Park, Steven I.

AbstractIntroductionWhile most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent‐behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy.MethodsOut of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high‐dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non‐intensive (n = 131).ResultsThere was no difference in progression‐free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non‐intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model.ConclusionsThese results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

PURPOSEDiffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)–directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.METHODSPatients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.RESULTSOf 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.CONCLUSIONTo our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.

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.

Abstract Abstract 955 Background: Hodgkin lymphoma (HL) is a lymphoid neoplasm defined by the presence of CD30-positive Hodgkin Reed-Sternberg (HRS) cells in a background of inflammatory cells. Frontline treatment is generally ABVD alone or in combination with other chemotherapy regimens or radiation. Although a standard ABVD regimen is curative for the majority of patients with advanced stage HL, up to 30% of patients will require a second-line 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 a phase 2 study, an objective response rate of 75% and multiple durable complete remissions (CRs) (34%) were obtained with single-agent brentuximab vedotin in highly treatment-refractory patients with HL. Methods: A phase 1, open-label, multicenter study is being 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 is based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: Interim data are presented for the first 31 patients treated. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD; 6 patients received 1.2 mg/kg with AVD. Baseline characteristics included: Stage IV, 55%; IPI score ≥4, 29%; male, 77%; median age, 35 years (range, 19–59). Combination treatment was generally well tolerated, with no DLT observed up to 1.2 mg/kg in either regimen. Overall, AEs reported in ≥45% of patients, regardless of severity, were nausea and neutropenia (77% each); peripheral sensory neuropathy (48%); and fatigue (45%). Infusion-related reactions occurred in 23% of patients. Grade 3/4 AEs observed in >10% of patients were neutropenia (74%), febrile neutropenia (16%), and anemia (13%). No Grade 5 events were observed. Overall, 6 patients discontinued combination treatment due to an AE. In the ABVD cohorts (n=25), AEs of pulmonary toxicity, dyspnea, and interstitial lung disease that could not be distinguished from bleomycin toxicity led to discontinuation of bleomycin in 7 patients. Five of these 7 patients continued treatment with AVD and brentuximab vedotin. All 10 patients who had a response assessment available after completion of frontline therapy achieved CR. Currently, an expansion cohort of approximately 20 patients is enrolling to explore 1.2 mg/kg brentuximab vedotin combined with AVD therapy. Conclusions: In this interim analysis of 31 patients with newly diagnosed HL, the maximum tolerated dose in combination with ABVD or AVD was not reached; no DLT was observed up to 1.2 mg/kg, the maximum planned dose. Brentuximab vedotin treatment was associated with manageable AEs; the most frequent AEs in the study were nausea and neutropenia. The safety profile observed thus far in this study suggests that brentuximab vedotin has potential for combination therapy with ABVD or AVD. Updated safety and response data will be presented at the meeting. Disclosures: Younes: Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel Expenses; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi-Aventis: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SBIO: Research Funding; Syndax: Research Funding; Celgene: Speakers Bureau; Gilead: Honoraria; Pharmacyclic: 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. Connors:Seattle Genetics, Inc.: Research Funding. Park:Seattle Genetics, Inc.: Research Funding. Hunder:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansell:Seattle Genetics, Inc.: Research Funding.

Abstract Background: Treatment of Hodgkin lymphoma (HL) requires a careful balance between providing enough therapy to cure the disease and avoiding unnecessary treatment that could result in excessive long-term treatment-related complications. The preferred treatment option for limited stage non-bulky HL currently involves the use of combined chemotherapy and involved-field radiation therapy. Given the unclear overall survival advantage and the long-term side effects associated with consolidative radiation, the use of this modality remains one of the most controversial topics in the treatment of HL. Therefore, alternative consolidation approaches are worthy of exploration for treatment of limited stage non-bulky HL. Brentuximab vedotin has been associated with favorable response rates in patients with relapsed or refractory HL. We hypothesize that brentuximab vedotin may be safe and effective in eradicating residual disease after induction chemotherapy and may potentially replace radiation therapy for consolidation in patients with newly diagnosed limited stage non-bulky HL. Methods: In this phase 2 multicenter study, patients with non-bulky (< 7.5 cm) stage I or II HL are being enrolled to determine the efficacy and safety of brentuximab vedotin when administered for consolidation after a standard chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (ClinicalTrials.gov #NCT01578967). The primary objective of the study is to estimate the proportion of patients who achieve PET-negative disease (Deauville score of 2 or less) after induction chemotherapy followed by consolidation with brentuximab vedotin. Involved-field radiation is recommended only if the PET scan is positive at the completion of therapy with brentuximab vedotin. Patients received 2 to 6 cycles of ABVD based on their baseline risk factors and the interim PET scan result; patients with favorable disease with negative interim PET received 2 cycles, favorable disease with positive interim PET or unfavorable disease with negative interim PET received 4 cycles, and unfavorable disease with positive interim PET received 6 cycles of ABVD. Approximately 6 to 8 weeks after the induction chemotherapy, 1.8 mg/kg of brentuximab vedotin was given every 3 weeks for 6 cycles for consolidation. Results: Interim analysis was performed per protocol for futility and safety after 15 evaluable patients were enrolled since April 2012. Out of 15 evaluable patients, 8 patients have completed 6 cycles of brentuximab vedotin, and the remaining 7 patients are currently under active treatment. The median age was 28 years (range 19 – 58), and 7 patients (47%) presented with unfavorable disease defined by the presence of B symptoms, ESR > 50, or > 3 sites of disease. All patients had masses measuring less than 7.5 cm in diameter except one patient who requested an exception to the eligibility criteria for a conglomerate mediastinal mass measuring 10 cm. No grade 3 or above adverse events have been observed with brentuximab vedotin therapy. No grade 2 or above peripheral neuropathy or pulmonary toxicity has been reported. Ten out of 12 patients, who completed ABVD, achieved PET-negative disease after 2 cycles of ABVD, and all 7 patients who completed brentuximab vedotin achieved PET-negative disease and remain in remission with a median follow-up of 7.6 months (range 5.6 – 15). Thus far, none of the treated patients on this protocol required consolidative radiation therapy. Conclusion: In this interim analysis of 15 patients with newly diagnosed limited stage non-bulky HL, brentuximab vedotin as consolidation therapy demonstrates promising safety and clinical activity following ABVD. Enrollment is currently open with the target accrual of 40 patients to assess the feasibility of achieving PET-negative disease and thereby avoiding radiation therapy in at least 85% of patients who receive ABVD followed by brentuximab vedotin consolidation. Table: PET results in HL patients who received ABVD followed by BV Consolidation Interim-PET2 (n = 12) Post ABVD (n = 12) Post BV (n = 7) Deauville 1 0 1 4 Deauville 2 10 11 3 Deauville 3 2 0 0 Deauville ≥ 4 0 0 0 PET, positron emission tomography; HL, Hodgkin lymphoma; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BV, brentuximab vedotin; Interim-PET-2, PET scan after 2 cycles of ABVD; Post ABVD, PET scan after 2 to 6 cycles of ABVD; Post BV, PET scan after 6 cycles of brentuximab vedotin Disclosures Park: Seattle Genetics: Research Funding; Teva: Research Funding; Janssen: Travel, Travel Other. Off Label Use: Brentuximab vedotin in previously untreated Hodgkin lymphoma patients.

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.