ALBERT

Description: Introduction: Treatment of PCNSL with high dose methotrexate (HD-MTX)-based chemotherapy and WBRT is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone. Patients and Methods: In an attempt to improve upon these dismal results, we treated eleven PCNSL pts aged 40–68 years (median=55) with TBC/ASCT without WBRT. These pts all received prior induction therapy with HD-MTX 3.5 or 5g/m2 q14d x 4-5 cycles +/− procarbazine 100mg/m2 po d1-7 q28d x 2 cycles concurrently with HD-MTX, and then underwent stem cell mobilization with Ara-C 3g/m2 IV d1 and 2, G-CSF d7-14, and apheresis d15 or 16. The TBC regimen consisted of thiotepa 300mg/m2 d-8 and -7, busulfan 3.2mg/kg IV daily d-6 to -4, and cyclophosphamide 2g/m² d-3 and -2. Poor prognostic features included relapsed/progressive disease (n=2), immune-deficiency (SLE, Imuran/Prednisone = 1), ECOG 2-4 (n=9), age 〉60 yrs (n=4), deep brain involvement (n=8), elevated LDH (n=2), elevated CSF protein (n=2). Results: Stem Cell Collection and Engraftment: A median of 24 (5–45) x 106 CD34+ cells/kg were collected with a median 14.1L (8.5-30L) apheresis. Engraftment to ANC〉0.5 and platelet〉20 both occurred at a median of day +9 (7–12). TBC Toxicity: Two early treatment-related deaths occurred in pts 65 and 66 years of age, who both originally presented with ECOG of 4. In addition, a 68 yr old man developed Bearman grade 3 regimen-related toxicity (RRT) requiring ICU admission for encephalopathy and respiratory failure. He survived and returned home to function independently. The remaining pts experienced significant Bearman grade 1–2 RRT including generalized skin rash, peripheral edema, mucositis, delirium and asthenia. All surviving pts experienced improvement in neurological function and ECOG. Six pts returned to work including a 62 yr old pianist. Only one pt developed late neurotoxicity with symptoms of mild dementia. Survival: One patient relapsed 30 months post-TBC and died 1 month post-cranial radiotherapy. Eight pts (73%) are currently alive and relapse-free at 9, 15, 17, 18, 25, 43, 52, and 55 months post-TBC/ASCT. Two pts received TBC/ASCT as the only treatment after rapid disease progression following initial chemotherapy. One of these pts relapsed 7 mo after prior HD-MTX/Ara-C and BEAM/ASCT, and the other progressed within 1 mo of completing induction HD-MTX/Ara-C. Both these 2 pts remain relapse-free 43 and 52 months post-TBC/ASCT. Conclusion: TBC/ASCT is capable of inducing prolonged remissions in pts with poor prognosis PCNSL, but is poorly tolerated in pts over 65 years. High dose chemotherapy for PCNSL should include drugs that penetrate the CNS well such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.

Description: Introduction Primary central nervous system lymphoma (PCNSL) is a rare disorder with a poor prognosis. The mainstay of treatment is single agent or combination high dose (≥3.5g/m2) methotrexate (HDMTX) based regimens. There is no consensus as to which dose of HDMTX improves outcomes in patients with PCNSL but doses of MTX greater than 3 g/m2 intravenously achieve therapeutic cerebrospinal fluid (CSF) concentrations. Purpose To determine if there is an optimal or total dose of HDMTX in PCNSL therapies that results in improved progression free (PFS) or overall survival (OS). Methods Patients at Moffitt Cancer Center with PCNSL were identified using our institutional database between January 1, 2000 and September 30, 2011. Patients with complete treatment data who were treated with HDMTX were included in this study. HDMTX was defined as MTX at a dose ≥ 3.5g/m2. Patient demographics, clinical, and treatment data were collected and analyzed. Treatment information collected included the starting dose of HDMTX, IV rituximab use, MTX toxicity and clearance, cycles of MTX, and total amount of MTX administered (g/m2). Data were analyzed using descriptive statistics and the Kaplan-Meier (KM) method was used to estimate median PFS and OS using the log rank test. P value of

Description: Introduction: Mantle Cell Lymphoma (MCL), a B-cell, non-Hodgkin lymphoma (NHL) characterized by cyclin D1 and Bcl-2 over-expression, is considered incurable with standard therapies. Reovirus, a double stranded RNA oncolytic virus has shown a consistent anti-neoplastic effect in a variety of cell lines both in vitro, in vivo and ex vivo. We recently demonstrated an anti-lymphoma effect of reovirus in two MCL cell lines and reovirus resistance in three. Here we report the effect of trypsinization of the reovirus envelope to generate intermediate subviral particles (ISVP) on the resistance of these cell lines in vitro. Methods Five MCL cell lines (Z138C, NCEB-1, Hb-12, JVM2 and Granta 519) and one Follicular Lymphoma cell line (DoHH2) were counted and resuspended in serum-free medium. 104 cells in 20ul were dispensed per well in a 96-well plate. 10ul of reovirus at appropriate MOI in serum-medium or 40MOI of ISVP was added to the cells. ISVP was prepared as follows; 1ul of reovirus at 40MOI was treated with 9ul of chymotrypsin at 37°C for 30 minutes before being added to the cells. Cells and viruses were allowed to be in contact at 4°C for 45 min -1 hour. 170 ul of warm complete medium RPMI 1640 containing 10% FCS and L-glutamine was then added and the plate was incubated at 37 °C. Each time point was performed in quadruplicate. WST-1 reagent was used to quantify cell proliferation and cell viability was assessed by absorbance at 450nm using a plate reader. Results MCL cell lines NCEB-1 and JVM-2 showed exquisite sensitivity to reovirus induced oncolysis after 4 days’ incubation at 40 and 80 MOI. Granta exhibited intermediate sensitivity to reovirus while Hb12 and Z138C demonstrated an innate resistance to reovirus induced oncolyis at this time point. Incubation of the resistant cell lines with ISVP overcame this resistance in the Granta and Z138C cell lines (as well as DoHH2). Viability of Granta and Z138C after 4 days’ incubation with ISVP approached that of the sensitive cell lines NCEB-1 and JVM-2 at the same time point. However, the Hb12 cell line retained a significant degree of resistance to reovirus when incubated with ISVP. Percent Viability of 5 MCL Cell Lines at 4 Days’ Incubation with Reovirus or ISVP Treatment NCEB-1 JVM-2 Hb-12 Z138C Granta DoHH2 Control 100 100 100 100 100 100 Reovirus 40 MOI 26 29 113 89 58 54 Reovirus 80 MOI 20 1 114 94 50 45 ISVP 40 MOI 22 5 45 9 12 8 Conclusion Although each of the five cell lines investigated has the karyotypic and molecular hallmarks of MCL, they exhibit heterogeneity of sensitivity to reovirus induced oncolysis. The resistance to reovirus oncolysis exhibited by the two cell lines Z138C and Granta can be overcome by 40 MOI ISVP. In contrast, incubation with the ISVP only partly overcomes reovirus resistance in the HB12 cell line. The molecular basis of this variation and the mechanism underlying reovirus resistance warrants further investigation at the proteome, transcriptome and genome level.

Description: INTRODUCTION: Severe neurotoxicity occurs in ~30% of Diffuse Large B Cell Lymphoma (DLBCL) patients treated with CAR-T cell therapy. The current treatment for severe neurotoxicity is glucocorticoids +/- tocilizumab (an IL-6 antagonist) depending on concurrent cytokine release syndrome. Even with these treatments, neurotoxicity can have a complicated course. It is therefore essential to find the optimal treatment to reverse neurotoxicity timely. METHOD:This is a retrospective cohort study of neurologic and oncologic outcomes among patients with grade ≥ 3 neurotoxicity treated with glucocorticoids and IVIG compared to glucocorticoids only. Severe neurotoxicity was defined as grade 3 and graded by CRES/CARTOX score. Time to resolution of severe neurotoxicity (TTR) was defined as improvement of severe neurotoxicity to grade ≤ 2. RESULTS: We identified a total of 20 patients who received CAR-T therapy and developed severe neurotoxicity. Ten patients received glucocorticoids and IVIG (group A) and ten patients received glucocorticoids alone (group B). The median age was 62 (range: 52-74) for group A vs 64 years (range: 48-75) for group B. Both groups had similar ECOG performance status (p=0.17), IPI scores (p=0.34), and onset of severe neurotoxicity (median=6 days in both groups). Median TTR was 3 days (range, 1-7) for group A and 4.5 days (range, 2-22) for group B. There was no significant difference in TTR of severe neurotoxicity among both groups (Log-rank p=0.18, Figure). The median time to administration of IVIG after initiation of glucocorticoids was 2 days (range, 0.5-8). The median TTR following initiation of IVIG was 0.5 day (0.5-4). The objective response rate at 30 days was 80% in both groups. None of the patients who received IVIG developed thromboembolism, renal failure, autoimmune hemolytic anemia or acute lung injury. CONCLUSIONS: Although the use of IVIG during severe neurotoxicity after CAR-T therapy appeared to be safe, this pilot retrospective analysis demonstrated no significant difference in resolution of severe neurotoxicity with addition of IVIG to glucocorticoids. Further controlled studies limiting selection bias inherent in this retrospective analysis will help to determine the efficacy of IVIG in severe neurotoxicity in the context of CAR-T cell therapy. Disclosures Mokhtari: KITE PHARMA: Other: Clinical Advisor; NOVARTIS: Other: Clinical Advisor. Bachmeier:Kite/Gilead: Speakers Bureau. Jain:Kite/Gilead: Consultancy. Forsyth:Department of Defense: Research Funding; Pfizer: Research Funding; State of Florida Bankhead Coley: Research Funding; Moffitt Center of Excellence Celgene Project: Research Funding; Florida Academic Cancer Center Alliance: Research Funding; NIH/NCI 1R21 Grant: Research Funding; NIT DT Study Section Grant Review: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tocagen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BTG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Inovio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor. Lazaryan:Kadmon: Consultancy.

Description: Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, vincristine, etoposide/methotrexate)–ASCT was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome.