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Febrile neutropenia (FN) is a major complication in patients with diffuse large B-Cell lymphoma (DLBCL). Diabetes mellitus (DM) has deleterious effects on the immune system resulting in an increased risk of infections. We evaluated patients with DLBCL who started frontline treatment with R-CHOP, and compared outcomes according to presence of DM comorbidity. Between 2013 and 2018, 218 patients with DLBCL were included. 46 patients (21%) had DM. Rate of admissions for FN was higher for patients with DM (0.7 vs. 0.46 admissions/patient

Almost half of patients with diffuse large B-cell lymphoma (DLBCL) have relapsed/refractory (R/R) disease after frontline immunochemotherapy. Although guidelines recommend histological confirmation of R/R disease, repeat biopsies are not always performed. We conducted a two-part study: a nationwide case-vignette survey among treating hematologists, and a single center retrospective analysis. In the survey part, all 64 participating physicians opted not to perform a repeat biopsy in at least one scenario, more often in refractory cases. In the retrospective part, 116 episodes of R/R aNHL among 61 patients were identified. Repeat biopsy was not performed in 72%, more often in refractory episodes, mostly due to low likelihood of alternative diagnoses or problematic location for biopsy. Our study suggests that many patients do not undergo repeat biopsy in R/R DLBCL, especially in refractory cases. Future studies and recommendations should address the necessity of repeat biopsy, according to patient and disease related characteristics.

Late onset neutropenia (LON) after rituximab is a previously described complication. We aimed to assess and characterize LON after obinutuzumab, a novel anti-CD20 antibody, in the real-world setting and compare it to LON after rituximab therapy. We retrospectively analyzed 330 consecutive patients with lymphoproliferative neoplasms (rituximab-treated n = 283; obinutuzumab-treated n = 47). LON occurred in 23% patients with similar incidence in rituximab (n = 66, 23%) or obinutuzumab (n = 10, 21%) groups (p = 0.853). Patients treated for CLL and post-transplantation lymphoproliferative disease (PTLD) were at higher risk to develop LON (multivariate analysis: HR for CLL - 6.62 CI 95% 1.33-32.92; HR for PTLD 15.82 CI 95% 2.04-122.4). Febrile neutropenia was uncommon during LON and occurred in 15 patients (4.5%; rituximab (n = 14) and obinutuzumab (n = 1).These data suggest that LON after obinutuzumab treatment is as common as with rituximab. The similarities in LON after rituximab and obinutuzumab argue for a possible class effect for anti-CD20 monoclonal antibodies.

Patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis and a median overall survival of less than 6 months. Outcomes and responses were evaluated in 134 patients with DLBCL administered selinexor. Our findings demonstrate that selinexor treatment in DLBCL patients can safely induce durable responses and improve outcomes regardless of prior treatments and refractory status. Background: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease. Patients: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly. Results: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%). Conclusion: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens. (C) 2021 Published by Elsevier Inc.

Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p = 3 adverse events and serious adverse events were not associated with clinically meaningful negative QoL impacts.

Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is standard of care first line treatment for diffuse large B-cell lymphoma (DLBCL), though outcomes remain suboptimal.We performed a systemic review and meta-analysis of randomized controlled trials comparing the efficacy and safety of R-CHOP vs. R-CHOP + X (addition of another drug to R-CHOP) as first line treatment for DLBCL. We searched Cochrane Library, PubMed and conference proceedings up to September 2020.Our search yielded ten trials including 4206 patients. The added drug was bortezomib or lenalidomide in three trials each, and gemcitabine, bevacizumab and ibrutinib, each drug in one trial. R-CHOP + X was associated with statistically significant improved disease control (HR 0.88, 95% CI 0.78-0.99). The point estimate was in favor of improved overall survival with R-CHOP + X (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.75-1.00), although this was not statistically significant. Subgroup analysis revealed improved disease control with the addition of lenalidomide and in patients younger than 60 years. R-CHOP + X was associated with an increase in serious adverse events and grade III/IV hematologic toxicity.The addition of another drug to frontline R-CHOP treatment for DLBCL did not result in a significant improvement in OS, although we did observe improved disease control compared to R-CHOP, perhaps most evident with the addition of lenalidomide. Yet, RCHOP + X was associated with an increased risk for serious and hematological adverse events. Further studies could reveal subgroups that would benefit most from augmentation of standard R-CHOP.

Rituximab, the first anti-CD20 monoclonal antibody, has dramatically improved outcomes for patients with B-cell lymphoproliferative disorders. Obinutuzumab was developed to potentiate activity and overcome resistance to rituximab. Clinical data suggest that obinutuzumab is superior to rituximab in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Yet, it has increased toxicity. This systematic review and meta-analysis compiled all randomized controlled trials (RCTs) comparing obinutuzumab-based regimens with rituximab-based regimens to better assess their toxicity profile. Primary outcome was grade 3-4 infections; secondary outcomes included any adverse events (AE), grade 3-4 AE, drug discontinuation rate, and 3-years mortality. Relative risks (RRs) were estimated and pooled using a fixed-effect model, unless there was significant heterogeneity, in which case a random-effects model was used. Our comprehensive search yielded five RCTs conducted between 2009 and 2014, including 4247 patients. The trials included FL patients, CLL and diffuse large B cell lymphoma. Monoclonal antibodies were given with different chemotherapy regimens (in four trials) or as monotherapy (in one trial). The point estimate favored increase in both grade 3-4 infections rate (RR 1.17 [95% CI, 1.0-1.36]) and any AE rate (RR 1.05 [95% 1-1.1]) with obinutuzumab, although this was not statistically significant. There was a significantly increased rate of grade 3-4 AE (RR 1.15 [95% CI, 1.09-1.2]), as well as grade 3-4 toxicities including thrombocytopenia (RR 2.8 [95% CI, 1.92-4.06]), infusion related reactions (RR 2.8 [95% CI, 2.16-3.64]) and cardiac events (RR 1.65 [95% CI, 1.11-2.46]). There was no significant difference in grade 3-4 anemia and neutropenia nor in the 3-year mortality rate. The point estimate favored increase in discontinuation rate due to AE with obinutuzumab, although without statistical significance (RR 1.24 [95% CI, 1.0-1.54]). In conclusion, physicians need to weigh the clinical benefits of this agent against higher toxicity.

High dose methotrexate (HDMTX)-induced acute kidney injury (AKI) is a well-known adverse event in hemato-oncology patients. Our purpose was to define factors and setup cut-offs that may help better identify patients at-risk for developing AKI following HDMTX. All consecutive patients who received MTX dose ≥1 g were retrospectively reviewed. We compared patients with or without renal toxicity. We used a logistic regression model to define baseline variables associated with AKI. Overall survival (OS) was estimated by the Kaplan-Meier method employing log-rank test. Between 2012 and 2017, 160 patients were included with a total of 265 courses. Indications included: primary central nervous system (CNS) lymphoma, CNS prophylaxis in other lymphoma types, acute lymphatic leukemia and others. Median age at diagnosis was 58 years (range, 18-84), 54% were males, median MTX dose was 1941 mg/m2 (range, 743-5442) and AKI developed in 9% of drug administrations (n = 24). In univariate analysis: age > 40, LDH > 380 units/L, eGFR 380 units/L (OR = 4.1, 95% confidence interval [CI] 1.04-20.9, P = .04) and albumin levels 380 units/L and albumin

The phase 2b, open-label, multicenter SADAL study evaluated single agent oral selinexor, a selective inhibitor of nuclear export (SINE) compound, in patients with diffuse large B cell lymphoma (DLBCL) after >= 2 lines of systemic therapy. Similar activity was observed in GCB- and non-GCB DLBCL with a trend to higher response rates in DLBCL transformed from follicular lymphoma. Lower response rates were observed in double expressor DLBCL; higher response rates were observed in patients with baseline hemoglobin >= 10 g/dL and normal levels of C-MYC or BCL-2 expression (51%). Overall, strong single agent activity with selinexor were observed in patients with relapsed/refractory DLBCL.Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor. Patients and Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate. Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels >= 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups. Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin. (C) 2021 Elsevier Inc. All rights reserved.

Background For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML), disease relapse remains the most common reason for transplant failure and patient death. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-transplant maintenance therapy. Methods We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with observation or placebo in patients with AML after allogeneic HSCT. We searched Cochrane Library, PubMed and conference proceedings up to Febuary 2021. Results Our search yielded five trials including 736 patients. Maintenance therapy consisted of tyrosine kinase inhibitors (TKIs) in 3 studies (sorafenib 2 studies; midostaurin 1 study) and hypomethylating agents (HMAs) in 2 studies (decitabine and azacytidine 1 study each). Maintenance therapy was associated with an improved overall survival (OS), HR = 0.61 (95% CI 0.47-0.80). Subgroup analysis revealed advantage in OS with either TKI or HMA maintenance. Relapse free survival (RFS) was also improved in the maintenance arm compared with the control arm HR = 0.51(95% CI 0.40 - 0.66). There was no difference between the two arms in overall grade 3/4 adverse events or overall infections, in grade 3/4 infections, or in acute and chronic graft versus host disease. Conclusions Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in improving RFS and OS, with a satisfactory safety profile.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251., SCOPUS: le.j, info:eu-repo/semantics/published

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.

Hodgkin lymphoma (HL) is common in young adults and considered curable in most patients. Young HL survivors (HLS) are at risk of long-term adverse effects. Our study aimed to assess various fatigue and quality of life (QoL) complaints, and their correlations with treatment. Self-reported questionnaires assessing fatigue (MFI-20) and QoL-related issues (EORTC-QOL-C-30) were used to examine HLS aged 18-65 who completed first-line chemotherapy ± radiotherapy (RT) and were in complete remission for at least six months post-therapy. The cohort included 120 HLS (median age 32 years), assessed between 6 months and 15 years post-treatment. About 28% presented with severe fatigue and severely reduced QoL. Higher fatigue levels were associated with four cycles of the ABVD + RT. Young HLS experience high levels of persistent physical fatigue, emotional distress, and cognitive decline that are insufficiently investigated. Assessment of these complaints is essential and further investigation may provide tailored solutions for a better QoL for HLS.

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.

The reported prevalence of hypercalcemia at diagnosis in non-Hodgkin-lymphoma ranges between 1.3% and 7.4%. These studies included all patients, regardless of lymphoma subtype. We performed a retrospective case-control study to determine the prevalence of hypercalcemia at time of diagnosis in patients with diffuse large B-cell lymphoma (DLBCL). Among 250 newly diagnosed patients, 46 (18%) had hypercalcemia. When compared with age-sex matched patients and normal calcium levels, those with hypercalcemia had higher levels of LDH, lower levels of albumin and more advanced stage. These differences were translated to shorter progression-free-survival and overall survival, but only in patients with hypercalcemia and low levels of parathyroid hormone (PTH). These findings suggest that in newly diagnosed patients with DLBCL, hypercalcemia is more frequent than previously appreciated. Furthermore, lymphoma-related but not primary hyperparathyroidism-related hypercalcemia is associated with adverse prognostic factors and adverse clinical outcomes in DLBCL. Hence, PTH should be obtained in patients with DLBCL and hypercalcemia at diagnosis.

60th Annual Meeting of the American-Society-of-Hematology (ASH) -- DEC 01-04, 2018 -- San Diego, CA Jurczak, Wojciech/0000-0003-1879-8084; Johnson, Peter/0000-0003-2306-4974; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Leppa, Sirpa/0000-0002-8265-511X WOS: 000468868300004 PubMed: 30901302 PURPOSE Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted. (C) 2019 by American Society of Clinical Oncology Amer Soc Hematol Janssen Global Services; Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748] Supported by Janssen Global Services, which also provided writing and editorial support, and by Memorial Sloan Kettering Cancer Center Support Grant No. P30 CA008748 (A.Y.).

We evaluated the role of 18-fluoro-2-deoxy-d-glucose positron emission tomography ([18F] FDG-PET) with computed tomography (CT) (PET/CT) as a diagnostic and prognostic tool in newly diagnosed marginal zone lymphoma (MZL) patients. This is a retrospective cohort study of patients with newly diagnosed MZL, treated with immunotherapy, chemotherapy regimens, surgery, or Helicobacter pylori eradication between 2008 and 2016 in a single tertiary center. Only patients who had a pretreatment PET/CT (P-PET/CT) were included. P-PET/CT, interim (I-PET/CT), and end-of-treatment PET/CT (E-PET/CT) studies were reviewed. P-PET/CT results were reported using two methods of evaluation, qualitative and semi quantitative: visual assessment (VAS) and maximal standardized uptake value (SUVmax), and I-PET and E-PET results were reported by Deauville 5-point score (DS) evaluation as well. Avidity of PET/CT was defined as abnormal uptake in any of these methods. The primary outcome was the prognostic role of P-PET/CT, I-PET/CT, and E-PET/CT on progression-free survival (PFS) and overall survival (OS). Data of 196 patients with MZL were identified, 110 of which had P-PET/CT and were included in this analysis. Median age was 67 years (range 18-93). The median follow-up period was 63 months (range 3-278). The median OS and PFS for the whole cohort were 63 (interquartile range 39-85) and 60 (interquartile range 37-76) months, respectively. The avidity of PET at baseline for the whole cohort was 70% (77/110 patients), for MALT lymphoma, 62.5% (40/64 patients), for NMZL, 76.4% (13/17 patients), and for SMZL, 82.7% (24/29 patients). When adjusted for IPI, sex, and comorbidities, positive E-PET/CT was associated with reduced PFS with a hazard ratio (HR) of 3.4 (95% CI, 1.27-9.14, P = 0.02). Positive E-PET/CT did not correlate with OS. However, there were only three events. P-PET/CT was not predictive of PFS or OS. Our study demonstrates that above 70% of MZL are FDG avid. Positive E-PET/CT is a strong prognostic factor for PFS.

7570 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the ‘optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 ( > 3,900 U/mL) and serum ferritin ( > 1,000 ng/mL), which in HM patients both identifies HLH and predicts mortality more accurately than conventional criteria for HLH. In this study, we examined whether mortality in our cohort is directly related to progressive malignancy vs. HLH-associated causes in OHI+ and OHI- patients. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed lymphoma from Israel, the USA, and Japan for whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH and classified patients by their OHI status. The International Prognostic Index, International Prognostic Score, and Follicular Lymphoma International Prognostic Index were used to estimate the predicted prognosis of T/B cell non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, and follicular lymphoma, respectively. Predicted five-year overall survival was calculated based on the relevant prognostic index and was compared between OHI+ and OHI- patients using the unpaired t-test. The actual survival at five years/last follow-up was recorded, as was the cause of death. The odds ratios (ORs) for observed vs. predicted mortality, and for HLH- vs. malignancy-related death were calculated using the Chi-square test. Results: 100 lymphoma patients were studied: 65% with B cell NHL, 18% with natural killer/ T cell lymphoma, 17% with Hodgkin’s lymphoma; 37 were OHI+, and 63 were OHI-. The disease-relevant international prognostic index-predicted five-year survival did not differ between OHI + and OHI- patients (a mean of 58% n OHI+ and 57% in OHI- p = 0.62). However, the observed five-year survival in OHI+ patients was lower (12%) than predicted, reflecting a mortality incidence that was four times higher than predicted by the relevant prognostic score (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted by their prognostic scores (OR 0.15; CI 0.07-0.34). More than half of the OHI+ patients died from non-malignant causes (39% multi-organ dysfunction or HLH, 18% infection), while most OHI- patients (92%) died from progressive malignancy. The likelihood of dying from multi-organ dysfunction or HLH was 26 times higher in OHI+ vs. OHI- patients (OR 26.2; CI 4.1-286.7). Conclusions: OHI index status strongly correlated with mortality in patients with lymphoma within our cohort, and death in OHI+ patients was largely due to causes other than progressive malignancy. The OHI index appears to identify a harmful inflammatory state and deserves further prospective study.

The efficacy of polatuzumab vedotin in relapsed/refractory diffuse large B-cell lymphoma outside clinical study are undetermined. This retrospective study examined the efficacy and safety of polatuzumab vedotin administered in real life settings. Forty-seven patients, 31 with

Positron emission tomography-computed tomography (PET-CT) performed after two chemotherapy cycles (PET-2) has become an accepted prognostic tool in Hodgkin lymphoma (HL). We evaluated the effect of PET-adapted strategy on outcome in advanced stage HL.In August 2017, we searched electronic databases, conference proceedings and ongoing trials. We included all studies in which treatment modification for advanced HL was performed based on the results of the interim PET scan. The primary analysis included randomized controlled trials (RCTs). Outcomes were progression-free survival (PFS) and overall survival (OS).We identified 13 studies (4 RCTs, 7 phase II and 2 retrospective studies), conducted between 1999 and 2014, including 6856 patients. Of the four RCTS: one used therapy escalation, one did de-escalation and two trials performed both. Outcomes were assessed at different time point between 2 and 5 years. Three RCTs for de-escalating therapy, obtained similar outcomes despite reducing therapy, with a 2-year PFS of 88-92% (6 escalated BEACOPP (EB) vs. 4 ABVD cycles), a 5-year PFS of 91-92% (6/8 EB vs. 4 EB cycles) and a 5-year PFS of 80-82% (6 ABVD vs. omitting bleomycin after two successful ABVD cycles). Two RCTs implemented escalation. The randomization was between adding rituximab or not. In both trials, it did not affect outcome, with a 4-year PFS of 68-69% (addition of rituximab to BEACOPP after 2 ABVD cycles) and 5-year PFS of 88-90% (addition of rituximab to EB after 2 EB cycles). Performing true randomization between PET-adapted and a standard ABVD control arm was not feasible, given historical data.This systematic review of PET-adapted therapy, mainly based on RCTs, suggests that a change to the treatment paradigm is appropriate in advanced HL.

Introduction - Data regarding efficacy and toxicity of different bridging strategies prior to CAR-T therapy are scanty. Tisagenlecleucel (Kymriah TM, Novartis) and axictagene ciloleucel (Yescarta TM, Kite/Gilead) were commercially approved for relapsed/refractory (R/R) DLBCL since 2019. We analyzed real-life data of CAR-T therapy among all consecutive patients who were treated in 4 different CAR-T centers in Israel. Methods - From May 2019, 144 R/R DLBCL patients underwent apheresis and continued to receive bridging therapy that included chemo/immunotherapy (n=78, 54%), radiation (n=11, 7.6%), chemoradiation (n=22, 15%), steroids only (n=5, 3.5%) and none (n=28, 19.4%). All patients were evaluated after bridging therapy and prior to CAR-T infusion by PETCT (96%) or CT scan (4%). Results - Median age was 68 (20-88) years and Median follow-up was 13 (4-26) months. All 144 patients underwent successful apheresis. Reasoning for choosing specific bridging therapy was based on low tumor mass (n= 23, 16%), high tumor mass (n=73, 51%), frailty of the patient (n=27, 19%), ongoing significant prior regimen's toxicities (n=14, 10%) and local disease (n=7, 4%). In patients given radiation therapy median dose was 23 (range, 8-30) Gy. In patients given chemo/immunotherapy or chemoradiation, sepsis was the main complications (9% of all patients) during bridging therapy. However, none of the patients had a fatal event. 14 patients (9.7%) did not proceed to CAR-T infusion; 6 (4.2%) had disease progression and died; 8 (5.6%) had manufacture failure). Among the 130 patients that received CAR-T infusion, PET-CT prior to preparative regimen demonstrated CR/PR status in 38%, 50%, 40%, 17%, and 16% of patients given chemotherapy, radiation, chemoradiation, steroids only, or no bridging therapy, respectively (p=.15), Figure 1. Any bridging therapy was associated with a better disease control compared to either steroids only or no treatment (p=.012). There were no differences in the incidences of overall CRS (p=.692), grade 3-4 CRS (p=.196), overall ICANS (p=.941), grade 3-4 ICANS (p=.281), acute kidney disease (p=.244), and liver dysfunction (p=.45) between the 5 different bridging strategies. Cardiovascular complications were more common after chemoradiation (36%), chemotherapy (19%) and radiation (13%), compared with steroids (0%) or no bridging therapy (4%), p=.05. Non-relapse mortality was 0 in all subgroups. PETCT at 1-month post CAR-T infusion demonstrated an increase in CR status percentage across all subgroups with no statistically significant difference in the incidence between the subgroups (p=.27), Figure 1. There was no difference in both progression-free survival (Figure 2) and overall survival between the 5 subgroups (p=.7, and p=.23). Cox regression model identified preinfusion lower ECOG status (HR=0.8, p=.04), preinfusion CR/PR status (HR=.46, p=.037) and 1-month post infusion CR status as a time dependent co-variate (HR=.14, p Conclusions - Bridging to CAR-T should be tailored based on patient's and disease's characteristics with the aim to achieve the best disease control prior to CAR-T. However the chosen strategy per-se does not impact long-term outcomes. Intensive bridging therapy is associated with more cardiovascular events after CAR-T infusion. A prospective-controlled-trial allocating patients to different bridging strategies is needed to verify these results. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Gurion: Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy; JC Health CARE; Roche: Honoraria. Levi: AbbVie: Consultancy, Research Funding.

Context: Allogeneic hematopoietic stem cell transplant (HSCT) is a standard therapy for patients with acute myeloid leukemia (AML), when the risk for relapse overweighs projected transplant-related morbidity and mortality. Disease relapse remains the most common reason for transplant failure and patient death, and treatment of relapse remains extremely challenging. Reducing the risk of post-transplant relapse without unwanted toxicity by means of post-transplant maintenance therapy has recently been studied in several prospective studies. Objectives: We aimed to evaluate the efficacy and safety of maintenance therapy for AML after allogeneic HSCT. Design, Setting and Patients: Systematic review and meta-analysis of randomized controlled trials which compared maintenance therapy with observation or placebo in AML patients after allogeneic HSCT. The Cochrane Library, PubMed, conference proceedings, and references were searched until February 2021. Primary outcome was overall survival (OS). Secondary outcomes included relapse free survival (RFS), relapse rate, and safety (including adverse events and GVHD). Results: Our search yielded five trials conducted between the years 2009 and 2018, including 736 patients, all published in peer-reviewed journals. Maintenance therapy comprised of tyrosine kinase inhibitors (TKI) – i.e., sorafenib - 2 studies and midostaurin - 1 study as well as hypomethylating agents (HMAs), namely decitabine and azacytidine - one study each. Maintenance after allogeneic HSCT was associated with an improved OS, HR=0.61 (95% CI 0.47-0.80). Subgroup analyses by type of maintenance therapy revealed advantage in OS with either TKI or HMA maintenance [HR=0.50 (95% CI 0.33-0.77) and HR=0.69 (95% CI 0.49-0.98), respectively]. Data from five trials was available for RFS analysis and showed improved RFS in the maintenance group compared to the control arm HR=0.51 [95% CI 0.40 - 0.66]. Relapse rate was significantly decreased in the maintenance arm compared to the control arm, RR=0.41 (95% CI 0.20-0.88, 4 trials). Regarding safety, there was no difference between the arms concerning adverse events (AE), including grade 3-4 AE, rate of infections and acute and chronic GVHD. Conclusions: Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in decreasing relapse rate and improving RFS and OS, with a satisfactory safety profile.

Context One of the major complications in patients with aggressive lymphoma receiving intensive chemo-immunotherapy is febrile neutropenia (FN). Diabetes mellitus (DM) has deleterious effects on the immune system, resulting in an increased risk for infections, as well as a complicated course of infections. Objectives We aimed to examine whether comorbidity with DM, as well as diabetic control, affects the risk of FN or complicates the course of FN in aggressive lymphoma patients. Design, Setting, and Patients This is a retrospective, single-center study. We included all consecutive patients diagnosed with aggressive large cell lymphoma treated at our institute between 2013 and 2017. Demographics, disease-related outcomes, and laboratory data were extracted from electronic medical records. Categorical variables were compared using the ×2 or the Fisher's exact test, and medians were compared with the Mann–Whitney U test. Results 226 patients with aggressive large cell lymphoma were treated in our medical center. Of these, 49 patients (22%) had type 2 DM. There were 129 hospital admissions due to FN in the entire cohort during lymphoma treatment. Patients with DM had higher mean admission rates due to FN compared to patients without DM (0.88 and 0.51 FN admissions per patient, respectively, P=0.004). The admission rate in patients with DM remained higher after age and gender-matched subgroup analysis (P = 0.005). However, the duration of hospitalizations and number of admissions to the ICU were similar in patients with and without DM. In patients with DM, improved glycemic control during hospitalizations due to FN was associated with shorter hospital stay. However, baseline hemoglobin A1c levels were not associated with increased risk for FN or infectious complications. Use of metformin was associated with an improved overall survival in diabetic patients (overall survival not reached compared to 43 months). Conclusions Patients with aggressive large cell lymphoma and DM had higher rates of hospitalizations due to FN. Furthermore, our data suggest that improved glycemic control during hospitalization is associated with a shorter length of hospitalization for FN. The positive effects of metformin in our study cohort may warrant further investigation.

R-CHOP is the standard therapy for patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the effect of reduced intensity R-CHOP on survival, and toxicity in patients 70 years or older with DLBCL. The retrospective analysis included 140 patients (median age 78 years). We showed that patients with a good performance status treated with reduced adriamycin dose had a statistically significant worse overall survival. In multivariable model, the HR with any 10% increase adriamycin-relative dose in the first cycle was, 0.81, 95% CI 0.70-0.94. Age, gender, albumin and IPI were also associated with overall survival. Hospitalizations of patients treated with reduced R-CHOP were longer; however, the rate of infection did not differ between the groups. Based on current data, the optimal treatment for elderly patients with DLBCL remains unclear, but it is apparent that the dose of chemotherapy should be tailored individually according to performance status.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients Results: Of the 134 patients enrolled in the study, 52 (39%) were 65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl >60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl >60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment proved to prolong PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. MATERIAL AND METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate-based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and maintenance ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 14 patients screened for the study 2 were excluded due to relapse while on screening. 12 patients have been enrolled with a median age of 74 (61–80) years. The median interval between diagnosis of PCNSL and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months and she is still alive after 24 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSION Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-Methotrexate based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.

The question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B-cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta-analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine-containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65-0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy-free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible.

Data in the literature are lacking regarding the infection-related adverse events of bendamustine-containing regimens. Therefore, we aimed to assess this risk. We conducted a systematic review and meta-analysis of all randomized controlled trials including bendamustine-containing regimens and those administered for any lymphoproliferative disorder or plasma cell dyscrasia compared with any other regimens. A comprehensive search was conducted until December 2015. Two reviewers appraised the quality of trials and extracted data. Primary outcomes were any infections, grade 3 to 4 infections; secondary outcomes were grade 3 to 4 neutropenia and grade 3 to 4 lymphopenia. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool data unless there was significant heterogeneity, in which case a random-effects model was used. Nine trials published between 2006 and 2016 and randomizing 2620 patients were included. There was no statistically significant effect for bendamustine on the rate of any infection (RR 1.09 [95% CI, 0.87-1.36]) or on the rate of grade 3 to 4 infections (RR 1.04 [95% CI, 0.64-1.71]). There was no increase in the rate of grade 3 to 4 neutropenia in the bendamustine arm (RR 0.84 [95% CI, 0.63-1.12]). Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared with either alkylating agents or fludarabine. Thus, bendamustine remains a safe therapeutic option.

The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it.We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib). We searched MEDLINE, conference proceedings and databases of ongoing trials up to August 2015.Our search yielded eight trials including 3554 patients. Treatment with the newer TKIs significantly improved major molecular response (MMR) at all time points and increased the rate of complete molecular response (CMR) at 12 and 24 months [relative risk (RR) 2.58, 95% CI 1.98-3.37, six trials and RR 2.05, 95% CI 1.63-2.58, three trials, respectively]. Early molecular response at three months was better with the newer TKIs (RR 1.33, 95% CI 1.26-1.40, six trials). Importantly, progression rate to accelerated or blastic phase was significantly lower with the newer TKIs at 12, 24 months and 5 years. Yet, there was no difference in all-cause mortality. The risk of adverse events requiring treatment discontinuation increased with the newer TKIs.With a longer follow-up, the newer TKIs remain more potent than imatinib, yet with no significant effect on survival. As CMR is a prerequisite for treatment discontinuation and cure, the newer TKIs favor treatment cessation.

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta-analysis. Systematic review and meta-analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first-line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression-free survival, event-free survival, or disease-free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78-1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65-0.89) and improved disease control, OR 0.74 (95% CI 0.65-0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47-0.79) and in the subgroup of R-CHOP induction studies OR 0.77 (95% CI 0.67-0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29-2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSIONS Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.

This study compared the value of several simple laboratory parameters with known prognostic models for predicting survival in patients with diffuse large B-cell lymphoma (DLBCL). The data of 157 adult patients with DLBCL diagnosed at Rabin Medical Center in 2004-2008 and treated with R-CHOP immunochemotherapy were retrospectively reviewed. Main clinical features of the cohort were as follows: mean age 63.0 years, 43% male, 63% stage III/IV disease, 28% ECOG performance status >2, 60% elevated lactate dehydrogenase level. Median duration of follow-up was 6.6 years. The NCCN-International Prognostic Index (IPI) was found to be a more powerful prognosticator than the IPI. Five-year overall survival (OS) was 69.6; 73.6% for patients with intermediate NCCN-IPI and 38.4% for patients with poor NCCN-IPI. On univariate analysis, pretreatment hemoglobin and albumin levels were significantly associated with survival. By albumin level, 5-year OS was 77.6 + 4% in patients with >3.5 g/dl and 53 + 7% in patients with 12 g/dl and 58.8 + 5% in patients with 3.5 g/dl (p = 0.022). In conclusion, pretreatment albumin level is a strong prognostic factor for OS in patients with DLBCL and can discriminate high-risk patients for good and poor prognosis. Copyright © 2015 John Wiley & Sons, Ltd.

R-CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin's lymphoma. It was suggested that decreasing the treatment interval from three weeks (CHOP-21) to two weeks (CHOP-14) may improve survival and disease control of patients with aggressive lymphoma.To evaluate the effect of CHOP-like-14 (with or without rituximab) compared to standard CHOP-like -21 on overall survival (OS), disease control and toxicity of patients with aggressive non-Hodgkin lymphoma.Systematic review and meta-analysis of RCTs. In October 2014 we searched The Cochrane Library, MEDLINE, LILACS, conference proceedings, and databases of ongoing trials. Authors were contacted for complementary data. The primary outcome was OS.We identified seven trials (4073 patients), conducted between the years 1999 and 2008. Trials were at low or unclear risk for selection bias, and at low or unclear risk of attrition bias. CHOP-like-14 improved OS of patients with aggressive lymphoma compared to the same regimen given every 21 days (all trials): HR of death 0.86, 95% confidence interval (CI) 0.77-0.97. There was no OS difference between rituximab-CHOP-like 14 to rituximab-CHOP-like-21 (3 trials): HR 0.93 95% CI 0.78-1.10. The rates of progression or death, complete response, treatment-related mortality, grade 3-4 infection, and discontinuation were similar between groups.R-CHOP-21 remains the standard of care for patient with aggressive B-cell lymphoma. CHOP-14 can be considered as in case rituximab is omitted.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography-computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of "genuine" stage I disease.

Introduction: R/R DLBCL patients who have received ≥2 lines of therapy, including those progressed post stem cell transplantation (SCT) or who are not candidates for SCT, have limited treatment options. Selinexor, a selective oral XPO1 inhibitor leads to nuclear accumulation and activation of tumor suppressor proteins and reductions in c-Myc and Bcl-2 oncogenes. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in relapsed/refractory myeloma in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. We conducted the SADAL study to evaluate the efficacy and safety of single agent selinexor in patients with R/R DLBCL. In this patient population, selinexor demonstrated deep and durable responses with an overall response rate (ORR) of 28.3% including a 11.0% complete response (CR) rate. The median duration of response (DOR) was 9.2 months. In patients with CR, the DOR was 13.4 months. Here we evaluate the effect of prior therapy on the efficacy and safety of selinexor. Methods: SADAL is a multicenter, open-label study in R/R DLBCL patients with 2-5 prior lines of therapy, who may have progressed post SCT or are not candidates for SCT. Patients were stratified by subtype (germinal center B-cell or non-GCB) and treated with 60 mg selinexor BIW per 28-day cycle. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR) and safety. We performed post-hoc analyses to compare outcomes based on the number (2 vs. >2) and type (SCT vs. no SCT) of prior lines of therapy received. Results: Of 127 patients, 83 (65%) received 2 prior lines of therapy and 43 (34%) received >2 prior lines of therapy. Thirty-six patients (28%) received prior SCT and 91 (72%) had no prior SCT. In general, patient demographic and baseline characteristics were well balanced in both subgroups. ORR was 30.1% vs. 25.6% (P=0.74) in patients with 2 vs >2 prior lines of therapy respectively. The CR rate was 10.8% in patients with 2 prior lines of therapy compared with 11.6% in patients with >2 prior lines of therapy (P=1.00). The median DOR was 9.2 months in patients with 2 prior lines of therapy compared with 8.4 months in those with >2 prior lines of therapy (P=0.64). Median progression free survival was 3.7 months and 1.9 months (P=0.37) and median overall survival was 11.0 months and 9.8 months (P=0.69) in patients with 2 and >2 prior lines of therapy respectively. In patients with prior SCT, the ORR was 44.4% compared with 22.0 % (P=0.02) in patients with no prior SCT. The CR rate was 16.7% in patients with prior SCT compared with 8.8% in patients with no prior SCT (P=0.34). The DOR was 8.4 months in patients with prior SCT and 9.2 months with no prior SCT (P=0.80). Median progression free survival was 5.9 months and 2.3 months (P=0.07) and median overall survival was 9.1 and 9.8 months (P=0.36) in patients with prior SCT and no prior SCT respectively. The most common related adverse events (AEs) [grade ≥3] included thrombocytopenia (2 prior lines: 36%, >2 prior lines: 42%; prior SCT: 58%, no prior SCT: 31%), neutropenia (2 prior lines: 19%, >2 lines: 23%; prior SCT: 25%, no prior SCT: 20%), and anemia (2 prior lines: 15%, >2 prior lines: 14%, prior SCT: 17%, no prior SCT: 14%). Treatment-related serious AEs were reported in 23%, 14%, 25%, and 19% of patients with 2 prior lines, >2 prior lines, prior SCT, and no prior SCT respectively. Conclusions: Single agent oral selinexor with its novel mechanism of action demonstrated deep and durable responses with no new safety signals regardless of prior therapy. Patients with 2 prior lines of therapy had a higher response rate (30.1% vs. 25.6%) compared with those with >2 prior lines of therapy. The greatest benefit, with an ORR of 44.4% was observed in patients with prior SCT. Collectively, these data support the clinical benefit of single agent selinexor and importantly in earlier lines of therapy. Further evaluation of selinexor in combination with other agents to improve outcomes in R/R DLBCL is ongoing. Disclosures Cavallo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Casasnovas:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Choquet:Keocyt: Honoraria. Gurion:Roche: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Sancho:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Astellas: Speakers Bureau; Actinium: Research Funding; Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. McCarthy:Karyopharm Therapeutics: Employment, Equity Ownership. Ma:Karyopharm: Employment, Equity Ownership. Corona:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Van Den Neste:Gilead: Other: travel support. Canales:Sandoz: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau.

Introduction - Salvage chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) is the standard-of-care for relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL) patients. Eligibility is based on the presence of chemo-sensitive disease as defined by complete remission (CR) or partial remission (PR) according to FDG PET/CT study post salvage therapy. Patients achieving CR prior to auto-HCT have better prognosis than those undergoing it in PR. However, to this date, it is not clear whether one should struggle to achieve CR prior to auto-HCT or is PR after first salvage therapy good enough. Aim - To evaluate the role of additional salvage regimen prior to autologous HCT in R/R DLBCL patients who achieved PR per FDG PET/CT following first salvage regimen. Methods - We retrospectively reviewed the medical records of all patients who underwent auto-HCT for R/R DLBCL at three Israeli stem cell transplant centers between 2008 and 2018. Patients were identified based on the reports to the EBMT registry or according to the center's surveillance data. We recorded and compared outcomes between patients who achieved PR after first salvage therapy and proceeded immediately to auto-HCT vs. patients who continued with additional salvage treatment (either the same or a different regimen) before auto-HCT. Outcomes were compared between these groups and between patients who achieved CR after first salvage and patients with chemo-refractory disease who proceeded to transplant. Continuous variables were described as the mean, median, standard deviation and range of n observations. Categorical data were described with contingency tables including frequency and percent. Differences between the two groups of patients were examined by the Mann-Whitney test for continuous variables, and the two-tailed Fisher's exact test for categorical variables. Progression Free Survival (PFS) was defined as the time from autologous HCT to post transplant disease progression or to death from any cause, whichever occurred earlier. Overall survival (OS) was defined as the time from HCT until the date of subject death from any cause. The Kaplan-Meier method was used to estimate the distribution and median PFS and OS. Disease response and disease progression were assessed according to the Lugano criteria. Results - Between the years 2008 - 2018 149 patients underwent auto-HCT for R/R DLBCL. After first salvage chemotherapy 81 patients (54%) achieved CR, 50 patients (33%) achieved PR and 18 (12%) had progressive disease (PD). Among the 50 patients achieving PR after first salvage, 30 patients (60%) proceeded immediately to transplant and 20 patients (40%) were treated with additional salvage treatment. There were no differences between the two groups in the characteristics of the patients, the disease and regimens being given (Table). Median PFS was better for patients proceeding to HCT in PR compared to those who continued with additional salvage therapy in order to achieve CR (not reached vs. 12.5 months, p=.089). This was also true, with respect to OS (105 months vs. 35 months, p=.019). Interestingly, OS was comparable between patients who proceeded to transplant in CR or in PR after first salvage (Median not reached, vs. 105 months, p=0.245). Among patients who received further salvage chemotherapy (either the same or a different regimen) and obtained CR before HCT (n=8), overall survival was comparable to those who achieved CR after first salvage (mean 84 months vs. 99 months, p=.35). Patients who were still in PR after second salvage had a dismal prognosis which was comparable to that of patients proceeding to HCT in progressive disease after first salvage (mean OS of 11 vs. 22 months, p=.24). Conclusions - Albeit the small number of patients, our results do not support the administration of further salvage treatments in R/R DLBCL patients achieving PR after first salvage treatment in order to achieve pre-transplant CR. Table Disclosures Gurion: Roche: Consultancy.

Introduction: Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has remained the standard of care as first line treatment for diffuse large B-cell lymphoma (DLBCL) for almost two decades. Treatment outcomes are still suboptimal, as approximately 40% of patients have refractory disease or relapse. Prospective studies recently examined whether the addition of various drugs to R-CHOP (termed R-CHOP+ X) could improve outcomes. The aim of this study was to compare the efficacy and safety of R-CHOP vs. R-CHOP +X as first line treatment for DLBCL. Methods: Systematic review and meta-analysis of randomized controlled trials including patients with DLBCL, comparing first line treatment with R-CHOP vs. R-CHOP+X (i.e. R-CHOP with the addition of another single drug). The Cochrane Library, MEDLINE, conference proceedings and references were searched until June 2019. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included overall response rate (ORR), complete response (CR) rate, disease control and safety. Results: Our search yielded seven trials conducted between the years 2010 and 2019, including 2939 patients (three abstracts, and four published in peer review journals). Median age of patients ranged between 50 to 67 years. The added drug was bortezomib and lenalidomide - each drug in two trials; gemcitabine, bevacizumab and ibrutinib - each drug in one trial. Three trials included all DLBCL patients regardless of cell of origin, whereas four trials included only patients with non-GCB DLBCL. Characteristics of trials included in the meta-analysis are described in Table 1. Regarding OS, the point of estimate favored improved OS with R-CHOP+X as compared to R-CHOP, yet without statistical significance, HR 0.87, [95% confidence interval (CI) 0.73-1.04, I2=0, 1984 patients, 5 trials]. The ORR and CR rates were similar in the two arms (RR 0.97 [95% CI 0.93-1.02, I2=65%, 2824 patients, 7 trials], and RR 0.99 [95% CI 0.93-1.05, I2=37%, 2826 patients, 7 trials], respectively). However, there was a trend towards improved disease control in the RCHOP+X arm, HR 0.89 [95% CI 0.78-1.01, I2=36]. Regarding safety, three trials (N=1200) reported serious adverse events. There was a significant increase in adverse events in the R-CHOP+X group, RR 1.42 [95% CI 1.24-1.64. I2=55%]. In addition, there was more hematologic toxicity in the R-CHOP+X arm, as reflected by higher rates of grade III/IV thrombocytopenia, anemia and neutropenia. Conclusions: The addition of an extra drug to the conventional first line R-CHOP regimen in patients with DLBCL resulted in a trend towards improved disease control compared to standard R-CHOP. However, there was no significant change in response rates or OS, and R-CHOP+ X was associated with an increased risk for serious and grade III/IV hematological adverse events. R-CHOP still remains the "gold standard" of treatment for DLBCL. Further analyses could perhaps reveal subgroups that would benefit from the addition of an additional drug to this regimen. Disclosures Gurion: Roche: Consultancy.

Background We characterized the incidence of central nervous system (CNS) involvement, risk factors and outcome in a large single institution dataset of peripheral T-cell lymphoma (PTCL). Methods Retrospective review of the PTCL database at Memorial Sloan Kettering Cancer Center. We identified 231 patients with any subtype of PTCL between 1994-2011 with a minimum six months of follow-up or an event defined as relapse or death. Results Histologies included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (31.6%), angioimmunoblastic (16.9%), anaplastic large cell lymphoma (ALCL), ALK- (12.1%), ALCL, ALK + (6.1%), extranodal NK/T-cell lymphoma (7.4%), adult T-cell leukemia/lymphoma (ATLL) (7.4%), and transformed mycosis fungoides (8.7%). Seventeen patients had CNS disease (7%). Fifteen had CNS involvement with PTCL and two had diffuse large B-cell lymphoma and glioblastoma. Median time to CNS involvement was 3.44 months (0.16-103.1). CNS prophylaxis was given to 24 patients (primarily intrathecal methotrexate). Rates of CNS involvement were not different in patients who received prophylaxis. Univariate analysis identified stage III-IV, bone marrow involvement, >1 extranodal site and ATLL as risk factors for CNS disease. On multivariate analysis, >1 extranodal site and international prognostic index (IPI) ≥ 3 were predictive for CNS involvement. The median survival of patients with CNS involvement was 2.63 months (0.10-75). Conclusions Despite high relapse rates, PTCL, except ATLL, carries a low risk of CNS involvement. Prognosis with CNS involvement is poor and risk factors include: >1 extra nodal site and IPI ≥3.