ALBERT

Description: Introduction Relapse in the central nervous system is an uncommon complication of diffuse large B cell lymphoma (DLBCL) associated with a poor prognosis. The addition of rituximab to chemotherapy has improved outcomes in patients with DLBCL but its effect on the outcome of patients with CNS relapse is not well characterized. Here we present the natural history of patients with CNS relapse in a large cohort of patients with DLBCL who were treated in the immunochemotherapy (IC) era. Methods Newly diagnosed patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) and treated with primary anthracycline based IC were prospectively enrolled on the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. Patients with documented CNS involvement at diagnosis, primary CNS lymphoma, or post-transplant lymphoproliferative disorder at diagnosis were excluded. All CNS relapse and retreatment details were verified by medical record review. Results 1017 patients with newly diagnosed DLBCL or PMBCL, no documented CNS disease at diagnosis, and treated with IC were enrolled in the MER between 2002 and 2012. At a median follow-up of 59 months (range 1-148), 36 patients had CNS relapse. The cumulative incidence of CNS relapse was 3.1% (95% CI: 2.2%-4.4%) at 2 years and 3.7% (95% CI: 2.7%-5.0%) at 5 years after diagnosis. CNS involvement was identified after first line IC in 25 patients, and after salvage therapy in 11 patients. 22 patients had an isolated CNS relapse, while 14 had both systemic and CNS disease at relapse. The incidence of isolated CNS relapse at two years from diagnosis was 1.9% (95% CI: 1.2%-3.0%, figure 1). CNS involvement was parenchymal in 22 patients, leptomeningeal in 11, and parenchymal and leptomeningeal in 3 patients. At diagnosis, this subset of 36 patients had a median age of 61 years (range 20-86); 25 (69%) were male. IPI was 0-1 in 6 patients, 2 in 13 patients, 3 in 11 patients and 4-5 in 6 patients. Cell of origin per Hans algorithm was available in 17 patients, 8 were GCB and 9 were non-GCB. Extranodal sites of disease at diagnosis included testicular (2), renal (5), bone (10) and bone marrow (6). 7 patients had no sites of extranodal disease. LDH was elevated in 71%. The German High-Grade Non-Hodgkin Lymphoma Study Group CNS risk score was low risk in 6 patients, intermediate risk in 22 patients, and high risk in 8 patients. 6 patients received CNS prophylaxis with their initial immunochemotherapy, including 3 of the 21 patients who subsequently developed isolated CNS disease. First line therapy after CNS relapse included high dose methotrexate based chemotherapy in 22 patients and other systemic regimens in 6, with intrathecal (IT) chemotherapy in 5. Overall survival in patients after CNS relapse was poor with a median survival of 6.3 months (95% CI: 2.9-15.5) and 12-month survival rate of 29% (95% CI: 17%-49%). Patients who had CNS relapse following initial IC had better subsequent survival (median OS = 7.6 months) compared to patients with first presentation of CNS relapse following salvage therapy (OS = 2.1 months, p=0.005, see figure 2). 10 patients (28%) proceeded to SCT after CNS relapse, of which 6 remain alive at a median follow-up of 39 months. There were no differences in post-CNS relapse survival by age, sex, CNS risk score, cell of origin, extranodal site involvement at diagnosis, or site of CNS relapse (all p〉0.10), though power was limited due to small numbers. Conclusions The incidence of CNS relapse in DLBCL is approximately 4% in the immunochemotherapy era. The vast majority of CNS relapses occur within 2 years of diagnosis. Isolated relapse in patients without CNS involvement at diagnosis is a relatively rare event with an incidence of approximately 2% at 2 years of diagnosis. Outcomes remain poor, and standard clinical variables do not predict survival after CNS relapse. Novel therapeutic approaches are needed in this population, with consideration to autologous SCT, which produces durable remission in a subset of patients. Disclosures Maurer: Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Description: Background: Checkpoint blockade therapies (CBT) have substantially improved outcomes for patients in a variety of cancers. However, they are associated with a unique spectrum of immune-related adverse events (AEs). Additionally, unlike standard chemotherapy, many patients (pts) remain on CBT for prolonged periods of time, thus immune-related symptomatic AEs may be chronic or low grade therefore important to capture long term tolerability when used as a single agent or in combination with chemotherapy. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which incorporates the dimension of time and includes chronic lower grade events, to the first 6 cohorts (A-F) of a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of Brentuximab Vedotin (BV) and the CBT therapies ipilimumab (Ipi) and nivolumab (Nivo) in pts with relapsed or refractory Hodgkin lymphoma (R/R HL). Methods: Pts with confirmed R/R HL were treated with BV 1.8mg/kg + Ipi 1or 3 mg/kg (n=23); or Nivo 3mg/kg + BV: 1.2 or 1.8 mg/kg (n=19). BV was administered every 21 days for 16 cycles; Ipi every 21 days x 4 and then every 3 months for one year and Nivo every 21 days for up to 2 years. Seven symptomatic (subjective) AEs were selected: fatigue, peripheral sensory neuropathy (PSN), nausea/vomiting (NV), rash/skin (RS), diarrhea, ocular-all types, and hair loss. Treatment-related AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods up to 12 cycles. Using ToxT, mean AE grades over cycles were analyzed for time trend with repeated measures models, time to grade 2 or higher AE (gr2+) was analyzed with time-to-event analysis; AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment groups: BV/Ipi(A-C arms) and BV/Nivo (D-F arms). Results: 9/23 (BV/Ipi) and 6/19 (BV/Nivo) pts completed 10 cycles. For BV/Ipi vs. BV/nivo, ToxC provides overall incidence rates (any grade): fatigue 52% vs 26% (p=0.09); PSN 61% vs 53%; NV 70% vs 53% ; RS 65% vs. 37% (p=0.07); diarrhea 57% vs. 21% (p=0.02); ocular 17% vs. 21% ; and hair loss 17% vs. 0% (p=0.06), respectively. Gr3 AE occurred in 1 pt (2.4%) each for PSN, NV, diarrhea, and 6 pts (14.3%) for RS, and were similar between BV/ipi and BV/nivo. AUC from ToxT which captures chronic lower grade AEs suggested for BV/Ipi: diarrhea (p=0.02) and NV (p=0.03) are significantly more substantial over time with a trend seen for fatigue (p=0.07), RS (p=0.07) and hair loss (p=0.07) . Additionally, ToxT captures the trajectory of AEs, demonstrated a rising incidence and worsening grade of PSN (BV-related) on BV/Ipi (c1: 9% gr1, c2: 21% gr1 5% gr2, c5: 11% gr1 and c10: 22% gr2 [p=0.005], Fig 1a). In contrast there was a slow but significant decreasing incidence of NV on both combinations; for BV/Nivo (c1:52% gr1, c5: 26% gr1 and c10: 22% gr1) and BV/Ipi (c1: 47% gr1 ,c5: 0% and c10 1% gr1) with p=0.006 (Fig 1b). RS and diarrhea appear early on treatment and are not cumulative (Fig1c and 1d). There is no significant difference in the time to gr 2+ toxicities in any of the 7 AE. Combining all 7 AEs and using the maximum grade as a pilot measure of overall AE burden , ToxC indicates no difference in any grade (100% vs 100%) but a significantly higher gr 3+ incidence (35% vs. 11%) for BV/Ipi. Additionally, ToxT further elucidates that BV/Ipi is associated with significantly higher overall AE over time (Fig 2a, p=0.02) and compared to BV/Nivo a significantly higher risk of developing gr 2+ toxicity ( 57% vs 16% gr2 + event by day 50) (HR=0.41, p=0.02, Fig 2b). Conclusions: The CBT therapies Ipi and Nivo, in combination with BV, are overall both well tolerated over time, although BV/Ipi has a higher overall AE burden. Neither regimen has significant cumulative immune toxicity. Results of this analysis should be interpreted in the context of limited number of pts in both cohorts. A larger scale examination of this analysis is planned to incorporate both phase 1 and the ongoing phase 2 components of E4412. Compared with conventional tox analysis, ToxT delineated important additional and clinically relevant depictions of AEs over time and adds a more comprehensive assessment of the tolerability of chronically administered immune therapies for lymphoma. Disclosures Hong: Merck: Consultancy. Ansell:Regeneron: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Advani:Kura: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Celgene: Research Funding; Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Forty Seven Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Kahl:Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Juno: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Genentech: Consultancy; Denovo: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding.

Description: Background: Bortezomib has efficacy in follicular lymphoma (FL). Though generally well tolerated, it is associated with a few known toxicities, including neurotoxicity. As a chronically administered agent, it is important to investigate the tolerability of bortezomib over time as a single agent and in combination with chemotherapy. The current method of summarizing adverse events (AEs) -focusing on the maximum grade and reporting only grade 3 or higher incidences- fails to capture toxicity that evolves over time or chronic low grade AEs that may occur at significant expense to patients' quality of life. In this study, we applied the Toxicity over Time (ToxT) analytic approach (Thanarajasingam et al, Lancet Oncol 2016), which graphically and analytically depicts AEs longitudinally, to a randomized Phase 2 ECOG-ACRIN sponsored study, E2408, to characterize chronic toxicity of bortezomib (V) when added to standard bendamustine-rituximab (BR) induction in previously untreated high risk FL. Methods: In E2408, patients (pts) were randomized to one of 3 arms at a 1:2:2 ratio: A) BR x 6 followed by maintenance rituximab (MR) x 2 years (yrs) vs B) BVR x 6 (bortezomib 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) then MR x 2 yrs vs C) BR x 6 then MR x 2 yrs + lenalidomide 20mg/day x 1 yr. Pts enrolled 1/2011-5/2015. This analysis focuses on the 6 cycles of induction only, with arms A and C combined. Six AEs of interests were selected, 4 symptomatic (subjective) AEs (peripheral sensory neuropathy (PSN), diarrhea, febrile neutropenia, fatigue); and 2 non-symptomatic (objective) AEs (neutropenia and thrombocytopenia). Treatment-related post baseline AEs of any grade were investigated by conventional maximum grade toxicity analysis (ToxC) and ToxT methods. The mean AE grades over cycles were analyzed by repeated measures models, time to grade 2 or higher (gr2+)AE were analyzed with time-to-event analysis; and AE profile over the entire course of the study was summarized by area under the curve (AUC) analyses. Comparisons were performed between treatment arms (BVR vs. BR). Results: All 280 randomized treated pts (187 on BR, 93 on BVR) were included in the analysis regardless of eligibility status; 87% (163/187 BR, 81/93 BVR) completed all 6 cycles. Analyzing the symptomatic AEs,ToxC indicates that the overall incidence of grade 3+ PSN was significantly higher in BVR (12%) than BR (1%) (p

Description: Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p

Description: Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin lymphomas. They carry a worse prognosis for most subtypes compared with their B-cell counterparts. Despite the recent approval of newer therapies, the response rate and duration of clinical benefit is short and the outlook for patients with relapsed/refractory (RR) PTCL remains poor. There is therefore a need for novel effective therapies in PTCL. Targeting the profoundly immunosuppressive tumor microenvironment (TME) in PTCL is one such approach. Preclinical data show that malignant cells in PTCL overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal further suppressing antitumor immunity. PD-1/PD-L1/2 interactions in PTCL are particularly complicated as both the receptor and ligands can be expressed on the malignant T-cell. While the use of anti-PD-1 blocking antibodies has shown remarkable efficacy particularly in relapsed Hodgkin lymphoma, only a small number of patients with PTCL have been treated with checkpoint blockade. We conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here the results of the prespecified interim analysis. Study design and patient selection: Nivolumab was given at a flat dose of 240 mg intravenously (IV) every 2 weeks for 8 cycles then 480 mg IV every 4 weeks starting cycle 9. The primary objective was to assess the overall response rate (ORR) defined as proportion of subjects achieving either a partial response (PR) or complete response (CR) within 12 cycles of treatment. Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Pre-planned sample size was 39, assuming that an ORR of 10% or less would be considered negative and an ORR of 30% or greater would warrant further study. We used a one-stage design with an interim analysis (upon enrolling 12 subjects) based on a Simon optimal design to assess efficacy. This design had a 90% power with a 1-sided 10% level test. The Duffy and Santner method was utilized to determine confidence intervals for the ORR. Kaplan-Meier methods were used to assess PFS, OS, and DOR. This study was sponsored by Bristol-Myers Squibb (NCT03075553). Results: Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Patient characteristics are illustrated in table 1. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified (NOS), one had ALK negative anaplastic large cell lymphoma (ALK- ALCL). Most (11/12) were advanced stage (stage 4), had extranodal disease and half of the patients had received a prior autologous transplant. The ORR was 33% (4/12) (95% CI: 12.3 - 63.7%): 1 CR seen in ALK-ALCL; 2 PR, 1 in PTCL, NOS and 1 in enteropathy associated T-cell lymphoma; 1 CR in AITL. The median DOR was 3.6 months (95% CI: 1.9-6.9). The median PFS for all 12 patients was short at 1.9 months (95% CI: 1.5-8.7); median OS was 7.9 months (95% CI: 3.4-10.8) (Panel A). Hyperprogressive disease (defined as dramatic progression within 1 cycle of treatment) occurred in 4 patients. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 5/12 (41.7%), while hematologic AEs were seen in 3/12 (25%) patients. Conclusions: Nivolumab had modest clinical activity in patients with R/R PTCL and the study met the criteria at interim analysis to continue accrual. However, due to the high number of patients with hyperprogressive disease, the moderate activity of the drug, and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases. Further studies are indicated using nivolumab in combination (rather than a single-agent) and use of biomarkers to better predict the responders. Disclosures Bennani: Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Ansell:Merck: Other: research funding for clinical trials; Seattle Genetics: Other: research funding for clinical trials; Takeda: Other: research funding for clinical trials; Bristol Myers Squibb: Other: research funding for clinical trials; Regeneron: Other: research funding for clinical trials; Affimed: Other: research funding for clinical trials; Pfizer: Other: research funding for clinical trials; AI Therapeutics: Other: research funding for clinical trials.

Description: Abstract 3069 Disease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies (HM), and the principal cause of failure after reduced intensity conditioning HSCT. Much work has focused on identifying the risk factors for relapse and devising strategies for its prevention, but comparatively little is known about the outcome of patients who relapse and the relevant prognostic factors in this setting. We conducted a retrospective study of 1080 consecutive adult patients with HM transplanted at our institution between 2004 and 2008. 351 (33%) relapsed at a median of 4.5 months after HSCT. The 4-year post-relapse overall survival (pr-OS) was 15%, with a median post-relapse follow-up of 39 months. Significant risk factors for post-relapse mortality included shorter time to relapse, higher disease risk index1 at HSCT, myeloablative conditioning, and high HCT-CI2 at HSCT. While being on immunosuppression at the time of relapse did not significantly affect outcome in multivariable models, a history of acute or chronic graft-versus host disease (GVHD) prior to relapse conferred a higher risk for death after relapse. Based on those 5 factors and their hazard ratio for mortality in the Cox models, we constructed a simple risk score that stratified patients into 4 groups, with 4-year pr-OS ranging from 64% in patients with fewer than 3 points (13% of the cohort, among whom over one third had myeloid diseases) to 0% in those with greater than 6 points (p

Description: Introduction: With the expanding use of CAR-T cell therapy, which is associated with serious adverse effects (AEs), there is a need to characterize the patient's experience over time to guide patient/provider education, and help optimize symptom management. This study reports on longitudinal evaluation of patient-reported quality of life (QOL) and symptom burden of CAR-T cell therapy compared with established forms of cellular therapy i.e autologous stem cell transplant (autoSCT) and allogeneic SCT (alloSCT). Methods: Patients with hematologic malignancies were prospectively recruited in three cohorts: CAR-T, autoSCT and alloSCT. The primary endpoint was change in QOL from baseline, using the FACT-G questionnaire. Secondary endpoints were patient-reported AEs (PRO-AEs) using 7 items from the PRO-CTCAE and assessment of cognition/memory using the NeuroQOLv2 questionnaire. PRO-CTCAE data was graded using a composite score (combining frequency, severity, and interference) and rates, using a method adjusting for pre-existing baseline symptoms, were compared using Fisher's exact test. We also evaluated the time profile of PRO-AEs using the Toxicity over Time (ToxT) approach, a longitudinal approach to AE analysis (Thanarajasingam Lancet Onc 2016). Patients completed questionnaires at baseline, week 2 and monthly thereafter. Results: From 07/2018 to 06/2019, 93 patients were recruited (CAR-T: 20; autoSCT: 37; alloSCT: 36). At data cut-off, week 2 and months 1, 2 and 3 data were available in 74, 62, 46 and 35 patients, respectively. There was no difference in patient age across the 3 groups (median age 63, range 23-77; p=0.26). Baseline QOL by FACT-G total score (mean=83.4, SD=14.7; p=0.77), side effect bother by FACT-G GP5 (66/93 [71%] a little bit or less; p=0.72), activities and function (70/93 [75%] fairly normal activities or no limitations; p=0.68) and cognition by NeuroQOL t-score (mean=52.2, SD=8.13; p=0.39) were similar across 3 groups at baseline. The CAR-T group experienced significantly less worsening in QOL (FACT-G) than both autoSCT and alloSCT groups (Fig. 1a). Worsening in overall QOL nadired at week 2, after which QOL gradually returned to baseline in all groups. When comparing changes from baseline in overall QOL, statistically significant differences between groups were evident at week 2 (CAR-T vs autoSCT p

Description: Introduction Primary testicular lymphoma (PTL) and testicular involvement of systemic lymphoma (secondary testicular lymphoma, STL) are uncommon. Most testicular lymphomas are aggressive B-cell lymphomas and portend a high risk of extranodal relapse, including CNS relapse. As such, when testicular lymphoma is identified, the management strategy is often changed to include CNS prophylaxis. It is, therefore, essential to evaluate testicular involvement in diagnosis and staging. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a standard imaging modality to stage aggressive lymphoma. Physiologic testicular FDG activity can be challenging to distinguish from involvement by lymphoma given a wide range of normal. An imaging threshold for testicular PET uptake would be clinically relevant and would help guide management. We compare testicular FDG avidity in testicular lymphoma with physiologic testicular FDG avidity. Methods Records of patients (pts) diagnosed with PTL or STL from 2002-2018 enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource were reviewed, yielding 36 pts with testicular lymphoma. Physiologic testicular avidity by FDG PET/CT was determined from analysis of 70 randomly selected patients who received FDG PET/CT from 2013-2018 prior to treatment for non-lymphoma indications including pulmonary nodule, lung carcinoma, head & neck squamous cell carcinoma, gastrointestinal carcinomas, and metastatic melanoma, without known hematologic malignancy, testicular pathology, or history of testicular infection/surgery by medical chart review. Imaging parameters compared in this analysis were SUVmax and SUVmean. All FDG PET/CT exams were reviewed centrally by a nuclear medicine radiologist and a radiology resident. Results Of the 36 pts with testicular lymphoma, 19 had an orchiectomy prior to FDG PET/CT and 7 pts did not have a staging FDG PET/CT scan. Of the 10 pts with intact testes at the time of staging FDG PET/CT, 1 pt with low-grade lymphoma was excluded. 9 pts with aggressive lymphomas were included in this analysis: 7 pts with diffuse large B cell lymphoma (DLBCL), and 1 pt each with Burkitt lymphoma and peripheral T-cell lymphoma, not otherwise specified. Testicular lymphoma was diagnosed by orchiectomy in 3 pts, and by percutaneous biopsy in 3 pts. 3 pts did not have tissue sampling of testes or scrotal contents, but had an overtly FDG-avid testicle highly suggestive of lymphomatous involvement. These 3 pts had biopsy-proven lymphoma in parotid, bone marrow, and stomach, respectively, with mean testicular SUVmax 6.8 among the 3 pts. The median age in this analysis cohort was 62 years (range 35-88). Of the 7 analyzed DLBCL pts, 6 were non-germinal center B-cell, and 1 was germinal center B-cell. The 70 control pts had a median age of 55 years (range 18-90). In known testicular lymphoma cases and control pts, SUVmax and SUVmean were assessed from the most FDG-avid testicle. Median SUVmax for the testicular lymphoma cases was 13.3 (range 5.5-29.9), compared to a median of 3.8 (range 2.1-5.5) for controls (Wilcoxon p

Description: Background: Non-endemic Burkitt lymphoma (BL) is a rare B-cell malignancy characterized by extreme tumor proliferation, frequent extranodal involvement, and the genetic hallmark of a MYC gene rearrangement. Despite an often dramatic initial presentation featuring tumor compression of vital organs and/or spontaneous tumor lysis syndrome, most patients who survive intensive immunochemotherapy induction are cured. Despite limited evidence of benefit, the current NCCN guidelines recommend that BL patients in CR are reviewed every 3 months for 2 years and every 6 months thereafter. Aims: To investigate outcomes, including relative survival and relapse risks conditional on event-free survival (EFS) milestones, in an international study of real-world BL patients treated with intensive immunochemotherapy. Patients and methods: This is a retrospective study of newly diagnosed BL patients identified from relevant population or hospital-based registers in Australia (Perth), Denmark (the Danish Lymphoma Registry), Sweden (the Swedish Lymphoma Registry) and Norway (Health Region South East). Patients who met the following criteria were included irrespective of HIV status: 1) age ≥18 years at diagnosis, 2) diagnosed during the period 2005-2017, 3) histology and immunohistochemistry consistent with BL, 4) MYC translocation detected by fluorescence in situ hybridization (FISH), and 5) intensive first line immunochemotherapy including rituximab (R-CHOEP or more intensive). Patient data were collected from registers and chart reviews. Overall survival (OS) was defined as time until death and EFS was defined as time to death, relapse/progression, or unplanned treatment, whichever came first. Prognostic features at baseline were evaluated using univariate Cox models with EFS as outcome. Standardized mortality ratios (SMRs), conditional relative survival estimates, and relapse risks were computed for the subset of patients achieving complete remission (CR or CRu), with follow-up measured from response evaluation and from different EFS milestones. Results: In total, 159 patients fulfilled the inclusion criteria of the study. The median age was 48 years (range 18-81) and the male:female ratio was 2.9. The baseline characteristics included stage III-IV (75%), elevated serum LDH (75%), extranodal involvement (83% - bone or bone marrow in 42% and CNS in 8%), B symptoms (60%), and ECOG performance score 〉1 (30%). The chemotherapy protocols used were CHOEP (2%), DA-EPOCH (13%), HYPER-CVAD (26%), CODOX-M/IVAC (28%), BFM or GMALL (31%), and others (1%). Clinical tumor lysis syndrome defined by severe electrolyte derangement, renal impairment, and/or cardiac arrhythmia, was noted in 16% of the patients, but no fatal episodes occurred. The overall response rate to first-line treatment was 88% (87% in CR/CRu) with 67% assessed by PET technology. The five-year EFS and OS estimates for the total population were 75% (95% CI 68-82%) and 82% (95% CI 76-88%), respectively, and the EFS and OS of patients

Description: Introduction: Relapse is the primary cause of death after reduced intensity conditioning (RIC) hematopoietic cell transplantation (HCT). Documented responses have been reported after combination chemotherapy, hypomethylating agents, donor lymphocyte infusions, and second transplants. For patients with early relapse after RIC HCT while still on immunosuppression (IS), IS taper alone may induce significant graft-versus-tumor (GVT) activity. We describe the clinical characteristics and subsequent course of 48 patients with disease recurrence that responsed to IS taper alone without any additional chemotherapy, radiation, or donor lymphocyte infusion. Methods: We reviewed medical records of all patients with frank histologic or radiographic evidence of relapse (n=477) and those with impending relapse defined by development of cytopenias with a fall in donor derived hematopoietic cell chimerism (n=87) within one year of allogeneic RIC HCT who were on IS at time of relapse between January 1, 2004 and December 31, 2013 at Dana Farber Cancer Institute/Brigham and Women's Hospital. Complete response after IS taper was defined as complete recovery of peripheral blood counts, bone marrow biopsy with absence of disease, negative radiologic imaging, or chimerism recovery to above 90 percent. Partial response was defined as improvement in disease burden in bone marrow or by imaging. Survival probabilities were calculated using the Kaplan Meier method. Results: Forty-eight patients (37 male, 11 female) who relapsed within one year of HCT responded to IS taper alone. Of these, 14 had impending relapse and 34 had frank relapse at time of IS taper. The median age of patients was 62 years at time of transplant. The most frequent indication for transplant was MDS (n=14) followed by AML (n=11), non-Hodgkin's lymphoma (n=8), CLL (n=6), Hodgkin's disease (n=4), CML (n=3) and multiple myeloma (n= 2). At time of transplant, 9 patients had standard risk disease and 39 had high risk disease. All patients except one underwent conditioning with busulfan (≤ 6.4 mg/kg) and fludarabine. Five patients had graft versus host disease (GVHD) prior to relapse. The median time to frank or impending relapse was 105 days (range 57-360) after HCT. The median interval between starting and completing IS taper was 30 days (range 0-251), but 13 patients could not come off IS completely due to GVHD. The median time to documented response after initiation of IS taper was 77 days (range 14-189). Thirty-five patients had a complete response and the remaining 13 patients had a partial response. Nine patients subsequently relapsed late after initial response to IS taper at a median time of 2.38 years (range 0.88-3.95). Forty-five of the 48 patients developed or had a flare of previous GVHD as a consequence of IS taper. Of these, 26 patients had grade II-IV acute GVHD and 19 had chronic GVHD. The median time to developing GVHD after starting IS taper was 39 days (range 7-261 days). Twenty-five patients died during follow-up (10 from GVHD, 6 from disease, 7 from infection, 1 from congestive heart failure and 1 unknown). The median follow-up time among survivors was 4 years (range 1.6, 9.4). The median overall survival (OS) time from IS taper was 4.78 years (95% CI 2.93-7.35, see figure). The 4 year overall survival was 56%. There was no difference in survival for those with frank or impending relapse. Conclusion: Immunosuppression taper alone in patients who relapse early after RIC HCT can produce durable remissions but is almost always associated with development of GVHD. Understanding the clinical, molecular and immunologic characteristics of underlying disease will allow us to better predict who will respond to this manipulation. When feasible, this strategy should be given sufficient time to allow for a GVT response to develop in order to possibly avoid the adverse effects of more aggressive therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.