Key Points• BV and AVD followed by ISRT is well tolerated, without significant pulmonary toxicity. • BV and AVD followed by ISRT is an effective therapy for unfavorable-risk early stage HL, including bulky disease.This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD.Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV 1 AVD, and 25 patients BV 1 AVD 1 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events ( ‡grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV 1 AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV 1 AVD 1 ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients ( ‡90%) achieved negative interim PET scans after 2 and 4 cycles of BV 1 AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was

Introduction: Limited information exists on the best treatment strategy for Primary Refractory (ref) Hodgkin Lymphoma (HL). For the past 20 years, we have treated patients (pts) on sequential ifosfamide, carboplatin, etoposide (ICE)-based clinical trials with the intent to undergo high dose therapy (HDT) and autologous stem cell transplantation (ASCT). As previously reported (Moskowitz, Blood 2010) and confirmed by other centers, a negative PET scan prior to ASCT predicts for marked improvement in outcome in pts with relapsed HL. We aimed to identify risk factors that predict PET response to salvage chemotherapy in ref HL and evaluate outcomes following HDT and ASCT in this patient population. Methods: From 10/1/94 to 7/10/15, 192 ref HL pts were treated on sequential trials at MSKCC. Demographic and clinical factors were collected. Event free survival (EFS) and overall survival (OS) were calculated from the date of histologic confirmation of ref disease, estimated by Kaplan-Meier method, and compared by the log rank test. Events included relapse or death. Cox regression was used for the multivariate regression model. Patients were selected to receive a radiation-based conditioning regimen if all sites of nodal disease could be encompassed into a radiation field. Results: Patient characteristics included a median age of 31 (range 14-79) with 54% female. B symptoms, extranodal disease, stage IV disease, and disease bulk > 5cm were present in 31%, 48%, 44%, 40%, respectively. In the intent-to-treat (ITT) population, 41% had a positive post-salvage PET scan. As analyzed by ITT, median EFS was 8.9 years with a median OS of 10.4 years. On multivariate analysis, the presence of B symptoms and bulk >5cm at documentation of ref disease predicted for a reduced chance of achieving a negative PET after salvage therapy, with an odds ratio (OR) of 2.03 for B symptoms and 2.13 for bulk >5cm. For the 169 (88%) transplanted patients, 68% had a negative pre-ASCT PET. Radiation based conditioning was used for 70% of the pts. Median EFS was 12.8 yrs and median OS was not reached with a median follow-up of 3.6 yrs (range, 0.55 to 18.04 yrs) for the surviving patients (Figure 1). On multivariate analysis, both stage (IV vs I-III) and persistent PET abnormality pre- ASCT correlated with a shorter EFS. A risk stratification model was created and pts could be divided into 4 groups. 1) stage I-III disease and a negative PET pre-ASCT, the median EFS was not reached; 2) stage I-III disease and a positive PET pre-ASCT scan-the OR of an event was 4.04 (95% CI 1.93 to 8.45) with the median EFS not reached, 3) Stage IV disease and a negative PET pre-ASCT, the OR was 3.78 (95% CI 1.64 - 8.74) with a median EFS of 8.9 yrs, 4) Stage IV disease and a positive PET pre-ASCT, the OR was 8.22 (95% CI 3.99 to 16.94) with a median EFS of 0.9 yrs (Figure 2). Conclusions: B symptoms and bulk >5cm predicted for residual PET avidity after salvage therapy in ref HL. Persistent PET abnormality pre-ASCT and stage were risk factors for earlier relapse and death and can be used to prognosticate survival. Further studies are needed to determine optimal therapy for patients with multiple risk factors. Figure 1. EFS for the Transplanted Patients Figure 1. EFS for the Transplanted Patients Figure 2. EFS for the transplanted pts based on the presence of risk factors (PET avidity pre-HSCT and Stage) Figure 2. EFS for the transplanted pts based on the presence of risk factors (PET avidity pre-HSCT and Stage) Disclosures Moskowitz: GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Summary We aimed to identify risk factors that predict functional imaging (FI) response to salvage chemotherapy and evaluate outcomes following autologous stem cell transplant (ASCT) in primary refractory Hodgkin Lymphoma (HL). From 1 October 1994 to 10 July 2015, 192 primary refractory HL patients were treated on sequential second line protocols. Event-free survival (EFS) and overall survival (OS) were calculated from the date of histological confirmation of refractory disease. Covariates were analysed for relationship with FI response and EFS. By intent-to-treat, the median EFS was 8·9 years and OS 10·4 years with 41% having positive post-salvage FI. On multivariate analysis, the presence of B symptoms and bulk ≥5 cm predicted for positive FI, with odds ratios of 2·15 and 2·03, respectively. For the 167 (87%) transplanted patients, 60% had a negative pre-ASCT FI. Median EFS and OS were not reached with at a median follow-up of 3·6 years in surviving patients. Both stage IV refractory disease and persistent FI abnormality pre-ASCT were associated with worse outcomes: 3-year EFS was 84%, 54% and 28% for zero, 1 and 2 risk factors, respectively (P < 0·001). Further studies are needed to validate our prognostic model and to determine optimal therapy for patients with multiple risk factors.

Background: Brentuximab vedotin has not been previously studied in combination with combined modality therapy for the frontline treatment of early stage Hodgkin lymphoma. We designed a pilot study to assess the safety and early efficacy of four cycles of brentuximab vedotin (BV) + AVD chemotherapy followed by 30 Gray involved-site radiotherapy (ISRT) for the treatment for early stage, unfavorable risk HL. Methods: Patients with newly diagnosed, stage I/II, classical HL with unfavorable risk profile (defined by the German Hodgkin Study Group (GHSG) with one of the following criteria: bulky mediastinal mass (≥1/3 maximum transverse thoracic diameter on PA-CXR or ≥10cm by CT imaging in transaxial plane), ESR≥50mm/h or ESR≥30mm/h in patients with “B” symptoms, extranodal involvement, or >2 involved lymph node sites) were eligible. Patients with stage IIB disease with disease bulk or extranodal involvement were included (conventionally classified as advanced stage per GHSG). Patients were treated with four cycles of brentuximab vedotin 1.2 mg/kg with AVD chemotherapy every 2 weeks followed by 30 Gray involved-site radiotherapy. The primary endpoint of the study was to evaluate the safety of this regimen, with particular attention to the development of pulmonary toxicity. A PET/CT was performed after 2 and 4 cycles of therapy. PET scans were interpreted using the Deauville 5-point scale and a negative scan was defined as Deauville 1-3. Results: Interim data for the first 19 of a planned 30 patients enrolled are presented here. Median age was 32 (range, 18-50), 47% female, 100% stage II disease, 53% with disease bulk by GHSG criteria, 53% elevated ESR, 34% B-symptoms, 37% extranodal involvement, 42% >2 involved lymph node sites. All patients with disease bulk had large anterior mediastinal masses measuring >10cm by CT in transverse plane (range, 10-16.9 cm). There were eight patients enrolled who would be considered to have advanced stage disease by the GHSG classification: 3 with IIBX, 3 with IIBE, and 2 with IIBXE disease. To date, 79% (15/19) and 63% (12/19) have completed interim PET-2 and PET-4 imaging studies, respectively. Ninety-three percent of patients (14/15) achieved a negative PET scan after 2 cycles (6, 8, and 1 patients achieved Deauville score of 2, 3, 4, respectively). All patients with disease bulk were PET-2 negative (10/10). Ninety-two percent of patients achieved a negative PET scan after 4 cycles of therapy (1, 8, 2, and 1 patients achieved Deauville score of 1,2,3,4, respectively). The patient with a positive PET-4 scan had a subsequent positive biopsy and will be treated off study for primary refractory HL. The study treatment has been well-tolerated. No pulmonary toxicity has been observed. Serious adverse events have been documented in two patients: febrile neutropenia and grade 3 hypertension. One patient discontinued protocol treatment due to the development of grade 3 peripheral neuropathy after one treatment with BV+AVD. The four patients who have completed combined modality therapy and an end-of-treatment imaging assessment achieved complete responses and no relapses have occurred to date. Conclusion: The combination of BV+AVD chemotherapy followed by ISRT appears well-tolerated with no early signal of increased pulmonary toxicity. In this interim analysis of 19 newly diagnosed patients with early stage, unfavorable risk HL, over ninety percent of the evaluable patients have achieved negative interim PET scans after 2 and 4 cycles of BV + AVD, suggesting this is a highly active treatment program even in patients with substantial disease bulk. Updated safety and response data will be presented at the meeting. Disclosures Hamlin: Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding; Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol Myers Squibb,: Consultancy; Jannsen: Consultancy. Matasar:Genentech: Consultancy; Spectrum: Consultancy. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding.

Background: In the post-rituximab era, half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response with standard salvage therapy, and are thus ineligible to proceed to consolidative autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, predominately of the non-germinal center B-cell (non-GCB) phenotype, with minimal toxicity. This single center, NCI-CTEP sponsored phase I study is the first to evaluate the combination of ibrutinib with standard salvage therapy of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in transplant-eligible rel/ref DLBCL patients. Methods: Patients with rel/ref DLBCL, including transformed B-cell non-Hodgkin lymphoma, are eligible for study. The phase I study design is a standard 3 x 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine safety and the maximum tolerated dose (MTD) of ibrutinib in combination with R-ICE. Secondary objectives include response rate according to computed tomography (CT) and functional imaging (FDG-PET) per Deauville criteria. Results: To date, 16 patients are evaluable for toxicity, and 15 are evaluable for response. The median age of the 16 evaluable patients is 51 years (range 19-75 years). Histologies of the patients evaluable for response are: GCB DLBCL n=3, non-GCB DLBCL n=4, primary mediastinal large B-cell lymphoma n=4, and transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (tCLL/SLL) n=4. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n=3), 2 (n=3), or 3 (n=10, currently in expansion). Of the 16 patients evaluable for toxicity, 15 experienced expected and transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. The median number of cumulative platelet transfusions per patient for 3 cycles was 2 (range 0-11). Eleven of the 15 patients evaluable for response underwent chemotherapy-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 10 of the 11 patients successfully collected HPCs with a median of 5.6 x 106CD34+/kg (range 1.7-8.6). The only patient that failed to collect HPCs was an HIV-positive patient at DL #3 in the setting of febrile illness. One patient experienced grade 3 atrial fibrillation/flutter and was subsequently removed from study per treating physician's decision. Per CT criteria, five patients achieved complete remission (CR), eight patients achieved partial remission (PR), and two patients had stable disease for an overall response rate of 87%. All eight patients with non-GCB DLBCL and tCLL/SLL that were evaluable for response achieved chemosensitive remission per CT criteria (CR=4, PR=4). Seven of the 15 total patients (47%) evaluable for response achieved a complete metabolic remission (Deauville 1-3) per FDG-PET, including all 4 patients of non-GCB phenotype. Conclusions: Currently, no DLTs have been observed with ibrutinib at dosing up to 840 mg daily in combination with R-ICE. We are currently expanding DL #3. Manageable and expected hematologic toxicities have been observed. Importantly, hematologic toxicity has not resulted in failure to complete protocol therapy on-schedule or mobilize HPCs. Encouragingly, 87% of patients achieved a CT response (CR/PR) and 47% of patients achieved a complete metabolic remission per FDG-PET, including 100% of patients with non-GCB phenotype. These results compare favorably to historic cohorts. Given the safety and efficacy observed in this phase I, later phase studies for this treatment program are warranted. Disclosures No relevant conflicts of interest to declare.