan platform (ThermoFisher). H&E slides of adjacent sections of the tissue used for CGAT were evaluated by a pathologist to ensure a minimum of 30% tumor content. Patients were followed for relapse and survival. Results: Among 30 treated pts with a median follow up of 32 months, there have been no additional DLBCL relapses or deaths since the published report. There has been one relapse of follicular lymphoma in a patient with initial composite lymphoma , who is now in remission 1 year after autologous stem cell transplantation. 3-year estimated PFS is 83% and OS is 86%. On univariate analysis, only tumor bulk 7.5 cm or greater (p=.02) and absence tumor PDL-1 expression by IHC (p=.001) predicted inferior PFS. Tumor bulk, (p=.03), IPI 3 or higher (p=.01), and absence of tumor PDL-1 expression (p=.001) predicted worse overall survival. PFS and OS were unaffected by cell of origin by IHC, double expresser status, or diagnosis to treatment interval greater than median (29 days). Regarding safety, there were late cases of paraneoplastic pemphigus and rheumatoid arthritis 5 and 8 months from last dose of pembrolizumab, respectively. Both of these were managed successfully with immunosuppression. Chromosome genomic array testing CGAT) was performed to assess copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH), particularly for the presence of gains or amplifications involving locus 9p24.1, containing the CD274 (PDL1) gene. Of 15 tested pretreatment baseline diagnostic tissue specimens, 14 provided informative result with 12 abnormal and 2 normal. Notably, no gain or amplification in 9p24.1 were seen; there was one case of deletion and 1 with cnLOH. The percent genome altered among abnormal cases ranged from 2% to 37% (median 12%). Complex karyotype, defined as genomic aberrations involving at least 3 chromosome arms (or % genome altered greater than 5% by CGAT), was seen in 10/14 pts (71%). This 14-sample data set included 6/14 pts with >30% PDL1 tumor expression (and 10 with 5% or greater PDL1-tumor expression). Conclusions: No additional safety signals have been observed, and PFS/OS remain favorable for the combination of pembrolizumab + RCHOP in this single arm trial with the best results in PDL-1+ disease. Despite frequent tumor PDL1-expression at baseline, no gains or implications of 9p24.1 were observed suggesting alternative mechanisms for overexpression of PDL-1. Further study this regimen and others testing combinations of immune checkpoint inhibition with first-line DLBCL therapy are warranted, to better ascertain the potential superiority of this strategy in this setting. Disclosures Smith: Portola: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Bristol Meyers Squibb: Research Funding. Fromm:Merck: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Lynch:Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding; Cyteir: Research Funding. Cowan:Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding. Ujjani:Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding. Cassaday:Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding.

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Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+ Lymphomas

Blood ◽

10.1182/blood.v118.21.3091.3091 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3091-3091 ◽

Cited By ~ 5

Author(s):

Tim Illidge ◽

Reda Bouabdallah ◽

Robert W. Chen ◽

Ajay K. Gopal ◽

Craig H. Moskowitz ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Objective Response ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Peripheral Sensory Neuropathy ◽

Advisory Committees ◽

Peripheral Sensory

Abstract Abstract 3091 Background: Allogeneic stem cell transplant (allo-SCT) for relapsed or refractory lymphoma is often limited by the amount of residual tumor burden following cytoreductive therapy. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). In recent phase 2 trials, brentuximab vedotin induced objective responses in 75% of patients with Hodgkin lymphoma (HL) (Chen 2011) and 86% of patients with systemic ALCL (sALCL) (Pro 2011). Fifteen of 160 patients (9%) who participated in these two phase 2 studies received an allo-SCT as their first subsequent antitumor therapy after treatment with brentuximab vedotin. This case series describes the initial experience of these patients. Methods: Patients received 1.8 mg/kg brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Antitumor activity was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). After discontinuing brentuximab vedotin, patients were followed for survival/disease status and information regarding subsequent therapy, including allo-SCT, was collected. Results: Fifteen patients (7 with HL and 8 with sALCL) received an allo-SCT as their first subsequent antitumor therapy following brentuximab vedotin treatment. The median age was 28.0 years (range 17–61 years) and the majority (67%) were female. The median time since initial HL/sALCL diagnosis was 27.3 months (range 6.2–108 months). The median number of therapies patients had received prior to brentuximab vedotin was 3.0 (range 2–5) and 12 patients had previously received an autologous SCT. Patients received a median of 9.0 cycles (range 4–16) of brentuximab vedotin and all 15 patients achieved an objective response per independent radiological review; best response was CR for 12 patients (5 with HL and 7 with sALCL) and PR for 3 patients (2 with HL and 1 with sALCL). The median time to objective response was 1.4 months (range 1.2–2.6 months) and all 15 patients maintained an objective response at the time of the last assessment prior to allo-SCT. The median time between the last dose of brentuximab vedotin and the start of the SCT conditioning regimen was 1.4 months (range 0.6–3.3 months). Thirteen of the 15 patients (87%) are alive and remain in follow-up post allo-SCT. The median duration of follow-up from first dose of brentuximab vedotin is 16.9 months (range 8.2–21.1 months). Five patients (1 with HL and 4 with sALCL) have either progressed or died post-transplant. Four of these 5 patients had achieved a CR with brentuximab vedotin treatment. Of the 2 patients who died (both patients with sALCL who had achieved a CR with brentuximab vedotin treatment), one death was disease-related (not formally restaged) and the other was due to transplant-related complications. The median PFS at the time of this analysis is 21.1 months (range 8.2–21.1 months). Treatment-emergent adverse events that occurred prior to allo-SCT in >20% of patients were peripheral sensory neuropathy and pyrexia (53%; n=8), diarrhea and neutropenia (47%; n=7), nausea (33%; n=5), and chills and dyspnea (27%; n=4). Thirteen of 15 patients (87%) experienced AEs of ≥ Grade 3 prior to allo-SCT; the most common (reported in >10% of patients) were neutropenia (47%; n=7), anemia and thrombocytopenia (27%; n=4), and abdominal pain, pain, and peripheral sensory neuropathy (13%; n=2). Two patients discontinued brentuximab vedotin treatment due to an AE (peripheral sensory neuropathy) before subsequently receiving allo-SCT. Conclusions: Treatment with brentuximab vedotin provided cytoreduction in patients with relapsed or refractory HL and sALCL, many of whom had failed a prior autologous SCT. Thirteen of the 15 patients (87%) achieved an objective response with brentuximab vedotin treatment prior to allo-SCT and remain in follow-up at the time of this analysis. Ten of the 15 patients (67%) remain in remission. Our results suggest that brentuximab vedotin may be an option for reducing tumor burden to facilitate a consolidative allo-SCT and warrants further study. Disclosures: Illidge: Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Bouabdallah:Seattle Genetics, Inc.: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Plexxicon: Research Funding. Ramchandren:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria. Tilly:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau. Trippett:Seattle Genetics, Inc.: Research Funding; OSI Pharmaceuticals: DSMB Chair. Grove:Seattle Genetics, Inc.: Employment; Seattle Genetics, Inc.: Equity Ownership. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Survival Analyses of an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v120.21.3689.3689 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3689-3689 ◽

Cited By ~ 1

Author(s):

Robert W. Chen ◽

Ajay K. Gopal ◽

Scott E. Smith ◽

Stephen M. Ansell ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Survival Rate ◽

Research Funding ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Observation Time ◽

Term Survival ◽

Time To Relapse ◽

Peripheral Sensory

Abstract Abstract 3689 Background: Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory HL is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT). However, approximately 50% of pts experience relapse of HL after auto-SCT and this population represents a pronounced unmet need. In a 756-pt retrospective analysis, the median overall survival (OS) in HL pts who relapsed after auto-SCT was 2.4 years, as measured from the time of auto-SCT, with shorter time to relapse after auto-SCT being the most predictive factor for shortened survival (Horning et al, 2008). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A pivotal phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in 102 pts with relapsed or refractory HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Long-term survival data from this ongoing trial are described. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up assessments to determine survival and disease status occurred every 3 months (mos) for 2 years, every 6 mos during Years 3 to 5, and annually thereafter. Results: In these heavily pretreated pts with poor prognosis, the median time to relapse after auto-SCT was 6.7 mos (range, 0–131 mos). Pts received a median of 9 cycles of brentuximab vedotin and the ORR was 75% (76 of 102 pts), with complete remissions (CRs) obtained by 33% of pts (n=34). At the time of this analysis (July 2012), the median observation time from first dose was 29.5 mos (range, 1.8 to 36.9 mos). 60 of 102 pts (59%) were alive at the time of last follow up and the median OS has not yet been reached. The estimated 24-mo survival rate was 65% (95% CI: 55%, 74%). Median OS by best clinical response was 31.6 mos for pts with partial remission (PR, n=42), 20.6 mos for pts with stable disease (SD, n=22), and 10.2 mos for pts with progressive disease (PD, n=3); median OS for pts who obtained a CR (n=34) has not yet been reached. Evaluation of numerous demographic and baseline characteristics including age, gender, bone marrow involvement, presence of B symptoms, tumor size, and ECOG performance status showed that the only subgroup of pts who had a significantly more favorable survival rate following brentuximab vedotin treatment were those with a baseline ECOG score of 0 (24-mo survival rate of 81% vs. 47% for pts with ECOG scores of 0 vs. 1, respectively). Notably, no significant difference in OS was evident in the subgroup of pts who had relapsed within a year of auto-SCT compared with those who had relapsed >1 year after auto-SCT. As previously reported, the most common (≥15%) brentuximab vedotin-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Conclusions: After a median observation time of approximately 2.5 years from first dose of brentuximab vedotin, 60 of 102 pts (59%) with relapsed or refractory HL were alive at the time of last follow up and the median OS has not yet been reached. The estimated 24-mo survival rate was 65%. The only pretreatment factor evaluated that was associated with a higher 24-mo survival rate was a baseline ECOG score of 0. Prolonged OS was observed in pts with both long and short progression-free intervals after auto-SCT. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR. Based upon these findings, combination regimens that incorporate brentuximab vedotin are presently being evaluated in clinical trials to determine whether the proportion of pts who achieve durable CRs might be further increased. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Honoraria, Research Funding. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding.

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Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study

Blood ◽

10.1182/blood.v126.23.587.587 ◽

2015 ◽

Vol 126 (23) ◽

pp. 587-587 ◽

Cited By ~ 11

Author(s):

Christopher A. Yasenchak ◽

Andres Forero-Torres ◽

Vivian Jean Mikao Cline-Burkhardt ◽

Rodolfo E Bordoni ◽

Dipti Patel-Donnelly ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Older Patients ◽

Research Funding ◽

Brentuximab Vedotin ◽

Observation Time ◽

Cell Transplant ◽

Phase 2 ◽

Frontline Treatment ◽

Grade 3

Abstract Introduction Older patients (pts) with Hodgkin lymphoma (HL) have inferior outcomes compared to younger pts treated with standard chemotherapy regimens, and tolerate therapy poorly. New therapeutic options that improve both efficacy and tolerability are needed for these pts. Brentuximab vedotin (ADCETRIS®), an anti-CD30 antibody-drug conjugate, has durable activity as monotherapy in relapsed HL with a manageable safety profile. For frontline single agent treatment of HL pts aged ≥60 yrs, the objective response rate (ORR) was 92% (73% complete remission [CR]) and the median progression-free survival (PFS) was 10.5 months (mo) (Forero-Torres 2015). Brentuximab vedotin + dacarbazine (DTIC) demonstrated compelling activity in preclinical models (McEarchern 2010), and brentuximab vedotin + bendamustine (benda) provided an 82% CR rate in pts with relapsed HL (LaCasce 2014). This phase 2, frontline, open-label study examines the efficacy and durability of response of brentuximab vedotin as monotherapy and in combination with DTIC or benda in HL pts aged ≥60 yrs (NCT01716806). Methods Approximately 70 treatment-naïve pts aged ≥60 yrs with HL (30 monotherapy; 20 for each combination) are to be enrolled. Eligible pts have ECOG ≤3 and are ineligible for or have declined conventional treatment. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks for up to 12 cycles with DTIC (375 mg/m2) and up to 6 cycles with benda (90 or 70 mg/m2). Pts with clinical benefit may receive additional cycles of brentuximab vedotin. Response is assessed after Cycles 2, 4, 8, 12, 16 and every 6 cycles thereafter. The primary endpoint is ORR per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Thus far, 60 pts have been treated (n=27 monotherapy; 22 DTIC combo; 11 benda combo). Median age for all pts was 76 yrs (range, 62-92), 55% were male, 65% had stage III-IV disease, 40% had B symptoms, 28% had ECOG 2-3, and 70% were deemed ineligible for conventional chemotherapy. To date, a median of 11.5 treatment cycles have been received by DTIC combo pts, compared to 8 cycles by monotherapy pts. Duration of treatment for the benda combo pts will be more clearly defined with additional follow-up time. A total of 45 pts have discontinued therapy. Discontinuations were due to adverse event (AE; n=18, including 15 for Grade 2 or 3 peripheral neuropathy), progressive disease (PD) after complete or partial remission (CR or PR; n=13), or other reasons (see table; n=14). Fifteen pts remain on therapy. For pts treated with the DTIC combo, the ORR was 100% (62% CR). The median PFS has not been reached (median observation time 9.8 mo) and 18/21 pts remain alive without PD. For pts treated with the benda combo, the starting dose of benda was reduced from 90 to 70 mg/m2 to improve tolerability after the first 10 pts were enrolled. The ORR was 100% (78% CR) in the first 9 pts; with limited observation time (median 3.6 mo), 8/9 pts remain alive without PD. Treatment-related AEs ≥ Grade 3 occurred in 43% of pts overall, SAEs were reported for 22% overall, and no pt died within 30 days of last dose. Conclusions This planned analysis demonstrated 100% ORRs for both the DTIC combo and benda combo with acceptable tolerability. Based upon these data, combinations including brentuximab vedotin appear to have promise as frontline therapy in this vulnerable patient population. Ongoing follow-up will define durability, and ultimately the potential role of these combinations as standard options for elderly patients with HL. Table. Monotherapy (N=27) DTIC Combo (N=22) Benda Combo a (N=11) Median treatment cycles (range) Brentuximab vedotin 8 (3, 23) b 11.5 (2, 16) 4 (2, 8) DTIC or benda - 11.5 (1, 12) 4 (1, 6) Pts remaining on therapy, n (%) 0 b 6 (27) 9 (82) Reason for treatment discontinuation, n (%) AE 11 (41) b 7 (32) 0 PD after CR or PR, n (%) 11 (41) b 2 (9) 0 Investigator decision 1 (4) b 4 (18) 1 (9) Pt decision 3 (11) b 2 (9) 1 (9) Completed treatment 0 b 1 (5) 0 Other non-AE reason 1 (4) b 0 0 Efficacy evaluable pts (N) 26 b 21 9 ORR, n (%) 24 (92) b 21 (100) 9 (100) CR rate, n (%) 19 (73) b 13 (62) 7 (78) PFS, median mo (range) 10.5 (2.6+, 22.3+) b - (4.2+, 14.3+) - (1.2+, 6.2+) Median observation time, mo (range) 20.4 (4.6, 30.4) 9.8 (4.9, 14.3) 3.6 (2.3, 7.0) Pts with progression or death, n (%) 16 (62) 3 (14) 1 (11) Treatment-related AE ≥ Grade 3, n (%) 13 (48) b 8 (36) 5 (45) Any SAE, n (%) 6 (22) b 2 (9) 5 (45) aEnrollment is ongoing bForero-Torres 2015 Disclosures Yasenchak: Seattle Genetics, Inc.: 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. This study evaluates brentuximab vedotin as frontline treatment, both as monotherapy and in combination therapy, in older patients with HL.. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Cline-Burkhardt:Seattle Genetics, Inc.: Research Funding. Bordoni:Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Flynn:Seattle Genetics, Inc.: Research Funding. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership.

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CD30 Expression Is Not Acquired at Time of Relapse in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.4225.4225 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4225-4225

Author(s):

Oscar Calzada ◽

Kyle T. Bradley ◽

Jeffrey Switchenko ◽

Ashley D. Staton ◽

Jean L. Koff ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Newly Diagnosed ◽

Advisory Committees ◽

Tissue Samples ◽

Genetics Research ◽

Large B Cell Lymphoma

Abstract Introduction: Prior series have identified CD30 expression by immunohistochemistry (IHC) is associated with improved overall survival (OS) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL; 5-year OS: 79% vs 59% in CD30(-) patients, Hu et al, Blood 2013). It is unclear, however, whether CD30(+) status is retained throughout the course of the disease. Conversely, it is also unknown whether patients with CD30(-) tumors at diagnosis may present with CD30(+) disease upon relapse. As there is a currently approved antibody-drug conjugate targeting CD30, brentuximab vedotin, an improved understanding of CD30 expression in DLBCL may inform therapy options for relapsed (and potentially newly diagnosed) patients. Here, we evaluated patients with relapsed DLBCL with available tissue samples, including those with paired tissue samples from the time of diagnosis to assess for CD30 status for the duration of their disease course. Methods: This cohort included patients ≥ 18 years old with relapsed DLBCL for whom biopsy samples and clinical data were available. Tissue samples at diagnosis and from time of relapse were collected from our institution's pathology archive, and IHC-staining for CD30 expression was performed on all available involved tissue. CD30 status was assessed using a comprehensive form including assessment of percentage of CD30(+) cells and distribution of staining within each cell. Both neoplastic and surrounding non-neoplastic cells were evaluated. All assessment of CD30 staining was completed by one hematopathologist. We also collected comprehensive clinical, demographic and pathologic data for each patient. Results: We identified 25 patients with relapsed/refractory DLBCL with available tissue samples from the time of relapse, including 12 patients with available paired diagnostic tissue. Among all patients, the median age at diagnosis was 58 years (range 34-76), 48% were male, 56% were stage III/IV, and 62% presented with B-symptoms. Eighty-eight percent of patients received R-CHOP as frontline therapy. Cell of origin by the Hans algorithm was germinal center B-cell-like (GCB) for 9 patients, non-GCB for 5 patients, and unknown for 11 patients. After pathologic review, all 25 samples were CD30-negative at relapse, including all 12 paired samples which were CD30-negative at diagnosis and relapse, suggesting that CD30 expression does not appear to be acquired at the time of relapse in DLBCL patients who present with CD30-negative disease. Conclusions: This retrospective, single-center cohort analysis suggests that patients with newly diagnosed DLBCL with tumors negative for CD30 expression retain CD30-negative status at relapse. Thus, assaying biopsies at relapse for CD30 positivity by IHC to investigate candidacy for salvage treatment with brentuximab vedotin in a patient with a tumor previously CD30(-) may be of limited value. Alternative computer-aided methods to assess CD30 expression in samples that are considered negative by conventional IHC may better identify the presence of CD30 among patients with relapsed DLBCL. Disclosures Calzada: Seattle Genetics: Research Funding. Flowers:Seattle Genetics: Research Funding; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Celgene Corporation: Consultancy, Honoraria; Millennium: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Cohen:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding.

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