ALBERT

Description: Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.

Description: Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL. Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR. Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed. Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. Table Preliminary findings form the Window Study: a phase II clinical trial Table. Preliminary findings form the Window Study: a phase II clinical trial Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.

Description: Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. In preclinical studies, we have shown the synergistic anti-tumor effect of combining lenalidomide with anti-CD20 molecules. (Wang 2007) The combination of rituximab and lenalidomide (R2) in relapsed and untreated iNHL is highly active. (Fowler 2014) We hypothesize these responses are related to augmentation of immune response and ADCC through alteration of immune cell subsets in tumor and peripheral blood. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this study was to determine the safety and maximum tolerated dose of lenalidomide and obinutuzumab in patients with relapsed/refractory iNHL. Methods: Patients with relapsed SLL, marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles. All patients received prophylactic steroids prior to obinutuzumab. In the absence of toxicity or progression, the combination was continued for up to 12 cycles. The standard '3+3' design was used with dose limiting toxicities (DLT) assessed during cycle 1. Patients attaining ≥partial response continued obinutuzumab every 2 months for up to 24 months. Prophylactic growth factors were not used. Adverse events were graded using CTCAE version 4.03. Results: 15 patients ( 9 during dose escalation, 6 during dose expansion at target dose) were enrolled; all were evaluated for safety and efficacy (all having had at least 1 post-baseline response assessment). The median age was 60 (36-82) years, and 7 (47%) were male. 21% of patients with follicular lymphoma had low, 29% intermediate, and 50% high FLIPI scores at study entry, 1 patient had SLL. No DLTs were observed during dose escalation. The most common grade 1-2 non-hematologic toxicities were fatigue 12/15 (80%), constipation 9/15 (60%), diarrhea 7/15 (47%), dyspnea 7/15 (47%), and myalgia 7/15 (47%). Grade ≥ 3 events included neutropenia (n=3, 20%), infection (n=2, 13%),thrombocytopenia (n=1, 6%), and two infusion related reactions (13%), both occurring during the first infusion of obinutuzumab. With a median follow up of 8.2 (4.1-14 mo), the overall response rate was 93% with 27% (4/15) achieving a complete response and 67% (10/15) with a partial response, all responding patients remain on active therapy. One patient progressed after 8 months and was withdrawn from study. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinatuzumab is safe and effective in patients with relapsed iNHL. Adverse events appeared similar to our prior experience with lenalidomide and rituximab. Overall response rates were high, with complete responses increasing with prolonged duration of therapy. Correlative efforts are ongoing to study the immunomodulatory potential of the combination and to identify biomarkers of response. The phase II portion of this study is currently enrolling with dose expansions in relapsed iNHL. Disclosures Off Label Use: Lenalidomide off label in low grade lymphoma Obinutuzumab off label in low grade lymphoma. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Nastoupil:Celgene: Honoraria; Janssen: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria.

Description: Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. As the incidence of DLBCL increases with age, the number of elderly patients with DLBCL in our aging society continues to increase. However, patients aged ≥ 80 years old are often frail and carry multiple comorbidities, and are generally underrepresented in prospective clinical trials. Patients and Methods: 207 patients, age ≥80 years of age at diagnosis of de novo DLBCL were identified between 2002 and 2014 at MD Anderson Cancer Center and included in this retrospective analysis. Failure-free survival (FFS) and overall survival (OS) were examined; baseline characteristics and frontline therapy were evaluated for the association with survival outcomes by hazard ratio (HR). Results: Median age was 83 years (range 80-96). Fifty-five percent of the patients were male, 66% had advanced stage and 37% had poor performance status (ECOG PS≥2). Forty-five percent of the patients were IPI high-intermediate or high risk. Eighty patients (39%) were GCB and 49 patients (24%) were non-GCB subtype, respectively, according to the Hans criteria, with 78 patients lacking data for classification. Thirty-two patients (15%) had ≥4 scores by Charlson comorbidity index (CCI, Charlson 1987). Treatment received included R-CHOP (n=144, 70%), R-EPOCH (n=12, 6%), and non-anthracycline based therapies including R-CEOP and R-CVP (n=20, 10%). Sixteen patients (8%) did not receive any treatment due to deteriorated condition or patient's decision. Fifteen patients received other treatment such as radiation and rituximab monotherapy. With a median follow up of 38.1 months, 88 patients (43%) experienced progression/relapse and 123 patients (59%) died. Sixty-two patients (50%) died of lymphoma, 32 patients (26%) died of other co-morbid conditions while in remission and 17 patients (14%) died as a result of treatment complication during frontline therapy. Thirteen patients died during R-CHOP, 2 patients each died during R-CEOP or R-CVP and R-EPOCH, respectively, most were the result of infection or multi-organ failure. The 3-year FFS and OS were 55% and 54%, respectively. After 3-years, almost all deaths were attributed to other diseases (Figure A). Patients who received R-CHOP or R-EPOCH had a significantly longer FFS than patients who received R-CEOP or R-CVP (Figure B). CCI ≥4 was not associated with inferior FFS but was significantly associated with inferior OS. Multivariate analysis for OS adjusted by IPI and frontline treatment revealed that being female was associated with significantly longer OS (HR: 0.50, 95% CI, 0.33-0.75, p2.0mg/l had significantly inferior OS (HR: 7.21, 95% CI, 1.67-31.1, p=0.01). Conclusion: Patients with DLBCL aged ≥80 years who received anthracycline-based regimens such as R-CHOP or R-EPOCH had outcomes similar to younger patients with de novo DLBCL. Although they carry higher risks of therapy-related mortality, anthracycline-based regimens are moderately well tolerated, and their use should not be minimized based solely on age. Inclusion of very elderly patients in prospective clinical trials is warranted to identify the most effective management strategy for this population. Figure 1. Figure 1. Disclosures Westin: Spectrum: Research Funding. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Rodriguez:Orthobiotech: Research Funding. Wang:Celgene: Research Funding. Nastoupil:AbbVie: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria; Celgene: Honoraria; Janssen: Research Funding.

Description: Background: CNS relapse is a rare but fatal complication of patients with peripheral T-cell lymphoma (PTCL). Several large studies have identified risk factors for CNS relapse in PTCL, such as elevated serum lactate dehydrogenase (LDH), 〉1 extranodal sites of involvement and high International Prognostic Index (IPI) score. We performed an analysis of histologic type of PTCL to identify additional risk factors for CNS relapse. Patients and Methods: A total of 616 patients with PTCL diagnosed between 1999 and 2014 were analyzed retrospectively including: 174 not otherwise specified (NOS), 144 angoimmunoblastic T-cell lymphoma (AITL), 76 ALK+ anaplastic large cell lymphoma (ALCL), 103 ALK-ALCL, 55 nasal type T/NK cell lymphoma (NK/T), 23 hepatopslenic T-cell lymphoma (HSTL), 16 enteropathy-type T-cell lymphoma (EATL), 13 adult T-cell leukemia/lymphoma (ATLL), and 12 subcutaneous panniculitis-like T-cell lymphoma (SPTL). Patients with CNS involvement at diagnosis (n=15) were excluded from this study. Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes by hazard ratio (HR). Cumulative incidence of CNS relapse was calculated by competing risk (death without CNS relapse) regression analysis. Results: The median age of the patients was 56 years (range, 17-93 years). With a median follow up of 57 months, 15 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 NK/T, and 2 ATLL) experienced CNS relapse, and 321 patients (52%) died without having had CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.8% (95%CI: 1.0-3.1%), 2.4% (95%CI: 1.3-3.8%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.3% in ALK+ALCL, 2.1% in ALK-ALCL and 3.6% in NK/T (Figure). All patients with CNS relapse eventually died, with median OS duration from CNS relapse of 1.6 months. Extranodal sites of involvement 〉1 (HR: 6.0, 95%CI: 2.0-17.4) and higher IPI score (HR: 1.8, 95%CI: 1.1-3.1, by one increase in IPI score) were risk factors of CNS relapse by univariate analysis. ALK+ALCL patients who had 〉 1 extranodal site of involvement (N=19) had very high risk of CNS relapse with one year cumulative incidence of 15% (95%CI: 3.7%-33.5%), with all occurring within six months after diagnosis. Summary: CNS relapse in patients with PTCL is rare as reported previously. However, the risk varies by histologic type. Specifically ALK+ALCL patients with 〉 1 extranodal site of involvement have a very high risk of CNS relapse in early phase of treatment, and CNS evaluation at the time of diagnosis and possibly CNS targeted prophylaxis may be appropriate. Figure Figure. Disclosures Westin: ProNAi: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fayad:Seattle Genetics: Consultancy, Research Funding. Wang:BeiGene: Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Dava Oncology: Honoraria; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; Juno Therapeutics: Research Funding. Fowler:Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Infinity: Consultancy, Research Funding; TG Therapeutics: Consultancy. Oki:Novartis: Research Funding.

Description: INTRODUCTION: More active high-dose regimens are needed for refractory or poor-risk relapsed non-Hodgkin's (NHL) and Hodgkin's lymphomas (HL), where standard BEAM offers unsatisfactory results. We previously developed a regimen of infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel), pursuing the inhibition by gemcitabine of DNA damage repair (Nieto et al, BBMT 2012). Since vorinostat induces chromatin relaxation and facilitates access of chemotherapy to DNA, we combined it with Gem/Bu/Mel, which resulted in a safe and markedly synergistic regimen (Nieto et al, BBMT 2015). Still, the addition of vorinostat to GemBuMel induced upregulation of DNA methyltransferase (DNMT) in lymphoma cells, which could be abrogated preclinically by azacitidine, further increasing tumor-cell kill (Valdez et al, Exp Hematol 2012). These observations led us to study the clinical combination of azacitidine with vorinostat/Gem/Bu/Mel. METHODS: Patients ages 12-65 with refractory or poor-risk relapsed lymphomas and adequate end-organ function were eligible. Azacitidine was given on days -8 to -3 at 15-35 mg/m2/day IV (levels 1-3), followed by vorinostat (1,000 mg PO daily, days -8 to -3), gemcitabine (loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 4.5 hours, days -8 and -3), busulfan (target daily AUC of 4,000, days -8 to -5) and melphalan (60 mg/m2/day, days -3 and -2). ASCT was on day 0. Patients with CD20+ tumors received rituximab (375 mg/m2) on day -9. Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting 〉3 days at peak severity. Dose escalation of azacitidine followed a Bayesian design targeting a maximal DLT probability of 25%. We assessed DNMT-3B levels by Western blot in peripheral blood mononuclear cells drawn at baseline and days -5 and -1 in 8 patients treated at the MTD. RESULTS: Between 11/13 and 6/15, 60 patients were enrolled: 25 DLBCL (10 double hit), 21 HL, 8 T-NHL (3 PTCL, 2 ALCL, 1 AITL, 1 NK/T, 1 panniculitis-like), 4 follicular NHL and 2 mantle cell (Table 1). Table 1. Patient population. Median age (range) 41 (16-65) Primary induction failure / high-risk/refractory relapse 28% / 62% Bulky lesions at relapse/PD 58% Secondary IPI (DLBCL): 0-1 / 〉1 44% / 56% LDH at relapse/PD (DLBCL): High / Normal 50% / 50% Median # prior chemotherapy lines (range) 3 (2-7) Prior xRT 17% PET+ at HDC 32% Status at HDC: 68% CR, 25% PR, 7% unresponsive Patients were treated at levels 1-3, with the MTD of azacitidine established at level 1 (15 mg/m2/day). The DLT was mucositis, observed at the following frequencies: level 1 (N=37): 16%, level 2 (N=18): 28%, level 3 (N=5): 40%. One patient died from early RSV pneumonia at level 3. The toxicity profile at the MTD was manageable: mucositis (40% G2, 32% G3), self-limited transaminitis (16% G2, 16% G3), self-limited elevation of bilirubin not associated with VOD (19% G2, 22% G3) and dermatitis (13% G2). There were no cardiac, pulmonary, renal or CNS toxicities. Neutrophils and platelets engrafted promptly at median days +9 (7-11) and +12 (8-64), respectively. This toxicity profile is identical to the one seen with Gem/Bu/Mel and vorinostat/Gem/Bu/Mel. DNMT-3B levels in PBMNC decreased from baseline to day -1 by a median 58% (19-80%) in 7/8 pts. Response assessment and patient outcomes at median follow-up of 11 months (2-21) at are shown on Table 2 and Figures: Table 2. Activity/outcomes. ORR CR % EFS % OS DLBCL 78% 44% 68% 86% HL 86% 86% 81% 100% T-NHL 100% 100% 87.5% 87.5% CONCLUSIONS: Azacitidine/vorinostat/Gem/Bu/Mel is feasible, with no increased toxicities compared to Gem/Bu/Mel ± vorinostat, and highly active in refractory or poor-risk relapsed HL and NHL. This regimen warrants further study. Figure 1. Figure 1. Disclosures Off Label Use: Azacitidine, vorinostat, gemcitabine, busulfan, melphalan: Use at high doses for lymphoma. . Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

Description: INTRODUCTION: More active high-dose regimens are needed for refractory or poor-risk relapsed Hodgkin's lymphomas (HL), where BEAM offers poor results. Post-BEAM maintenance treatment with brentuximab vedotin (BV) x 48 weeks has recently been shown in the AETHERA trial to prolong progression-free survival (PFS) compared to placebo (2-year PFS 63% vs. 51%). We previously developed a regimen of infusional gemcitabine combined with busulfan and melphalan (Gem/Bu/Mel) pursuing inhibition by Gem of DNA damage repair. The encouraging results we saw in HL patients led us to conduct a phase 2 trial of Gem/Bu/Mel in HL patients at high risk of post-ASCT relapse. METHODS: HL patients ages 12-65 with ≥1 of the following criteria were eligible: Persistent active disease after 1st-line chemotherapy, CR1 〈 1 year, or extranodal disease at relapse/PD. Gem was administered as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 4.5 hours on days -8 and -3 (total daily dose of 2,775 mg/m2). Each Gem infusion was immediately followed by the corresponding dose of Bu or Mel. Bu was administered intravenously from days-8 to -5 targeting a daily AUC of 4,000. Mel was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Post-HDC involved field radiotherapy (IFRT) was considered to lesions 〉5 cm at the time of HDC or persistently PET+ at the 1-month post-HDC evaluation. The trial had 80% power to detect a 2-year PFS increase from 50% to 65%.The concurrent BEAM cohort included all patients eligible for this trial who received BEAM off study due to no financial coverage for ASCT in a trial or patient/physician preference. RESULTS: Eighty patients were enrolled on study between 6/11-04/15 (Table 1). There was no transplant-related mortality (TRM). The toxicity profile was manageable, including mucositis (49% G2, 40% G3), skin (22% G2, 11% G3), self-limited transaminase elevation (30% G2, 19% G3), and hyperbilirubinemia (24% G2, 19% G3) with no cases of VOD. There was 1 case of G2 pneumonitis and none of cardiac, renal or CNS toxicity. Neutrophils and platelets engrafted at median days +10 (8-12) and +12 (9-21), respectively. Eight patients received post-HDC IFRT to mediastinum ± neck ± sternum at 30.6-39.6 Gy, starting on median day +42 (41-53) post-HDC, which was well tolerated. No patients received maintenance BV. Table 1. Patient characteristics Variable Study file (N=80) Concurrent BEAM cohort (N=31) P Median age (range) 31 (13-65) 39 (23-65) 0.02 Primary refractory / poor-risk relapse 41% / 59% 37% / 63% 0.6 # prior relapses 1 80% 70% 0.3 〉1 20% 30% Median # prior chemotherapy lines (range) 2 (2-6) 2 (2-7) 0.3 Prior disease-free interval (months) 12 20% 23% Prior xRT 21% 27% 0.6 Relapse within prior xRT field 10% 3% 0.4 Extranodal relapse/PD 36% 53% 0.08 B symptoms at relapse/PD 11% 10% 0.8 Bulky relapse (any lesion 〉5 cm) 39% 17% 0.02 # risk factors (primary refract/CR11 relapse 50% 73% 0.08 B symptoms 55.6% 70.4% 0.2 Bulky relapse 67% 72% 0.2 Extranodal 67% 72% 0.4 The BEAM cohort included 31 patients treated between 06/11-04/15 (Table 1) with no BV maintenance. There were fewer cases of PET+ tumors at HDC (P=0.003) and of bulky relapses (P=0.02) than the Gem/Bu/Mel file, but was matched for the other risk factors. It had no TRM. Despite a higher number of PET+ tumors at HDC, the Gem/Bu/Mel file had significantly superior 2-year PFS (65% vs. 51%, P=0.03) and 2-year OS (95.5% vs. 70%, P=0.001) than the BEAM cohort. CONCLUSIONS: Gem/Bu/Mel without maintenance BV was safe and effective in patients with refractory or poor-risk relapsed HL, with comparable results to those from the AETHERA trial using BEAM and maintenance BV. A randomized trial is necessary to compare Gem/Bu/Mel and BEAM. Figure 1. Figure 1. Disclosures Off Label Use: Gemcitabine, busulfan and melphalan are not FDA approved at high doses for Hodgkin's lymphoma. Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

Description: Background: We have previously reported the favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), grade 3 follicular lymphoma (FLG3) and transformed lymphoma (TL) (Wang et al, Leukemia 2013). Here we report results of the final data analysis of this phase 2 trial after an extended follow-up. Methods: Patients with R/R DLBCL, FLG3 and TL were enrolled in this single arm trial. Lenalidomide (20 mg daily) was administered orally on days 1-21 of each 28-day cycle, and rituximab (375 mg/m2 weekly) was administered intravenously during the first cycle only. Treatment was continued with dose-reduction allowance until disease progression, stem-cell transplantation or severe toxicity. The primary endpoint was overall response rate (ORR), and the secondary endpoint was survival. Analysis was by intention to treat. Results: In total, 45 patients were enrolled, with 32 DLBCL, 4 FLG3 and 9 TL. 29 were male and 16 were female. The median age was 66 years (range 23-84). Median ECOG PS was 1 (range 0-3). 41 patients (91.1%) were stage 3-4. Median number of prior lines of therapy was 3 (range 1-4). The median follow-up time was 9.8 months (range 0.8-77.7). Overall, 10 patients (22.2%) achieved CR, and 5 patients (11.1%) achieved PR, with an ORR of 33.3%. An additional 11 patients (24.4%) achieved SD. The ORR was 28.1% for DLBCL, 25.0% for FLG3, and 55.6% for TL. In Chi-square test, lower IPI score (0-2) was associated with higher ORR (P = 0.043). Patients with fewer prior lines of therapy tended to respond better (P = 0.118). In multivariate logistic regression, lower IPI was predictive of better ORR (P = 0.023). Median time to initial and best response was 1.8 months (range 0.8-2.1) and 1.8 months (range 0.8-20.1), respectively. Median duration of response was 10.2 months (95% CI 0.0-24.7). The median progression-free survival (PFS) was 3.7 months (95% CI 1.8-5.6), and the median overall survival (OS) was 10.8 months (95% CI 6.5-15.1). The 6- and 12-month PFS rates were 22.5% and 11.3%, respectively. The 1-, 2- and 5-year OS rates were 43.5%, 38.9% and 15.4%, respectively. Median OS was 50.3 months (95% CI 42.8-57.8) in responders and 6.6 months (95% CI 4.0-9.1) in non-responders (P 〈 0.001). In multivariate Cox regression, lower IPI was significantly predictive of longer OS (HR = 0.323, 95% CI = 0.157-0.668, P = 0.002) and showed a clear trend in predicting longer PFS (HR = 0.495, 95% CI 0.234-1.048, P = 0.066). Gender, Ki67 at registration and number of prior lines of therapy were not predictive of PFS or OS. Conclusions: Lenalidomide plus rituximab is an efficacious treatment regimen for relapsed or refractory aggressive B-cell lymphoma. IPI is strongly predictive of ORR and OS in this setting. Ki-67 and number of prior lines of therapy are not predictive of ORR, PFS or OS. Disclosures Neelapu: Celgene: Consultancy, Research Funding. Shah:Celgene: Consultancy, Research Funding. Thomoas:Celgene: Research Funding. Wang:Celgene: Research Funding.

Description: Purpose: We assessed the survival outcome of patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of recently approved drugs (pralatrexate and romidepsin) in these patients. Patients and Methods: A total of 321 patients (180 PTCL-NOS, 141 AITL) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OSP2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the histopathologic subtype focusing on the use of new drugs. Results: The median age of the patients was 60 (range: 20-83). With a median follow up of 52 months, 240 patients (135 PTCL-NOS, 105 AITL) experienced progression/relapse after the first-line therapy, of whom 17 were post upfront stem cell transplant (SCT). A total of 54 patients received pralatrexate (n=41) and/or romidepsin (n=26); in 1st salvage in 9 and 17 patients, and after 2nd salvage in 17, 24 patients, respectively (13 patients received both). Thirty-three and 28 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. Three patients received both auto and allogeneic SCT. In patients with PTCL-NOS, the median PFS1, PFS2 and PFS3 were 8.4, 3.1 and 2.5 months, respectively (Figure). The median OS1, OS2 and OS3 were 28.5, 10.9 and 7.0 months, respectively. In patients with AITL, the median PFS1, PFS2 and PFS3 were 13.1, 10.9 and 2.4 months, respectively (Figure). The median OS1, OS2 and OS3 were 47.7, 15.1 and 8.1 months, respectively. Use of pralatrexate or romidepsin at the 1st or after 2nd salvage therapy were not associated with longer PFS2 or PFS3, but, the patients who received pralatrexate at some point during therapy had significantly longer OS than who did not in patients with PTCL-NOS (median OS2: 8.5 vs 31.1 months), which however should be interpreted with caution as use of pralatrexate may be the consequence, not the cause, of longer survival. Multivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of romidepsin at any time during the treatment was associated with significantly longer OS2 in patients with PTCL-NOS (HR: 0.51, 95%CI: 0.28-0.93). Use of pralatrexate or romidepsin after relapse were not associated with longer PFS or OS in the patients with AITL. Summary: Survival outcome for relapsed/refractory patients with relapsed/refractory PTCL-NOS and AITL remains poor. However, newer targetes agents may have potential to prolong survival in relapsed/refractory patients with PTCL-NOS. Caution is needed, however, in interpretation of this result due to the retrospective nature of the analysis. Further analyses are urgently needed to investigate the role of the use of newer agents at earlier lines of therapy to improve the survival outcome. Figure 1. Figure 1. Disclosures Westin: Spectrum: Research Funding. Nastoupil:Janssen: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Genentech: Honoraria; Celgene: Honoraria. Wang:Celgene: Research Funding.

Description: Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma