Abstract: MCL is incurable. Bortezomib has shown single agent activity of 33% in relapsed MCL. Pre-clinical published data shows additive/synergistic activity of BCR. Materials and methods   MCL pts  ages 18 through 85, with adequate organ function unless due to lymphoma, and without HIV-1 infection or any significant medical/mental condition, were treated under an IRB-approved study, consisting of Bortezomib  1.3 mg/m2 IV given on days 1, 4, 8, and 11 (dose on day 11 omitted early on study); fractionated cyclophosphamide 300 mg/m2 q 12 hrs days 1, 2, and 3, and rituximab 375 mg/m2 day 1. Cycles were repeated every 21 days for a total of 6 or less if a response was achieved and patient qualified for SCT. Results From  9/2009 to 8/2012, twenty-one patients were entered in the study. Their clinical characteristics are as follows: Overall response (OR)/CR rates:  71%/53%. One patient had stable disease and 4 patients progressed. With a Median follow-up of 31 months, the median TTP was 15.8 months and the median OS was 36.4 months. Toxicity was mainly hematologic. With 77 cycles given, grade 3 anemia was 5%, grade 3 / 4 neutropenia was 16%/9%, and grade 3 / 4 thrombocytopenia was 19%/8%. Early in the study, day 11 dose of bortezomib was omitted because of low counts by day 11 of cycle. Non-hematologic toxicity included grade 3 neutropenic fever (1%), and grade 3 fatigue (3%). No patient developed sensory neuropathy grade ¾. Conclusion Bortezomib can be safely combined with cyclophosphamide and rituximab and results in high rates of overall/complete responses in patients with relapsed/refractory MCL. Disclosures: Off Label Use: Gemcitabine, fludarabine and melphalan for transplant conditioning. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other.

Abstract: Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking. Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP. Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was 〉 1 in 2%, and 〉 1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease ( 〉 7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values 〉 3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%). Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.

Abstract: Introduction. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Elevated biomarkers, such as ferritin and LDH, have been shown to correlate with more severe toxicity. The endothelial activation and stress index (EASIX) is a surrogate of endothelial activation, and correlates to other biomarkers of endothelial dysfunction. In allogeneic hematopoietic cell transplantation (HCT), it is predictive of toxicity such as fluid overload, which is correlative with endothelial dysfunction, as well as sinusoidal obstruction syndrome, non relapse mortality and overall survival (Luft et al, BMT 2019, Varma et al, BBMT, 2020, Jiang et al, Haematologica, 2020). In this study we describe the correlation of EASIX to CAR T cell related CRS and ICANS. Methods. Retrospective data from consecutive patients treated with standard of care axi-cel for non-Hodgkin's lymphoma at MD Anderson Cancer Center between January 2018 and April 2020 were included in the study. CRS and ICANS were graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018), and after 5/2019, according to the ASTCT criteria (Lee et al, BBMT, 2019). EASIX parameters were recorded prior to lymphodepletion (the latest value on days -12 to -6) and were available for all 171 patients. The score was defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (10^9 cells per L), with LDH adjusted to the upper limit of normal. Predictors of toxicity were evaluated using Fine and Grey regression analysis considering death before grade 2-4 toxicity as a competing risk. Results. 171 consecutive patients treated with commercial axi-cel for diffuse large B cell lymphoma (n=133), transformed follicular lymphoma (n=28) and primary mediastinal lymphoma (n=10) were included in the study. Median age was 59 years (range, 18-85), and 120 (70%) were male. 151 patients had an ECOG performance status ≤1, 45 patients (26%) had a previous autologous HCT, and 3 (1.8%) had a previous allogeneic HCT. Prior to lymphodepletion, 96 (56%) patients had a high IPI score (≥3) and 134 (78%) were refractory to the previous line of treatment. With a median follow-up of 259 days (range: 25-800) since infusion, ICANS of any grade was noted in 109 (64%) patients, with 84 (49%) having grades 2-4. CRS of any grade was observed in 160 (93%) patients, with 81 (47%) having grades 2-4 CRS. A total of 56 (33%) patients were diagnosed with grade 2-4 ICANS and CRS. The median EASIX score for the entire cohort was 2.1 (range: 0.3-283; inter-quartiles: 1.1 and 4.6). On univariate analysis, EASIX levels above the median were associated with higher cumulative incidence (CI) of grade 2-4 ICANS (% CI: 61 vs 31%; HR=2.4, p & lt;0.001); and levels above the upper quartile were associated with grade 2-4 CRS (% CI: 71 vs 38%; HR=2.2, p=0.02), (Figure 1,2). Additional predictors of grade 2-4 toxicity included IPI score ≥3 (HR=1.6, p=0.03) and female gender (HR=1.7, p=0.05) for ICANS; and IPI score ≥ 3 (HR=1.6, p=0.04) and lack of prior autologous transplant (HR=2, p=0.02) for CRS. Multivariate analysis showed EASIX score to be an independent predictor of grade 2-4 ICANS (HR=2.3, p=0.001) or CRS (HR=2.3, p=0.001); female gender of ICANS (HR=1.7, p=0.03) and lack of prior autologous transplant of CRS (HR=1.9, p=0.02). The impact of IPI did not reach statistical significance for either ICANS (HR=1.3, p=0.3) or CRS (HR=1.2, p=0.4). Further multivariate analysis for other biomarkers and their incorporation into a revised biomarker score will be presented at the meeting. Conclusions. Our results suggest that the EASIX score prior to lymphodepletion predicts higher grade CRS and ICANS in patients receiving axi-cel. These results of routinely available clinical variables require further prospective studies for validation, however our study shows that this score may better stratify patient risk of toxicity, and possibly inform clinical decisions and prevention strategies for patients at higher risk. Disclosures Nieto: Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Westin:47: Research Funding; Amgen: Consultancy; Morphosys: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Lee:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Guidepoint Blogal: Consultancy; Aptitude Health: Speakers Bureau; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding. Nastoupil:Celgene: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Wang:Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; OncLive: Honoraria; InnoCare: Consultancy; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding. Flowers:AbbVie: Consultancy, Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Bayer: Consultancy; National Cancer Institute: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy. Hawkins:Kite: Membership on an entity's Board of Directors or advisory committees. Rezvani:GemoAb: Membership on an entity's Board of Directors or advisory committees; Affimed: Other: Educational grant; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Virogen: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing agreement; Formula Pharma: Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; Cytonus: Consultancy. Shpall:Magenta: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Neelapu:Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Adicet Bio: Other; Calibr: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; N/A: Other. Kebriaei:Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support.

Abstract: Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients 〈 65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were 〈 65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger ( 〈 65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: Commercially available chimeric antigen receptor (CAR) T-cell therapy has improved the outcomes for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma. Many pts have highly symptomatic, rapidly progressive disease that untreated could be fatal during the 3-4 week manufacturing interval. We examined the outcomes of pts treated with axicabtagene ciloleucel (axi-cel) and bridging interventions, including systemic therapy (ST) and radiation therapy (RT). Methods: We reviewed clinical efficacy and toxicity outcomes for 80 pts who underwent apheresis for axi-cel therapy between 12/2017 and 1/2019 at a single institution. Disease specific survival (DSS), progression free survival (PFS), toxicity free survival (TFS) and overall survival (OS) were defined from the date of CAR T-cell infusion. For the pts who received bridging treatment (defined as therapy given between apheresis and CAR T cell infusion), baseline clinical, treatment and toxicity characteristics were compared between cohorts that received ST versus RT. All comparisons were 2 sided. Results: Of the 80 pts who underwent apheresis, 73 (91%) received CAR T-cell therapy. Among these 73, 32 (44%) received bridging therapy and 41 (56%) did not. Pts who received bridging therapy were more likely to have an IPI of ≥3 at the time of apheresis (72%) compared to those that did not (39%; p=0.009). Of the 32 pts who received bridging therapy, 24 (75%) were treated with ST (corticosteroids [n=3], targeted therapy [n=4] and chemotherapy [n=17]) and 8 (25%) with RT. RT was administered to a median dose of 44.6 Gy (range 9-46 Gy) with a median fraction size of 2.5 Gy (range 1.8 -3 Gy). The median time between the end of RT and the CAR T-cell infusion was 16 days (range 0 -21). The median age of the entire bridging therapy cohort was 59 (range 24 - 85 years). Twenty five pts (78%) were male, 23 had DLBCL (72%). Comparing the ST (n=24) to the RT (n=8) cohort, there were no differences in ECOG PS ≥2 (p=0.296), IPI of ≥3 (p=0.654), double hit or triple hit status by IHC (p=0.378) or FISH (p=0.578), bulky disease (≥10 cm, p=1.0), or elevated LDH at the time of apheresis (p=1.0). Upon completion of bridging therapy, cytopenias requiring G-CSF administration prior to initiation of fludarabine/cyclophosphamide conditioning occurred in 18 pts with no difference between ST and RT cohorts (p=0.252). The median WBC and absolute lymphocyte count after bridging therapy and just prior to conditioning was 5.3 K/uL (range 1.5 -20.6) and 0.59 K/uL (range 0.07 - 1.9) respectively and was not statistically different between the ST and RT cohorts (p=0.851 and p=0.317). Twenty pts (62.5%) required G-CSF ≥ 14 days post CAR-T cell therapy infusion and did not differ between the groups (p=1.00). Rates of grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS) were 25% in the RT cohort and 63% in the ST group (p=0.106). Rates of grade ≥ 3 cytokine release syndrome (CRS) were 12.5% in the RT cohort compared to 16.7% among ST treated bridging patients (p=1.00). Rates of ICU admission were not significantly different between the groups (p=0.423). At a median follow up of 6.1 months (95% CI 4.0 - 6.9), there have been 13 deaths; the median OS for the entire bridging cohort has not been reached. Five deaths occurred due to toxicity (5/24 in the ST cohort and 0/8 in the RT group, p=0.296) as a result of infectious complications (n=3), ICANS (n=1) and hemophagocytic lymphohistiocytosis (HLH, n=1). Eight deaths occurred due to lymphoma (6/24 in the ST cohort and 2/8 in the RT cohort, p=1.00). For the entire bridging group of 32 pts, 13 experienced lymphoma progression with a median DSS of 4.4 months. The median DSS was 4.43 months among the ST cohort and not reached in the RT cohort (p=0.644). The PFS was 3.5 months for all bridging pts with a median PFS of 3.5 months among the ST treated pts and not reached for the RT pts (p=0.314). Conclusion: Bridging therapy is often utilized at physician discretion to temporize aggressive disease and facilitate successful CAR T-cell infusion. In this single institutional study, judicious use of bridging therapy permitted 91% of patients to undergo CAR-T cell infusion. This preliminary data suggests that RT can be an effective bridging tool for pts with R/R large B cell lymphoma prior to axi-cel therapy. Larger cohorts are required to determine if RT bridging strategies may result in lower rates of treatment related mortality and improved disease control. Figure Disclosures Pinnix: MD Anderson Cancer Center: Employment; Merck and Company: Research Funding; International Journal of Radiation Oncology Biology and Physics: Honoraria; Global Oncology One: Consultancy. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Westin:Curis: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Unum: Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding. Fowler:Abbvie: 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; Celgene: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iyer:Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Genentech/Roche: Research Funding; Arog: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Kite Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Aviara: Research Funding; BeiGene: Research Funding; Loxo Oncology: Research Funding. Neelapu:Poseida: Research Funding; Cell Medica: Consultancy; Precision Biosciences: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Novartis: Consultancy; Karus: Research Funding; Cellectis: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Allogene: Consultancy. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria.

Abstract: Background: Mantle cell lymphoma (MCL) has poor clinical outcome and is a significant therapeutic challenge in patients with relapsed or refractory disease due to its resistance to salvage chemotherapy. Although recent studies have shown the clinical utility of radioimmunotherapy (RIT) in relapsed and transformed indolent B-cell lymphoma, the clinical efficacy of this treatment modality in patients with MCL is not well described. We report the results of a completed phase II clinical trial of yttrium 90 ibritumomab tiuxetan (Zevalin) in patients with relapsed and refractory MCL. Patients and Methods: Patients with relapsed or refractory MCL with measurable disease, age ≥18 years, and performance status 〈 3 were eligible. Patients were required to have adequate function of the bone marrow (ANC ≥1,500/mm3, platelets ≥100,000/mm3), liver, and kidneys. Patients were excluded if they had prior stem cell transplantation, RIT, CNS lymphoma, HIV infection, pleural effusion, HAMA reactivity, or circulating lymphoma cell count ≥5,000/mm3. Patients with pretreatment platelet counts ≥150,000/mm3 received a dose of Zevalin at 0.4 mCi 90Y/kg (maximum dose 32 mCi), whereas those with platelet counts 〈 150,000/mm3 received 0.3 mCi 90Y/kg. Results: Thirty-five patients were enrolled at MDACC. The median age was 68 years (range 52–79), and 27 patients were men. All patients had an ECOG performance status of 0 or 1 and had been previously treated with rituximab with or without other chemotherapy. The median number of prior regimens was 3 (range 1–6). Twelve of the patients did not respond to their last regimen. Twenty-two patients were previously treated with Hyper-CVAD alternating with MTX/Ara-C, and 7 previously received bortezomib. Thirty-one of 35 patients are eligible for evaluation of treatment response and toxicity. There were no grade 3 or 4 non-hematologic toxic events. Grade 1 non-hematologic toxic events included fatigue in 7 and nausea in 3. Grade 2 non-hematologic toxic events included non-neutropenic fever in 1 and melana in 1. Grade 3 or 4 hematologic toxic events included thrombocytopenia in 8, neutropenia in 2 and anemia in 1. Objective responses were observed in 13/31 patients for an overall response rate (ORR) of 42% including 8 CR/CRu’s (26%) and 5 PR’s (16%). Three patients had stable disease. Among the 4 patients who received a Zevalin dose of 0.3 mCi 90Y/kg, 1 achieved a CRu while the 3 others had progressive disease. Eight of the 13 responding patients were previously treated with 3 or more regimens; two patients achieved CR after having received 4 prior lines of therapy. Median progression free survival for the responded patients was 6 months after a median follow up time of 16 months. Conclusion: Zevalin treatment was generally well tolerated; with the most common toxicity being hematological. The observed responses to Zevalin in heavily pretreated patients with MCL are promising and warrant further investigation of its activity after first or second relapse, and in conjunction with front-line therapy.

Abstract: Blastoid MCL has a very poor prognosis, with a median survival of 16–20 months after treatment with CHOP-like chemotherapy regimens. We recently described an intense regimen where R-HyperCVAD is alternated with R-M/A for 6–8 cycles, capable of achieving 87% complete remission (CR) rates and an overall 3-year FFS rate of 64% in a group of 97 patients with newly diagnosed aggressive MCL treated under an institutionally approved clinical trial from March 1999 to March 2001 (J Clin Oncol 23:7013–7023). Fourteen of these patients presented with the blastoid cytologic variant and the following clinical features were compared with those without a blastoid cytology: age 〉 65 years, beta 2 microglobulin ≥ 3 gm/dL, elevated serum lactic dehydrogenase (LDH), and high international prognostic score (IPI). Only serum LDH was significantly different, being higher for those with blastoid presentation (p = 0.03). Rates of complete remission were lower for blastoid when compared to non-blastoid cytology (79% vs 89%, respectively) but not statistically significant (p = 0.72). With a median follow up of 57 months, there is a plateau in the FFS curve for blastoid MCL as shown below. At 57 months the median overall survival has not been reached. Contrary to what we had expected, the improved outcome in this group of patients with blastoid cytology suggests a potential for long term remission after intense, non-myeloablative chemotherapy. Figure Figure

Abstract: This phase II trial evaluated the safety and efficacy of yttrium-90 ( 90 Y)–ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL). Patients and Methods Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/μL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/μL received a dose of 0.4 mCi/kg of 90 Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/μL received a dose of 0.3 mCi/kg. Results Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P 〈 .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015). Conclusion The single-agent activity of 90 Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.

Abstract: Purpose: The purpose of this study was to evaluate the clinical activity and toxicity of recombinant human Interleukin (IL)-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease (HD). Experimental Design: Forty-two previously treated patients (32 patients with NHL and 10 patients with HD) were enrolled on the study. Patients were treated with either intravenous (n = 11) or subcutaneous (n = 31) administration of IL-12. The patients had received a median of three prior treatment regimens, and 16 patients had undergone prior autologous stem cell transplantation. Results: All patients were assessable for toxicity, and 39 of 42 (93%) patients were assessable for response. Six of 29 (21%) patients with NHL had a partial or complete response, whereas none of the 10 patients with HD responded. Furthermore, 15 patients had stable disease that lasted for up to 54 months. Progression-free survival in patients with indolent NHL, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Treatment was well tolerated, and the most common toxicity was flu-like symptoms. Reversible grade 3 hepatic toxicity was observed in three patients requiring dose reduction. IL-12 therapy increased the median number of peripheral blood CD8 T lymphocytes from 423/μl to 576/μl (P = 0.0019). Furthermore, IL-12 therapy decreased serum vascular endothelial growth factor and basic fibroblast growth factor concentrations in 37% of the patients. Conclusions: The ability of recombinant human IL-12 therapy to increase the number of circulating CD8+ cells and induce clinical remissions in patients with relapsed NHL warrants further investigation of the drug.