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Background: Patients with B-cell lymphoma have poor clinical outcomes to SARS-CoV-2 infection (COVID-19) and are also more likely to have suboptimal responses to immunization. An understanding of which lymphoma patients are at greatest risk of poor COVID-19 vaccine response and what aspects of immunity are most impaired is critical for developing strategies to protect these patients from a potentially fatal infection. Methods: We enrolled 149 participants, including 129 with lymphoma and 20 age-matched controls, who received a complete COVID-19 vaccination series to assess how B- and T-cell vaccine responses vary among clinically relevant subgroups and over time. This cohort included 99 patients with prior anti-CD20 treatment, ranging from 1 week to 17 years prior, allowing us to assess relationships between timing and intensity of anti-CD20 exposure and vaccine response. The cohort also included 18 patients who began treatment with an anti-CD20-containing regimen after being fully vaccinated, in whom we are assessing the potential efficacy of a pre-therapy vaccination strategy. Peripheral blood samples were taken on average 28 days and 4 months after last vaccine dose. B-cell responses are being profiled by measuring anti-Spike serum IgG, RBD-ACE2 blocking activity, and spike-specific memory B cells. T cell assessments include quantitation of spike-specific activation and cytokine production via interferon-gamma ELISPOTs and multiparameter flow cytometry. Results: The 129 participants with lymphoma had a median age of 68, were 59% male, and 70% had either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Thirteen percent had no therapy prior to vaccination, half had not been treated in the past six months and 36% had been treated recently or were currently being treated. Ninety-three percent received an mRNA COVID-19 vaccine. Although we did not detect a statistically significant difference in vaccine response between previously untreated lymphoma patients and controls, 3/17 were negative for blocking antibodies post-vaccine, compared to 0/20 controls (Fishers exact test p=0.09, Figure 1A). Lymphoma patients with any history of treatment had impaired serologic responses to the vaccine compared to previously untreated patients (p=0.01). Responses did not vary by specific lymphoma histology. Blocking antibodies were evident in only 45% and 3% of patients recently/currently treated with a BTK inhibitor or an anti-CD20 antibody, respectively (Figure 1A). Closely evaluating all patients who had ever received anti-CD20 antibody therapy, we found a strong linear correlation between time since last anti-CD20 treatment and RBD-ACE2 binding inhibition (p Conclusions: Treatment with anti-CD20 antibodies significantly impaired COVID-19 vaccine-induced humoral responses in patients with lymphoma in a manner dependent on the time elapsed since last anti-CD20 treatment. Vaccination at least six months after anti-CD20 treatment, likely co-incident with recovery of the B-cell compartment, was associated with positive blocking antibody titers. These data suggest that booster vaccination strategies are more likely to succeed in lymphoma patients who have not received anti-CD20 treatment for at least 6 months and that those patients with recent anti-CD20 treatment may benefit most from passive immunization strategies. Forthcoming results from the pre-therapy vaccination cohort will also help inform sequencing of additional vaccine doses, passive immunization, and anti-cancer treatments. Figure 1 Figure 1. Disclosures Shree: Gilead: Other: Spouse's employment. Beygi: Kite/Gilead: Current Employment. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Khodadoust: CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Kurtz: Roche: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech: Consultancy. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; Celgene: Consultancy, Research Funding; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Levy: GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Kira: Membership on an entity's Board of Directors or advisory committees; Abintus Bio: Membership on an entity's Board of Directors or advisory committees; Khloris: Membership on an entity's Board of Directors or advisory committees; Virsti: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees.

Background: MM clinical trials often have stringent eligibility criteria that limit the enrollment of patients (pts) reflective of the general patient population (Shah, Clin Lymphoma Myeloma Leuk 2017). The Connect® MM Registry, a prospective observational study of pts with newly diagnosed MM (NDMM) in the US, provided the opportunity to examine differences between pts with MM who were identified as RCT-eligible vs -ineligible, to observe the generalizability of clinical trial results to real-world clinical settings. Differences in baseline characteristics, treatment, clinical outcomes, and HRQoL were examined in RCT-eligible and -ineligible pts from this registry, which represents an unselected, broad real-world population. Methods: Pts with NDMM were enrolled at 250 community, academic, and government sites. Eligible pts were ≥18 y of age with symptomatic MM diagnosed ≤2 months preenrollment per the International Myeloma Working Group (IMWG) criteria. For this analysis, pts were considered ineligible for RCT per the following key exclusion criteria previously described: absolute neutrophil count ≤1.5 × 109/L, platelet count ≤75 × 109/L, creatinine >2.5 mg/dL, AST/ALT >3 times the ULN, peripheral neuropathy grade >2; ECOG PS 3/4; history of myelodysplastic syndromes/other hematologic malignancies, or solid tumors (Shah 2017). Sites administered pt HRQoL questionnaires and provided clinical data at baseline and quarterly during follow-up until death or study discontinuation. Differences in HRQoL at baseline, changes from baseline to 1 and 2 years, and survival outcomes, adjusted for covariates via propensity score, were compared between RCT-eligible/-ineligible pts. Results: Of the 3011 pts enrolled, 2873 pts met the CRAB (hyperCalcemia, Renal failure, Anemia, and Bone disease) criteria per IMWG at enrollment. Of these, 1622 (56.5%) were identified as RCT-eligible and 1251 (43.5%) as RCT-ineligible (data cut-off February 7, 2019). Both groups were similar in median age, sex, race, and ethnicity distribution, although the RCT-ineligible group had more pts aged ≥75 y (26.3% vs 23.2%) and more pts with ECOG PS 3/4 (6.2% vs none). Overall, 34.5% of RCT-ineligible pts received a transplant vs 42.8% of RCT-eligible pts. More RCT-ineligible pts had ISS stage III disease (39.4% vs 19.8%), elevated calcium (≥11.5 mg/dL; 12.7% vs 6.8%), elevated creatinine (>2.0 mg/dL; 40.3% vs 6.5%), and low hemoglobin (2 g/dL Conclusions: The CONNECT MM registry provided the opportunity to examine key differences between RCT-eligible and -ineligible pts. By applying common RCT eligibility criteria, a substantial proportion of MM pts (43.5%) in this real-world population may have been ineligible to participate in a RCT. RCT-ineligible pts had advanced disease, poor performance status, and poor laboratory parameters at baseline vs RCT-eligible pts, which could affect PFS and OS. These findings enhance our understanding of HRQoL among MM pts, which at present, is largely based on RCT participants. A similar magnitude of HRQoL improvement in both groups at 1 and 2 years suggests the need to evaluate RCT eligibility criteria in MM to help broaden enrollment and maximize external validity. Disclosures Wagner: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Toomey:Celgene: Consultancy. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Jagannath:Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Rifkin:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline plc: Research Funding; Amgen: Consultancy, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Catamero:Celgene: Employment, Equity Ownership. Abonour:BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

BACKGROUND: Rd continuous is now a standard treatment option in patients (pts) with transplant-ineligible NDMM based on the results of the large phase 3 registrational FIRST trial showing significant PFS and OS benefits of lenalidomide (LEN) + low-dose dexamethasone until disease progression (Rd continuous) vs melphalan + prednisone + thalidomide (MPT). However, pts who relapse on frontline LEN represent a growing population for whom there is limited clinical evidence on subsequent treatment. Factors associated with relapse within 12 mos in Rd- and MPT-treated pts (LDH ≥ 200 U/L, ISS stage III, high-risk cytogenetics, ECOG PS ≥ 2, and baseline platelet count ≤ 150 × 109/L) indicate that the individual risk of progression may involve a combination of disease biology, genetics, and pt-specific factors (Facon, EHA 2019). Physicians may consider these early relapse factors when making treatment decisions. To characterize pts relapsing while receiving frontline LEN, this analysis evaluated Rd-treated pts from the FIRST trial who progressed while receiving LEN based on their time of relapse, type of relapse (CRAB [symptomatic] vs non-CRAB [nonsymptomatic]), and second-line treatment. METHODS: Pts randomized to Rd continuous (n = 535) or Rd for 18 cycles (n = 541) arms and who progressed while receiving LEN or within 60 days of treatment end (per IMWG criteria) were pooled and grouped according to their time of relapse after randomization (< 12 mos = early< 12; 12-18 mos = early12-18, and > 18 mos = late relapse). The data cutoff was January 2016. RESULTS: Of the 389 pts who relapsed, 203 had early< 12 relapse, 69 had early12-18 relapse, and 117 had late relapse. Pts who relapsed within the first 12 mos or between 12 and 18 mos had higher rates of elevated LDH, ISS Stage III disease, and ECOG PS 2 compared with those who relapsed beyond 18 mos (Table). Early< 12 and early12-18 relapses were also associated with poor PFS and OS outcomes. Median PFS in pts with early< 12, early12-18, and late relapse was 6.5, 15.9, and 26.4 mos, and median OS was 26.8, 41.6, and 78.0 mos, respectively (Figure). Pts with late relapse had more dose reductions prior to PD vs those with early relapse and were more likely to experience nonsymptomatic progression. Across the 3 groups, in pts experiencing a nonsymptomatic progression who started second-line treatment, 88% started second-line treatment prior to experiencing CRAB symptoms. The median time from PD to second-line treatment was shorter in those with CRAB relapse (1.4-2.5 mos) vs non-CRAB relapse (2.5-5.9 mos). Second-line treatment was reported in 170 (83.7%), 62 (89.9%), and 99 (84.6%) pts with early< 12, early12-18, and late relapse, respectively. The majority of these pts received bortezomib-based regimens (65.6% overall), most commonly bortezomib + dexamethasone, bortezomib + melphalan + prednisone, or bortezomib + alkylator (cyclophosphamide or bendamustine). Second PFS was similar regardless of time of relapse. CONCLUSIONS: This analysis focused on an emerging and clinically relevant population of transplant-ineligible pts relapsing on frontline LEN. Pts with late relapse on LEN more commonly had nonsymptomatic progression vs pts relapsing early. This raises the question on the possible impact of the immune stimulatory effects of LEN in pts able to remain on therapy and achieve a longer OS and warrants further investigation of the biological impact of IMiD agent-based therapies on long-term disease control. The increase in dose reductions in the late- vs early-relapse groups is also an important consideration for continuous treatment. Consistent with the prior analysis of the FIRST study exploring Rd and MPT-treated pts with early< 12 relapse (Facon, EHA), pts relapsing on LEN within 12 mos and between 12-18 mos both appeared to have functionally high-risk disease and represent a population with an unmet need that should be considered for inclusion in clinical trials investigating new therapeutic strategies. Due to the timing of the FIRST trial, limited novel-novel agent combination treatments were available at relapse, and the majority of pts received bortezomib-based second-line regimens. These results highlight the need for effective therapies for pts with early relapse. Further characterization of first- and second-line outcomes according to type of relapse are ongoing and will be reported at the meeting. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Merck: Honoraria. Delforge:Amgen, Celgene, Janssen , Takeda: Honoraria. Weisel:Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding. Srinivasan:Celgene: Employment, Equity Ownership. Costa:Celgene: Employment, Equity Ownership. Robinson:Celgene: Employment, Equity Ownership. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Introduction: The treatment of acute myeloid leukaemia (AML) with intensive induction regimens remains a challenge in low and middle incomes countries. Early induction related deaths particularly due to infectious complications are a major problem. This is in stark contrast to high-income countries where induction mortality has declined significantly over the last 2 decades with improved antibiotic use and supportive care. In this study we assess induction mortality (all cause and infection related) in AML patients who received intensive induction therapy in a tertiary cancer centre in India over a 10-year period (2008-2017). Methods: We included patients with newly diagnosed AML treated at Cancer Institute, Chennai in South India who received intensive induction therapy. Intensive therapy was defined as use of any anthracycline with cytarabine (3+7/ADE/others). We assessed baseline demographics including age, gender, cytogenetic risk status, and type of induction regimen used. We also assessed key clinical outcomes including patterns of antimicrobial prophylaxis and treatment, infectious complications, cause of death, ICU stay, and length of hospital stay. Induction mortality was defined as deaths occurring within 45 days of initiating treatment for AML or start of 2nd induction. Results: Between January 2008 and December 2017, 510 patients with AML were evaluated at Cancer Institute, Chennai and accepted for treatment. Excluding 51 patients with APML and 55 patients who were unfit for intensive induction, 404 patients received treatment with an intensive induction regimen. Median age was 23 years (Range: 1-74 years) and 219 (54.2%) were male patients. 165(40.8%) patients were less than 18 years of age. Among those who had cytogenetic and/ molecular data for risk stratification [N=341 (84.7%)], 101 (29.6%) were low risk, 166 (48.7%) intermediate risk and 74 (21.7%) high risk. Therapy details: 318 (78.7%) patients received daunorubicin and cytarabine ('3+7'), 52 (12.9%) received ADE, and 38 (8.4%) received other combinations ofdaunorubicin and cytarabine. 87(21.5%) of the cases had infection at the time of presentation. 389(96.8%) had an episode of febrile neutropenia with 184(45.5%) requiring management in Intensive Care Unit (ICU). Focus of infection could be identified in 294(72.7%) of the patients with 207(51.2%) having a positive culture. The overall incidence of induction mortality over the entire study period was 15.6%(n=63)and 14.8% for the most recent year included (2017). The majority of the deaths (n=53; 84.1%) were due to infectious complications (fig1). Median time to death from start of induction was 19 days. The incidence of fungal pneumonia significantly reduced since 2012 when thethe antifungal prophylaxis was switched from fluconazole to voriconazole (p=0.03). Starting in 2012, an increase in the incidence of multi-drug resistance (MDR) gram negative septicaemia and mortality (MDR: carbapenem resistant enterobacteriacea sensitive only to colistin and tigecycline) was noted. This led to proactive use of colistin in patients with febrile neutropenia and septic shock, a GI focus or baseline stool colonisation by MDR gram negative organisms.Despite this, during the last 4 years(2014-2017), there has been a significant rise in the incidence of sepsis and death due to MDR gram negative organisms (fig2). The proportion of deaths attributable to MDR sepsis is 23.8%. The early use of colistin, tigecycline and carbapenems did not significantly decrease the mortality. Conclusions: The induction mortality remains high at 15.6% and is in contrast to the declining induction mortality in high-income countries. While the morbidity and mortality due to specific infections (specifically fungal pneumonia) have changed over time, there is no signfiicant decline in infectious or all cause induction mortality over the 10 years. In the last four years, MDR gram negative sepsis has been a major cause of morbidity and mortality. The early and increased use of broad spectrum antibiotics like tigecycline, colistin and carbapenems has not led to a decrease in MDR gram negative sepsis. Overall, despite improvements in supportive care and early use of broad spectrum antimicrobial agents, infection related morbidity and mortality remains a substantial challenge in treating acute myeloid leukaemia in low- and middle-income countries. Disclosures No relevant conflicts of interest to declare.

Background : Treatment for relapsed multiple myeloma (MM) has evolved with the availability of many novel agents; outcomes in patients with newly diagnosed MM have improved with IMiD® agents (lenalidomide [R] or pomalidomide) and proteasome inhibitor (PI) use. Regardless of autologous stem cell transplant, many patients receive R maintenance therapy (Jagannath, Blood Adv 2018; Palumbo, N Engl J Med 2012). However, there is a lack of data describing the nature of relapse and treatment choices for patients progressing on R maintenance therapy. Recent phase III data do not evaluate these patients who are relapsed or refractory to R; current treatment guidelines do not specifically recommend second-line (2L) treatment options for these patients (Laubach, Leukemia 2016). However, phase III data show that pomalidomide in combination with bortezomib and dexamethasone improves progression-free survival (PFS) (HR 0.54; P = 0.0027) in R-exposed and refractory patients, including those with 1 prior line (Richardson, J Clin Oncol 2018). The Connect MM Registry is a US, multicenter, prospective observational cohort study designed to examine diagnostic and treatment patterns, clinical outcomes and quality of life in patients with MM. For patients who received R maintenance therapy, we describe patterns of relapse, 2L treatment choice, and outcomes. Methods : From 250 sites, transplant eligible and ineligible adult patients ≤ 60 days from MM diagnosis were enrolled (N = 3011). Patients were treated at physicians' discretion and followed up for treatment and outcomes until early discontinuation or study end. Patients who relapsed during R maintenance therapy (≤ 15 mg; assessed by treating physician), were analyzed for baseline (BL) characteristics, nature of relapse, and 2L treatment. Patients with symptoms at time of relapse were defined as the presence of ≥ 1 CRAB (hyperCalcemia, Renal failure, Anemia, and Bone disease) criterion ± 60 d from PD; absence of CRAB criteria at PD in this window was considered nonsymptomatic relapse. Primary endpoint was PFS from start of 2L; safety (serious adverse events; SAE) from start of 2L was also assessed. Logistic regression analyses on all BL factors and factors before start of 2L treatment were performed to determine covariates differentiating comparator groups. Survival outcomes were analyzed using a Cox regression after adjusting for covariates. Results : Data cutoff: 1/15/18. Of 2938 treated patients, 1102 entered 2L, 236 having received R maintenance therapy in 1L. Of those patients, 52% (n = 123) and 47% (n = 112) experienced symptoms at time of relapse and nonsymptomatic relapse, respectively (data not available for 1 patient). The top ten 2L regimens are presented in the Table. Median duration of prior maintenance therapy (367 d [IQR: 577] vs 489 d [IQR: 599]) and time from first progression to start of 2L treatment (0.3 vs 0.3 mo) did not notably differ between nature of relapse groups. Prolonged median PFS from start of 2L was observed for patients receiving triplet+ (≥ 3 agents) vs doublet (≤ 2 agents) regimens (HR: 0.72; Figure 1). PFS was better for IMiD agent + PI group compared with PI (without IMiD agents) group (HR, 0.68; Figure 2). Results of sensitivity analyses and overall survival will be presented. SAEs occurred similarly among treatment groups: 42.6% with IMiD agent + PI, 34.5% with IMiD agent (without PI), and 35.8% with PI. Conclusions: This is the first description of relapse patterns, 2L treatment choice and survival outcomes after PD on R maintenance therapy in community-based patients. Nearly equal numbers of patients had symptoms at time of relapse and nonsymptomatic relapse on R maintenance therapy. After PD on R maintenance, approximately 50% of patients switched to PI regimens without IMiD agents, 25% continued with IMiD agent + PI regimens, and 25% continued in the IMiD agents group. Our data show PFS benefit for triplet+ over doublet treatment in 2L. Patients in the IMiD agent + PI group gained survival benefits over patients in the PI group. Further characterization of the patients continuing with IMiD treatment in 2L after R maintenance therapy relapse (~ 25% of patients) are ongoing. Follow-up with recently approved agents (elotuzumab, daratumumab) and their use in 2L is limited in this analysis. These data may be used to better inform treatment choices after relapse on R maintenance therapy. Disclosures Jagannath: Celgene: Consultancy; Merck: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Rifkin:Celgene: Consultancy; Boehringer Ingelheim: Consultancy; McKesson: Equity Ownership; EMD Serono: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Sandoz: Consultancy. Terebelo:Celgene: Consultancy; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Pharmacyclics: Speakers Bureau. Toomey:Celgene: Consultancy; Myriad Genetics: Speakers Bureau; Dava Oncology: Other: Travel. Durie:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Hardin:Celgene: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Wagner:EveryFit: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene: Employment. Kitali:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background: The use of PET CT has become instrumental in the management of Hodgkin's lymphoma (HL), with multiple studies favoring PET adapted therapies. Current guidelines recommend using the Deauville score (DS) for assessment of end therapy PET-CT scans. We looked at the predictive ability of end therapy PET CT DS in a cohort of HL. Methods: Adult patients diagnosed with, and treated for, Hodgkin's lymphoma between 2007 and 2015 with end-of-treatment PET CT scans were included in this retrospective analysis. Results: One hundred and ninety-eight patients [median age- 35 (18-74) years, advanced disease: 147 (74%); bulky disease: 54 (27%)] underwent end-of-therapy PET CT scanning with Deauville scoring. The chemotherapy regimens used were as follows: ABVD in 167 patients (84%); COPP/AVD in 20 patients (10%) and other regimens in 11 patients (6%). The end of therapy Deauville score (DS) was 1 or 2 in 160 patients (81%), 3 in 9 patients (5%) and 4 or 5 in 29 patients (14%). The median follow-up was 62 months. The 5-year DFS for patients with DS 1 or 2 was 85%, DS 3 was 65% and DS 4 or 5 was 40% (p Based on this analysis, the positive and negative predictive values for predicting treatment outcome on the basis of end of therapy PET CT by Deauville scoring were 0.48 and 0.85 respectively. Conclusions: DS 1 and 2 were highly predictive of excellent survival while DS 4 and 5 were predictive for treatment failure. However, the positive predictive value was overall lower than reported from other studies. DS score of 3 was seen in very few patients at end therapy. Further modification of this is required for clear interpretation. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo.

CD8 T cells are classified as naı̈ve, effector, or memory cells on the basis of CD45RA, CD62L, and CCR7 expression. Sequential engagement of cell-surface CD62L and CCR7 receptors is required for efficient trafficking to lymphoid tissue by means of high endothelial venules. Naı̈ve CD8 T cells are CCR7+CD62L+ CD45RA+, whereas long-term memory cells are CCR7+CD62L+CD45RA−. Effector cytotoxic T cells are thought to be CCR7−CD45RA+. The distribution of CD8 subsets and cytolytic protein expression in healthy donors and donors seropositive for human immunodeficiency virus (HIV) were compared. In HIV-infected subjects, CCR7− CD8 T cells expanded at the expense of naı̈ve and long-term memory cells. In both healthy donors and HIV-infected donors, CCR7+ CD8 T cells were uniformly negative for perforin. In all subsets, perforin and granzyme A were not coordinately expressed, with perforin expression being more tightly regulated. The properties of CD8 T cells specific for cytomegalovirus, Epstein-Barr virus (EBV), and HIV were studied by staining with major histocompatibility complex peptide tetramers. Antigen-specific cells for chronic infections with these viruses were uniformly CCR7− and predominantly CD62L−. In 2 HIV-seropositive donors, 3- to 4-fold fewer EBV-tetramer–positive cells were present in lymph nodes compared with blood. Antigen-specific CD8 T cells are therefore preferentially excluded from lymphoid sites, even when infection is primarily in lymphoid tissue. This may protect lymphoid tissues from immunopathological changes but compromise immune defense against viruses, such as HIV and EBV, that target lymphocytes. HIV-specific CD8 T cells do not express CD45RA, whereas EBV- and CMV-specific CD8 T cells are heterogeneous in CD45RA+expression. Lack of CD45RA expression may indicate incomplete differentiation of HIV-specific CD8 T cells to cytotoxic T cells.

The functional status of circulating human immunodeficiency (HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T cells that produced IFN-γ after stimulation with HIV-infected primary CD4 T cells. In 2 subjects, the frequency of IFN-γ–producing cells increased 4-fold when IL-2 was added to the culture medium; in another subject, IFN-γ–producing cells could be detected only after IL-2 was added. IFN-γ–producing cells ranged from 0.4% to 3% of CD8 T cells. Major histocompatibility complex–peptide tetramer staining, which identifies antigen-specific T cells irrespective of function, was used to evaluate the proportion of HIV-specific CD8 T cells that may be nonfunctional in vivo. CD8 T cells binding to tetramers complexed to HIV gag epitope SLYNTVATL and reverse transcriptase epitope YTAFTIPSI were identified in 9 of 15 and 5 of 12 HLA-A2–expressing seropositive subjects at frequencies of 0.1% to 1.1% and 0.1 to 0.7%, respectively. Freshly isolated tetramer-positive cells expressed a mixed pattern of memory and effector markers. On average, IFN-γ was produced by less than 25% of tetramer-positive CD8 T cells after stimulation with the relevant gag or reverse transcriptase peptide. In all subjects tested, freshly isolated CD8 T cells were not cytolytic against peptide-pulsed B lymphoblastoid cell line or primary HIV-infected CD4 T-cell targets. Exposure to IL-2 enhanced the cytotoxicity of CD8 T cells against primary HIV-infected CD4 targets in 2 of 2 subjects tested. These results suggest that a significant proportion of HIV-specific CD8 T cells may be functionally compromised in vivo and that some function can be restored by exposure to IL-2.

Cytotoxic T lymphocytes (CTL) lyse antigen-bearing target cells by two distinct pathways. Whereas granule exocytosis targets any antigen-bearing cell, fas-mediated cytotoxicity kills only fas-expressing cells and does not require antigen expression. Fas pathway activation can potentially lead to lysis of uninfected bystander cells. We examined the relative usage of the two pathways by CTL clones and cell lines directed against four different human immunodeficiency virus (HIV) proteins in lysing primary HIV-infected targets. Although fas was expressed on HIV-infected primary CD4+ T cells, their lysis by antigen-specific CD8+ CTL was only by the granule pathway. Fas ligand (fasL) was not detectable on antigen-specific CD8 clones, T-cell lines, or circulating HIV-specific CD8 T cells from HIV-infected donors, stained with a tetrameric HLA-A2-HIV-peptide complex. FasL expression by HIV-specific CTL clones was not activated by exposure to HIV-presenting cells, but was after unphysiological stimulation with phorbol myristate acetate (PMA). CTL clones did not lyse bystander Jurkat cells, but HIV-infected primary CD4+ T cells lysed uninfected bystander cells by the fas-mediated pathway. These results suggest that HIV-specific CD8+ CTL do not cause HIV immunopathology by lysing bystander cells. On the contrary, fas-mediated lysis of uninfected cells by HIV-infected cells may contribute to CD4 decline.