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PDF file - 339K, Flow cytometry histograms of serial levels of p-ERK and p-mTOR in patient samples.

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown.Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation.Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027).Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.

PDF file - 50K, Primers for KIT gene mutation testing.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

ImportanceTo our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant.ObjectiveTo evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose–positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma.Design, Setting, and ParticipantsA single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT.InterventionsTwo cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment.Main Outcomes and MeasuresThe primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety.ResultsForty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting.Conclusions and RelevanceResults suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant.Trial RegistrationClinicalTrials.gov Identifier: NCT03077828

PURPOSE Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Melphalan at a dose of 200 mg/m(2) (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database (n = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32–62) in favor or the BuMelVel group (95% CI; 23–37) (p=0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44–0.97)(p=0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

As new data sources arrive, novel methods of defining undiscovered distributions are increasingly useful. In this presentation, the Hazard-Product method of generalizing survival functions is intro...

Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Introduction: Approximately 30-35% of patients with classic Hodgkin Lymphoma will prove refractory to frontline therapy or relapse subsequently. Traditional second-line chemotherapy regimens including ifosfamide, carboplatin, and etoposide (ICE) result in complete response rates of ~50%. Achievement of complete metabolic response (CMR) assessed by PET/CT imaging prior to autologous hematopoietic stem cell transplant (AHSCT) predicts favorable progression free survival (PFS) and overall survival (OS). PD-1 blockade is a well-established therapeutic strategy for the treatment of cHL. Pembrolizumab (PEM) is a checkpoint inhibitor targeting PD-1 currently FDA approved as monotherapy in relapsed cHL. We hypothesized that PEM in combination with ICE (PEM-ICE) chemotherapy would be a safe and effective regimen that would yield high CMR rates prior to AHSCT. Methods: This single arm, phase II, multi-institutional clinical trial evaluated the addition of PEM to ICE chemotherapy in AHSCT eligible patients with relapsed and refractory cHL (NCT03077828). The regimen consisted of 21 day cycles of PEM 200 mg IV on day 1 with standard ICE including ifosfamide 5 g/m2 with MESNA as a 24hr continuous infusion on day 2, carboplatin AUC 5 IV (max 800 mg) on day 2, and etoposide 100 mg/m2/day IV on days 1 to 3. Two cycles of PEM-ICE were followed by stem cell mobilization/collection. One cycle of PEM 200 mg IV monotherapy was then administered. Our primary endpoint was the rate of CMR on PET/CT (PET2) imaging defined as a Deauville score of ≤ 3. Images were reviewed centrally. An optional third cycle of PEM-ICE was permitted for patients achieving CMR to allow for appropriate timing of AHSCT. Secondary objectives included clinical outcomes (PFS and OS), safety and tolerability, and transplantation related metrics including ability to collect stem cells and time to engraftment. Results: A total of 42 patients were enrolled with 37 patients evaluable for the primary endpoint. Median age was 34 (19-70) with female predominance (n=27, 64%). 16 patients had primary refractory disease. The CMR rate assessed by PET/CT imaging following 2 cycles of PEM-ICE was 86.5% (95% CI, 71.2-95%), meeting our primary endpoint of improvement over historical outcomes to 70%. The PET2 ORR was 97.3% with 11% PR and 2.7% PD. PET2 scores were Deauville 1 in 45% (n=17), Deauville 2 in 27.0% (n=10), Deauville 3 in 8.1% (n=3), Deauville 4 in 13.5% (n=5), and Deauville 5 in 5.4% (n=2). New areas of PET-positivity in two cases were biopsied showing noncaseating granuloma in one case and EBV but no cHL in another. Five patients received the optional third cycle of PEM-ICE chemotherapy with 35 of the 37 evaluable patients proceeding to AHSCT. Seven patients had radiation as part of the conditioning regimen with an additional 4 patients receiving consolidative radiation following transplant. After a median follow up of 27 months, the median PFS was 26.9 months with survival probability at 24 months of 88.2% (Figure 1). Median OS was not reached with too few events but remained 95.1% at 27 months. The addition of PEM to ICE did not impair stem cell mobilization and all patients successfully collected, with 35 (87%) within 2 apheresis sessions (range 1-7). No patients had engraftment delays or failure. Of the 42 patients, all received at least one dose of PEM and were therefore eligible for toxicity analyses. 34 patients (81%) experienced adverse events (AEs) attributed to PEM and 22 patients (52.3%) had grade 3-4 AEs comprised of cytopenias, elevated AST/ALT, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe AEs attributed to PEM which included anemia, back pain, decreased EF, fever, and thrombocytopenia. There were no significant PEM-related autoimmune events that delayed a patient's treatment on protocol. There were two grade 5 toxicities on the protocol including a patient with cardiac arrest during stem cell collection and a patient with acute respiratory distress syndrome attributed to engraftment syndrome. Both were judged "possibly" related to PEM. Conclusions: Pembrolizumab with ICE chemotherapy is a tolerable and efficacious regimen with high CMR rate as assessed by PET/CT. Despite short follow up, patients had excellent PFS and OS in the post-transplant setting. The results support further investigation of PEM-ICE as second-line treatment for AHSCT eligible patients with relapsed and refractory classical Hodgkin lymphoma. Figure 1 Figure 1. Disclosures Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Allen: Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria; Secure Bio: Consultancy, Honoraria. Karmali: Epizyme: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Genentech: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy. OffLabel Disclosure: new combination of study agent with standard of care chemotherapy regimen

Introduction: There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era. Methods: This retrospective analysis included a subcohort from a recent study across 30 US sites (Evens et al. Blood 2020) augmented by data from 5 UK centers treated 2009-2018. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier & differences assessed by log-rank test. Univariate (UVA) associations were derived via Cox model and multivariable (MVA) models were constructed by forward selection of significant variables with P Results: 249 (US: 140 & UK: 109) pts with newly diagnosed HIV-BL were included. Clinical features included median age 43 (IQR 35-50 years [yrs]); male sex: 84%; ECOG PS: 2-4: 48%; elevated LDH: 85% (> 3x upper limit of normal (ULN) 49% & >5xULN 39%); >1 extranodal (EN) site: 60%; any CNS involvement (CNSinv) 25%; and +bone marrow (BM) 46%. MYC rearrangement was reported in 93% of pts with t(8;14) in 49%, break-apart probe in 41% and MYC-light chain in 3%; the rest had classical BL with negative MYC testing (4%) or missing result (3%) (otherwise classical BL). Median CD4 count was 217 (IQR 90-392 cells/µL) with 68% pts having CD4>100 cells/µL. At BL diagnosis, HIV viral load was detectable in 55%; 39% of pts were on cART. Baseline features were similar between the US & UK cohorts with significant differences only in ECOG PS 2-4 (32% vs 65%; P Tx regimens included: CODOX-M/IVAC (Magrath) 60%, DA-EPOCH 25%, HyperCVAD/MA 13%, & other 1%; most pts (87%) received rituximab (R). Similar regimens were used in pts with baseline CNSinv: Magrath 64%, DA-EPOCH 24% & HyperCVAD 12%. In the US, pts most frequently received DA-EPOCH (42%) followed by Magrath (32%) & HyperCVAD/MA (24%), whereas in the UK, 96% received Magrath. R was more frequently given in the US (94% vs 79%, P With median follow-up of 4.5 yrs, 3-yr PFS & OS were 61% & 66%, respectively, and nearly identical in both countries (Fig A). Pts with CD4>100 cells/µL had better 3-yr PFS (Fig B) & OS (68% vs 57% P=0.03). We observed significantly worse outcomes in pts with baseline CNSinv (3-yr PFS 36% vs 69%, P The incidence of CNS recurrence at 3 yr across all Tx was 11%. Higher incidence was observed with DA-EPOCH (P=0.032 vs other regimens; Fig F) with no difference according to CD4 count. Variables associated with PFS & OS on UVA included: ECOG PS 2-4, >1 EN, +BM, baseline CNSinv, LDH>ULN, CD4 5xULN (HR 2.09, P1 EN sites (HR 1.58 P=0.043). The same variables were significant on MVA for OS. Adjusting for all of the prognostic variables, Tx with Magrath was associated with longer PFS (adjusted HR, 0.45, P=0.005). Conclusions: These data represent the largest analysis of HIV-BL to date. There were favorable tolerance and outcomes with intensive R-containing regimens with Magrath being associated with lower TRM and the highest PFS. In addition, prognostic factors for pt outcomes were associated with lymphoma characteristics rather than with HIV-related features. Pts with baseline CNSinv represent a high-risk group with unmet therapeutic needs. Disclosures Alderuccio: Oncinfo: Honoraria; Puma Biotechnology: Other: Family member; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Celleron: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Pfizer: Honoraria. Danilov:Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy; Abbvie: Consultancy. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding. Reddy:Genentech: Research Funding; Abbvie: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy. Farooq:Kite, a Gilead Company: Honoraria. Bond:Seattle Genetics: Honoraria. Khan:Celgene: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Karmali:Karyopharm: Honoraria; Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Martin:Janssen: Consultancy; Regeneron: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Haverkos:Viracta THerapeutics: Consultancy. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board. Kamdar:Roche: Research Funding. Feldman:Eisai: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Smith:AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Bristol Meyers Squibb: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding. Portell:Amgen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; NCI: Research Funding; Seattle Genetics: Consultancy, Other; Janssen Scientific: Consultancy, Other. Cwynarski:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau.

In the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months.Patients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up.Between April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup.Despite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care.The National Cancer Institute.

Summary Background A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma. Methods A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1–21 in a 28 day cycle, oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1–21 every 28 days and oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Findings Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9–20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3–4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. Interpretation The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug–drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. Funding National Cancer Institute of the National Institutes of Health.

Introduction Clostridium difficile infection (CDI) is a leading cause of hospital-acquired infection. Allogeneic hematopoietic stem cell transplant (aHSCT) recipients in the peri-transplant periods represent an especially vulnerable population due to chronic immunosuppression, prolonged hospital stays, and routine use of antibiotics (abx). Previous attempts to identify potential risk factors (RF) for CDI are inconsistent in the literature. Objectives Our study goals are to describe CDI incidence, associated risk factors, and CDI characteristics in our own aHSCT population. Study results will be utilized in designing future infection prevention strategies and to promote abx stewardship. Methods We retrospectively evaluated all aHSCT recipients between Jan 2011-May 2017 at Loyola University Cardinal Bernardin Cancer Center. Inclusion criteria included age >18, 1st aHSCT, and hematological malignancy. Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification. RF for CDI included comorbid conditions, proton pump inhibitor (PPI) and abx use during the 1st 100 days after aHSCT, and development of acute (aGVHD) and chronic (cGVHD) graft vs host disease. Data pertaining to CDI classification was collected. aGVHD was graded based on the International BMT Registry System and cGVHD per the NIH consensus criteria. The peri-transplant period evaluated included 6 months prior to 2 years following aHSCT. Logistic regression analysis was performed to estimate adjusted odds ratios for factors associated with development of CDI. Results A total of 322 patients (pt) met our inclusion criteria, of which 89 (27.6%) developed CDI, 55 pts were classified as severe or severe-complicated per ACG criteria and 18 (20.2%) had recurrence within 60 days. Graft type consisted of 109 (33.9%) allogeneic matched related, 124 (38.5%) matched unrelated and 89 (27.6%) cord blood. This was a high risk group with most pts having either intermediate (60.1%) or high/very high (31.5%) disease risk. Infections were common, as 225 (69.9%) pts developing an infection during the 1st 100 days after aHSCT. In multivariable analysis, cord blood graft source (OR=1.99, 95% CI: 1.05-3.8, p = 0.036), PPI use (OR=2.02, 95% CI: 1.08-3.8 p = 0.028), and chronic GI GVHD (OR =5.86, 95% CI: 1.64-20.98, p = 0.018) were associated with increased odds of CDI. Lastly, female sex (OR=0.4, 95% CI: 0.25-0.78, p = 0.005) and GI tract infection (including hepatobiliary source) in first 100 days after HSCT (OR=0.41, 95% CI: 0.17-0.98 p=0.045) were associated with decreased odds of CDI. Of note, rates of II-IV aGVHD were low (N=49, 15%). Conclusion Our population had 27% incidence of CDI and we note that cord blood graft, PPI use, GI cGVHD were associated with increased risk for CDI. These findings may have important implications for the supportive care plans for aHSCT pts.

Introduction Liposomal daunorubicin/cytarabine (Vyxeos® or lipo-CD) is a dual drug liposomal encapsulation, delivering these drugs at a fixed 1:5 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, lipo-CD pts had improved survival and remission rates in a pivotal phase III study, with more reaching allogeneic transplantation (HCT), with lower post-HCT mortality and improved survival. With its enhanced pharmacokinetics, lipo-CD may provide a potent bridge to second transplant for early relapses after HCT. Here, we report our experience. Methods We retrospectively reviewed recipients of lipo-CD at our institution since FDA approval 8/2017. Of 23 pts, 8 relapsed Results Median age was 60 yrs. They received 1-4 lines of therapy (median 2) prior to first HCT with 5/8 pts having received 7+3 (cytarabine 100-200mg/m2 × 7 days + dauno 60-90mg/m2 × 3 days). 6 had adverse cytogenetics/genomic profiles. 7/8 had AML and 1 high grade MDS. Pts relapsed at 2 to 7 mo (median 4 mo) after first HCT, and all 8 received full lipo-CD induction (dauno 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy. [Table] 7/8 had Day 14 bone marrow biopsies: 3 were clear, 2 had >80% cytoreduction, and 2 had similar blast count. 3 with persistent disease underwent re-induction with lipo-CD (Days 1 and 3). All successfully proceeded to second transplant at 15-70 days after lipo-CD: 7 with same donor after melphalan 140mg/m2, and 1 from a different donor after busulfan/fludarabine. Tacrolimus was started on day + 7 and discontinued at day + 28 if no GVHD. 4/8 remain alive. 2 relapsed at 3 and 6 months post-HCT and are remarkably in CR at 19 and 16 mo after second transplant despite isolated CNS relapses, which were successfully treated. The other two relapsed at 2 and 3 mo post-HCT and are alive after second transplant. Conclusion Outpatient lipo-CD as a bridge to second transplant is feasible and effective in treating AML/MDS with early relapse after first HCT. While preliminary, survival appears favorable to that reported (14-23% at 1 year) in this very poor risk group, including those with adverse cytogenetics. Prospective multi-center trials are planned.

BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P

The purpose of this pilot study was to determine whether supplementation of a high-glycemic index breakfast meal with peanut butter attenuates the glycemic response.Sixteen healthy adults, aged 24.1 ± 3.5 years, reported in the morning to a nutrition assessment laboratory for two days of data collection, having fasted 8 to 12 hours. On day 1 (control), fasting blood glucose (BG) was measured using glucometers, then participants consumed two slices of white bread and 250 mL apple juice (60 g carbohydrate) within 15 minutes. BG was measured again at 15, 30, 60, 90, and 120 minutes after the first bite of the meal. On day 2, the protocol was repeated, except 32 g (2 tbsp) of peanut butter was added to the meal (treatment).The spike in BG was significantly lower on the treatment versus control day (35.8 ± 16.4 vs. 51.0 ± 20.8 mg/dL, respectively; p 0.01), and BG was significantly lower on the treatment day at 15, 30, and 60 minutes post-meal consumption (p 0.05).This study indicates that supplementation with 32 g (2 tbsp) peanut butter attenuates the magnitude of BG spike and overall glycemic response to high-glycemic index meal and may be a practical, beneficial strategy to prevent undesirable elevations in BG.

Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Summary Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC-amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2-year progression-free survival rate (PFS) was 49% and 48% and 2-year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2-year PFS (59% vs. 23%, P = 0·006) but similar 2-year OS as compared with SHL patients receiving R-CHOP. SHL DLBCL patients treated with R-CHOP, but not intensive induction, experienced significantly lower 2-year PFS and OS (P

High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

e20004 Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]

e20505 Background: Immunoparesis (hypogammaglobinemia) has been shown to impact outcomes in patients with newly diagnosed multiple myeloma (MM). Its impact in the post-transplant setting and potential risk of both infections and immune dysregulation impacting relapse is less clear. We sought to assess the role of immunoparesis both pre and post autologous stem cell transplant (ASCT) in newly diagnosed MM patients. Our primary outcome was the impact of immunoparesis on progression free survival (PFS) post-ASCT controlling for maintenance therapy. Methods: We evaluated all MM patients between 2008 and 2017 at Loyola University who underwent ASCT. Inclusion criteria included first ASCT and age > 18 years. We evaluated both the presence of and number of impacted immunoglobulin (Ig) classes pre-transplant and day 100, 6-months, and 12 months post-ASCT. Results: The most common MM isotype was IgG Kappa (41.01%). Immunoparesis pre-ASCT and post-ASCT at day 100, 6 months, and 12 months was seen in 75%, 89.5%, 80%, and 58.5% respectively. Median time from diagnosis to transplant was 7.75 months (5.98 – 13.73). When adjusting for pre-transplant response, conditioning regimen, and post-transplant maintenance, neither the absolute presence of or number of Ig-classes impacting was predictive of hazard of disease progression or death (OS) while ISS-stage, best response post ASCT, and time from diagnosis to transplant were (table). Conclusions: Contrary to studies in the pre-transplant setting, our analysis indicates that immunoparesis is not predictive of relapse or survival in the post-transplant setting, suggesting modification of disease process with treatment and ASCT. When controlled for maintenance therapy, immunoparesis does not increase risk of progression or decrease overall survival alleviating the concern for increased morbidity/mortality secondary to infections in the face of immunoparesis in the era of maintenance therapy. [Table: see text]

Introduction: Liposomal daunorubicin/cytarabine (Vyxeos®) is a dual drug liposomal encapsulation of cytarabine and daunorubicin, delivering drugs at a fixed 5:1 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, liposomal cytarabine/daunorubicin (lipo-cytara/dauno) patients had improved survival and remission rates in a pivotal phase III study of elder adults with high-risk acute myelogenous leukemia (AML). Furthermore, more lipo-cytara/dauno patients went to allogeneic stem cell transplantation (HCT), with lower mortality and improved survival compared to those induced with 7+3. With its enhanced pharmacokinetics, lipo-cytara/dauno may provide a potent bridge to transplant. We report our experience using lipo-cytara/dauno as a bridge to same donor lymphocyte infusion (DLI) or different donor HCT in high-risk AML. Methods: We retrospectively reviewed all patients who received lipo-cytara/dauno at our institution since the FDA approval in August 2017. Of the 21 patients who have been treated, 9 received it as a bridge to cell therapy. All patients received the drug by usual means under the FDA label. Results: The median age of the 9 patients who received lipo-cytara/dauno as a bridge to cell therapy was 59 years. Seven were male, and two were female. Patients had had 1-4 prior lines of chemotherapy (median 2) with 7 of 9 patients having received prior standard 7+3 induction (cytarabine 100-200 mg/m2 x 7 days infusion and daunorubicin 60-90 mg/m2 x 3 days). Most had adverse cytogenetics, and all 9 patients received full lipo-cytara/dauno induction (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy [Table]. Of the 9 patients, 6 had AML with very early relapse after HCT, with median time to relapse of 4 months (range 3 to 7 months). All 6 successfully proceeded to their planned cell infusion: 5 received same donor DLI after melphalan at 140 mg/m2, and 1 underwent second HCT from a different donor with busulfan/fludarabine conditioning at Days 15-40 after lipo-cytara/dauno. Of the remaining 3, two had relapsed AML after an initial remission (one was in first complete remission (CR1) for 3 months after 7+3/midostaurin induction and the other was in CR1 for 7 months after 7+3 induction/high dose cytarabine consolidation) and one had primary refractory disease (PREF) after 7+3 and azacitidine/venetoclax induction regimens. All 3 successfully underwent first HCT at Days 15-100 days after lipo-cytara/dauno bridge. The PREF patient received fludarabine/cyclophosphamide/TBI conditioning followed by matched unrelated donor transplant. Of the 2 with relapsed AML after initial remission, one received busulfan/fludarabine/thiotepa conditioning followed by umbilical cord stem cell transplantation and the other patient received fludarabine/cyclophosphamide/TBI conditioning prior to matched related donor transplant. Six of 9 had Day 14 bone marrow biopsies after lipo-cytara/dauno: 2 were in CR, 2 had >80% cytoreduction, and 2 had similar blast count. Three with persistent disease underwent reinduction with lipo-cytara/dauno (Days 1 and 3) and proceeded straight to cell therapy after. Median days to hospitalization after outpatient lipo-cytara/dauno was 6 days (range 3 to 14 days). Four out of 9 patients remain alive. Two were very early post HCT relapses (relapsed at 3 and 6 months post-HCT), both of which are remarkably in CR at 14 and 17 months after second cell therapy. Interestingly, both had CNS relapse, which were successfully treated, and both remain alive and in remission today. The other two had relapsed AML and PREF AML and underwent first HCT after lipo-cytara/dauno bridge. They remain alive and in remission at 1 and 8 months. Conclusion: In this retrospective study, outpatient lipo-cytara/dauno as a bridge to cell therapy is feasible and effective in very high-risk AML with no other viable options. While preliminary, survival appears favorable to that reported elsewhere at 14-23% at 1 year in this poor risk group, including those with adverse cytogenetic and/or very early post-HCT relapse. Prospective multi-center trials are planned to further evaluate lipo-cytara/dauno as a bridge to DLI/HCT in those with early relapse post-HCT and in those with refractory disease, with therapy to include CNS prophylaxis. Disclosures Stiff: Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Tsai:Jazz pharmaceuticals: Speakers Bureau; Jazz pharmaceuticals: Consultancy.

Introduction: Historically, outcomes for BL have improved in adults using dose intensive chemotherapy regimens and early CNS prophylaxis. More recent data using a less intensive regimen, DA-EPOCH, have been reported. We analyzed detailed patient (pt) & disease characteristics and treatment patterns across 26 US CCs over a recent 9 year (yr) period and also determined survival rates & prognostication. Methods: We conducted a large multicenter retrospective study of newly diagnosed (dx) adult BL pts (6/2009 - 6/2018). Dx was established by institutional expert pathology review; all cases were verified for BL based on 2016 WHO criteria (high grade B cell lymphoma, BL like, etc were excluded). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. Univariate (UVA) associations were derived via Cox model with variables P ≤0.05 entered stepwise into a multivariate (MVA) model. Using significant factors from the MVA, a prognostic survival model was constructed. Results: Among N=557 verified BL cases, clinical features included: median age 47 yrs (17-88 yrs; 24% ≥60 yrs); male 76%; HIV+ 22%; ECOG PS 0/1 76%; B symptoms 51%; elevated LDH 78% (3, 5, & 10x elevation: 44%, 29% & 15%, respectively); hemoglobin 1 EN 43%; and 76% stage 3-4 disease (10% stage 1). Additionally, 16% and 3% of pts had baseline leptomeningeal (CSF or cranial nerve palsy) or parenchymal CNS involvement, respectively (see Zayac A et al. ASH 2019 for details). For MYC partner, 68% had t(8;14), 4% light chain, 5% negative FISH (otherwise classic BL) and 23% + break apart probe. HIV+ pts had several clinical differences: CSF+ 23% vs 12% P=0.003; CNS 19% vs 8% P1 EN 60% vs 38% P For all pts, 87% had Tx at an academic CC (13% at community CC). Tx regimens were: CODOX-M/IVAC (Magrath) 31%, HyperCVAD/MA 29%, DA-EPOCH 28%, other 10% (mostly CHOP-based & CALGB Tx) & 1% were never treated. 90% of pts received rituximab as part of Tx (69% inpatient (inpt) & 31% outpatient) & 2% had consolidative autologous SCT. Response among all pts were CR 72%, PR 6%, SD 1%, PD 14%, 7% not evaluable. The treatment related mortality (TRM) rate across all pts was 8.9% (HIV+ vs not: 13% vs 8% P=0.09); most common: sepsis 48%, GI bleed/perforation 14% & respiratory failure 12%. TRM by Tx: hyperCVAD/MA 11.5%, EPOCH 6.4%, Magrath 6.3% & other 18.9%. With 39 month median follow-up, 3 year progression-free survival (PFS) and overall survival (OS) were 65% and 72%, respectively (Fig 1A). Among all pts who experienced disease progression, 90% occurred For prognostication, outcomes were inferior for pts ages ≥40 yrs & LDH >3x normal (Fig 1B/C). Notably, survival rates were not different based on HIV status (Fig 1D) or by the 3 most common Tx regimens (Fig 1E). However, there were important Tx differences based on presence of CNS involvement (see Zayac A et al. ASH 2019). Additionally, use of rituximab was associated with improved PFS & OS (Fig 1F), while outcomes were similar whether rituximab was given inpt vs outpatient (inpt PFS HR 1.25, P=0.19). Furthermore, Tx at an academic CC was associated with improved outcomes, which persisted on MVA (PFS HR 0.54, 95%CI 0.33-0.88 P=0.01; OS HR 0.50, 95%CI 0.29-0.87 P=0.01) & achievement of initial CR was strongly prognostic (Fig 1G). Baseline factors significant on UVA for PFS & OS were: age ≥40 yrs; PS 2-4; LDH >3x; anemia, low albumin; BM involvement; Stage 3-4; CSF+; & >1 EN. On MVA, factors associated with inferior survival were: age ≥40 yrs (PFS HR 1.57, P3x (PFS HR 2.28, P Conclusions: Outcomes for adult BL in this contemporary, large, multicenter RW analysis appear inferior to smaller published series. Interestingly, despite increased adverse prognostic factors, survival rates appeared similar in HIV+ pts. In addition, use of rituximab, achievement of initial CR, and Tx at an academic CC were associated with improved survival. Finally, a novel BL-specific survival model identified pts with markedly divergent outcomes. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Tesaro: Research Funding; Verastem: Consultancy, Honoraria. Danilov:Janssen: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy; Takeda Oncology: Research Funding; Janssen: Consultancy; TG Therapeutics: Consultancy; Curis: Consultancy; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Gilead Sciences: Consultancy, Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding. Reddy:KITE Pharma: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Research Funding; Abbvie: Consultancy. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Khan:Janssen: Other: Educational Content/Symposium; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Other: Research Funds; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Yazdy:Genentech: Research Funding; Bayer: Honoraria; Abbvie: Consultancy; Octapharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Martin:Janssen: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy. Diefenbach:LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Feldman:Eisai: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Roche: Research Funding. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Naik:Celgene: Other: Advisory board. Kamdar:Celgene: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Speakers Bureau; University of Colorado: Employment; Pharmacyclics: Consultancy. Portell:AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; Amgen: Consultancy. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding. Alderuccio:Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; Targeted Oncology: Honoraria; Inovio Pharmaceuticals: Other: Immediate family member; OncLive: Consultancy.

Background: Despite excellent outcomes in the front-line management of classical Hodgkin lymphoma (cHL), patients with relapsed or refractory disease typically undergo second-line cytotoxic chemotherapy before proceeding to consolidation with autologous hematopoietic stem cell transplant (autoHSCT). Pre-transplant F18-FDG-PET imaging is a well-established predictor of outcomes following autoHSCT; a complete metabolic response (CMR) to second-line therapy defined as a Deauville score 1-3 predicts a favorable outcome and is a requirement for transplant at many centers. The PD-1 pathway plays an important role in the pathogenesis of cHL and checkpoint inhibition with agents including PEM and nivolumab have shown efficacy as monotherapy in heavily pretreated disease. We hypothesized that the addition of PEM to ICE (ifosfamide, carboplatin, and etoposide) chemotherapy will increase the rate of CMR by PET-CT prior to autoHSCT without impairing the mobilization of peripheral blood progenitor cells (PBPC) or engraftment. Here we present interim safety and toxicity data from this ongoing trial (NCT03077828) including the yields of PBPC mobilization and engraftment. Methods: Enrollment criteria include patients age >18 years medically fit for autoHSCT with relapsed/refractory cHL and excludes those with prior PD-1 inhibitor exposure, CNS involvement, more than 2 prior regimens or history of autoimmune disease. Patients are treated with 2 cycles of PEM 200 mg IV on day 1 in combination with ICE chemotherapy (ifosfamide 5000 mg/m2 day 2 CIV over 24hr, carboplatin AUC 5 IV day 2, etoposide 100 mg/m2 IV days 1-3) on a Q21 day cycle. PBPC mobilization and harvest are performed per institutional protocol on recovery post-cycle #2. A cycle of PEM 200 mg IV is then administered as monotherapy followed by response assessment with PET-CT. Patients with Deauville scores ≤3 proceed to autoHSCT per institutional protocol. A third cycle of PEM+ICE is optional following the PET-CT assessment. Neither the conditioning regimen nor management during transplantation is dictated by the protocol. Results: As of July 2019, 23 of 40 planned patients have evaluable safety and toxicity data. One patient had inconclusive pathology and was removed from study after one cycle of PEM-ICE but is included for this report. The median age was 32 (range 19-62) and 17 of 23 patients were females (74%). 8 patients were refractory to first-line therapy, and 9 relapsed within one year of treatment. 19 patients had received ABVD. Following protocol directed therapy, all but one patient had successful mobilization and collection; one had a severe allergic reaction to filgrastim and underwent bone marrow harvest instead. 16 patients collected in a single day of apheresis; the remainder collected within 4 days. The median number of stem cells harvested was 12.6 x 106 CD34+ cells/kg (range 4.2 - 46.1 x 106/kg). 3 patients underwent the 3rd cycle of PEM + ICE chemotherapy. 3 patients had Deauville scores >3 on FDG-PET response assessment; two had biopsies showing only benign processes and proceeded to transplant. Following stem cell reinfusion, all patients successfully engrafted, with a median time to absolute neutrophil and platelet recovery of 11 days (range: 9 - 24) and 12 days (range: 9 - 23), respectively. The combination of PEM + ICE chemotherapy was well tolerated. There were no reports of pneumonitis, colitis, hepatitis, or endocrinopathies. The most common toxicities were cytopenias, mucositis, diarrhea and febrile neutropenia. A single death on protocol was deemed secondary to advanced cardiovascular disease discovered mid-treatment during the patient's pre-transplant assessment. There was no clinical evidence to suggest an inflammatory process resulting in the cardiac arrest. Conclusions: The combination of PEM with ICE chemotherapy in relapsed / refractory cHL appears tolerable and safe. We found no significant hindrance to peripheral blood stem cell harvest and PEM- related AEs were uncommon. Additionally, pre-treatment with a checkpoint inhibitor prior to autoHSCT appears safe thus far and does not appear to delay engraftment. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Karmali:Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Pro:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Gordon:Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Winter:Merck: Consultancy, Research Funding.

Introduction: Multiple myeloma (MM) remains incurable when treated with novel myeloma therapies in combination with high dose chemotherapy and autologous stem cell transplantation (ASCT). In contrast to the accelerated development of effective new drugs for induction, maintenance, and relapse, single-agent melphalan remains the standard for conditioning before ASCT. Is this phase II trial, we prospectively evaluated a conditioning regimen consisting of high-dose intravenous busulfan and melphalan followed by bortezomib (BUMELVEL), an agent shown to be potentially synergistic in combination with alkylating agents. We report our 7 year long term follow up with direct comparison to a contemporaneous CIBMTR cohort with the primary aim of both long term progression-free (PFS) and overall survival (OS). Methods: This phase I/II study was conducted between July 2009 and May 2012 at Loyola University Medical Center. MM patients with any disease response following induction were enrolled at time of stem cell transplantation. 43 patients received BUMELVEL conditioning followed by ASCT on the phase II portion of this study. Busfulan was administered intravenously (i.v.) daily for 4 days with the first 2 days (days −6 and −5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (days −4 and −3) adjusted to achieve a target AUC total of 20,000 μM·min determined by pharmacokinetic (PK) analysis. Melphalan at 140 mg/m2 and bortezomib at 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Maintenance therapy was not planned. Patients received prophylaxis for oral mucositis with palifermin. Data from this phase II clinical trial were compared against a matched control cohort of contemporaneous North American MM patients from the CIBMTR database (n = 162) receiving conditioning with single agent iv melphalan at a dose of 200mg/m2. The primary objectives of this study were median PFS and toxicities. Results: Baseline patient characteristics are described in Table 1. More patients in the BUMELVEL arm received greater than one line of therapy prior to transplant (53 v 33%). There were more standard risk patients per Mayo Stratification (Kumar et al, Mayo Clin Proc 2009) in the MEL200 group (78%) v the BUMELVEL group (40%). There was no difference in response rates at day 100 (p=0.48) but a trend toward improved response at 1 year in the BUMELVEL arm with 77% achieving a VGPR or better versus 60% in the MEL200 group (p-0.09). No patients in the BUMELVEL group received planned maintenance therapy post-transplant whereas 112 (69.6%) in the MEL200 control arm received planned post-transplant maintenance. Non-relapse mortality was 2% (range 0-9%) in the BUMELVEL group and 10 (6%, range 3-11) in the MEL200 but this was not statistically significant in both univariate and multivariate modeling (p=0.25). There were no episodes of sinusoidal obstructive syndrome in the BUMELVEL group and 37% of patients experienced grade 3 mucositis with no grade 4 mucositis. After a median of more than seven years of follow up, the five year PFS was 47% (95% CI; 32-62) in the BUMELVEL group versus 30% (95% CI; 23-37) in the MEL200 group (p=0.05) (Figure 1). Notably the 7-year PFS in the BUMELVEL group was 32% (range 18-48). In multivariate analysis for PFS, BUMELVEL conditioning (HR 0.65; 95% CI 0.44-0.97)(p=0.036), time from diagnosis to transplant of greater than versus less than 12 months (HR 1.64; 95% CI 1.18 - 2.27), and disease status at transplant CR versus other (p=0.006) were all predictive of PFS (table 2). OS was not different between the two groups with a 7 year survival of 64% (95% CI; 48-79) in the BUMELVEL group versus 55% (95% CI; 46-64%) in the MEL200 group (Figure 1) which was confirmed on multivariate analysis (p=0.33). Discussion: Similar to recent reports in the literature comparing busulfan and melphalan to melphalan alone (Bashir et al, Lancet Hem 2019), we show that although depth of response was similar between the BUMELVEL group and the historical MEL200 comparator, the BUMELVEL group experienced an improved PFS. Importantly, we report no cases of SOS and a low non-relapse mortality of only 2% (v 6% in the historical control) reinforcing that the preparatory regimen in myeloma can be intensified safely with improved duration of unmaintained PFS. These long term results confirm a sustained benefit of novel combination conditioning in MM and the need for novel transplant preparative regimens. Disclosures D'Souza: EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Stiff:Unum: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Amgen: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding.

Umbilical cord blood (UCB) as an allogeneic transplant source is generally limited to units with pre-cryopreservation total nucleated cell (TNC) doses ⩾2.5 × 10(7) NC/kg. We prospectively investigated single UCB transplantation, with cord units as low as 1 × 10(7) NC/kg, all processed with post-thaw albumin-dextran dilution. We transplanted 104 adult patients with 84% having relapsed/refractory disease. The median TNC dose was 2.1 × 10(7) NC/kg (range: 1.0-4.4 × 10(7)) and median CD34+ cell dose was 1.0 × 10(5)/kg (range: 0.0-3.7 × 10(5)/kg). Post-manipulation cell recovery and viability were 96% and 99%, respectively. Median times to neutrophil and platelet engraftment were 16 and 43 days, respectively. Univariate factors predicting neutrophil engraftment included TNC (P=0.03) and CD34+ cell dose (P=0.01). CD34+ dose predicted platelet engraftment (P

tudy Objectives The primary objective was to determine the impact of hematologic malignancies and/or conditioning regimens on the risk of developing Clostridium difficile infection (CDI) in patients undergoing hematopoietic stem cell transplantation (HSCT). Secondary objectives were to determine if traditional CDI risk factors applied to patients undergoing HSCT and to determine the presence of CDI markers of severity of illness among this patient population. Design Single-center, retrospective, case-control study. Setting Quaternary care, academic medical center. Patients One hundred five patients who underwent HSCT between December 2009 and December 2014; of these patients, 35 developed an initial episode of CDI (HSCT/CDI group [cases]), and 70 did not (controls). Controls were matched in a 2:1 ratio to cases based on age (± 10 years) and date of HSCT (± 6 months). Measurements and Main Results Baseline characteristics of the two groups were well balanced regarding age, sex, race, ethnicity, and type of HSCT. No significant differences in conditioning regimen, hematologic malignancy, total body irradiation received for HSCT, use of antibiotics within 60 days of HSCT, or use of prophylactic antibiotics after HSCT were noted between the two groups. Patients in the control group were 10.57 (95% CI 1.24 – 492.75) more likely to have received corticosteroids prior to HSCT than patients in the HSCT/CDI group (p=0.01). Use of proton pump inhibitors at the time of HSCT was greater among the control group than among patients in the HSCT/CDI group (97% vs 86%, p=0.048). No significant difference in mortality was noted between the groups at 3, 6, and 12 months after HSCT. Metronidazole was frequently prescribed for patients in HSCT/CDI group (34 patients [97%]). Severe CDI was not common among patients within the HSCT/CDI group (13 patients [37%]), but vancomycin was infrequently prescribed for these patients ([31%] 4/13 patients). Conclusion Hematologic malignancies and conditioning regimen administered for HSCT were not significant risk factors for the development of CDI after HSCT. Use of corticosteroids prior to HSCT and use of proton pump inhibitors at the time of HSCT were associated with significantly decreased risk of CDI. This article is protected by copyright. All rights reserved.

Older adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (60 years, median age 32). Exposure to brentuximab vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab vedotin may represent a meaningful clinical option for older patients with relapsed CD30-positive lymphomas.

Introduction Cardiovascular (CV) complications occur after hematopoietic stem cell transplantation (HCT). Risk factors for events are unclear making it difficult to determine optimal pre-transplant screening. Solid organ transplants programs calculate pre-transplant risk to determine indication for further cardiac testing. Based on this, we investigated whether several commonly used CV risk calculators predicted for CV events after HCT. Methods This was a prospective case control study at a single academic institution. CV risk was estimated using the Framingham General CVD Risk Score (2008), ACC/AHA Pooled Cohort Hard CVD Risk (ASCVD; 2013) calculator, and JBS3 QRISK Lifetime calculator. Results Forty-eight patients transplanted between 2012 and 2016 were analyzed. 27 (56%) were female. Ages ranged from 53-74 with a median of 64. Diseases transplanted were: AML (38%), MDS (31%), Non-Hodgkin's lymphoma (15%), and others 47% had high risk for CVD (score>2) by Framingham score. 67% had high risk by ASCVD calculator (10 year risk >7.5%). 70% had high risk by QRISK Lifetime calculator. 9%were low risk by Framingham score, but high risk by QRISK Lifetime calculator. Cardiac events evaluated included atherosclerotic events (myocardial infarction and stroke), atrial fibrillation (a-fib), and others (other arrhythmia, CHF, drop in LVEF, and cardiac arrest). 40% had any cardiac event. 15% had an atherosclerotic event (MI or CVA). 21% had a-fib. Framingham Risk, ASCVD and QRISK calculators did not predict for either atherosclerotic events or any cardiac events after HCT [Table 1]. Risk factors for a-fib specifically, were also evaluated: history of MI, diastolic or systolic dysfunction, CHF, valvular disease, tobacco use, diabetes, and hypertension. Only CHF was a predictor for a-fib (p=0.08). Conclusion CVD risk calculators commonly used in the general population and by solid organ transplant programs did not predict for CV events post-HCT here. However, this analysis was limited by small study size. Study in a larger population is being planned to allow incorporation of transplant related variables to develop a HCT-specific multivariate risk calculator to accurately predict post-HCT CV events.

Allogeneic stem cell transplantation (alloHCT) remains the only curative option for a variety of hematological malignancies. AlloHCT is being increasingly offered in elderly patients with acceptable transplant related mortality. Umbilical cord blood (UCB) is established as an alternate donor source however some are reluctant to consider its use in elderly patients due to anticipated morbidity. We evaluated outcomes in alternate donor sources, prior to the initiation of haploidentical transplantation at our institution, of matched unrelated donor (MUD) and UCB in elderly patients (median age 64, range 60-74) from 2005-2015. One hundred and eighty four patients were included (MRD: 57; MUD: 69; UCB: 58). Eighty seven underwent myeloablative conditioning (52.7%). There was no difference in acute (aGVHD) or chronic graft versus host disease (cGVHD) between donor sources. ATG was protective for grade III-IV aGVHD (p=0.0498) and high disease risk index per Armand et al predictive of cGVHD (p=0.0496). UCB engraftment was longer for both neutrophils (p=0.005) and platelets (p 2) comorbidity index (42%) per Sorror et al. There was a trend toward inferior progression free survival (PFS) amongst both UCB (5.50 months; 95% CI 2.83—9.36) and MUD (5.59 months; 95% CI 3.68-17.68) as compared to MRD (18.3 months; 95% CI 8.38-64.79)(Table 1). Compared to MRD, UCB experienced inferior median overall survival (OS) HR 1.877 (95% CI 1.160-3.037) but no difference was seen between UCB and MUD or MUD and MRD in multivariable analysis (Table 1 and 2). The leading cause of death in UCB recipients was infections (40%) followed by relapse (17%). Our experience shows that even in this very high risk elderly cohort, UCB continues to be a viable alternate donor source. Methods to reduce late infectious complications are needed such as new approaches to accelerate T cell engraftment which is currently being explored at our center.

Introduction: The most effective initial therapy for older adults with CLL has not yet been established due to the lack of comparison of chemoimmunotherapy (CIT) and targeted therapy with the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib. CIT has been the gold standard since studies showing that addition of CD20 antibody to chemotherapy prolongs survival. Bendamustine plus rituximab (BR) is one standard, more aggressive CIT regimen for patients (pts) age 65 or older. While ibrutinib has been FDA approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT. Additionally, the benefit of the addition of rituximab to ibrutinib in this setting has not been prospectively studied in a phase 3 trial. As part of a randomized phase 3 trial, the Alliance sought to answer these important clinical questions. Pts and Methods: Alliance A041202 is a multicenter NCI National Clinical Trials Network phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to CIT in terms of PFS. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone. At time of progression, pts on Arm 1 could cross over to Arm 2. Eligible pts were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified based upon Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. With 166 pts per arm, the trial was powered to detect an improvement in 2-year PFS from 61% in Arm 1 to 75% in Arms 2 or 3 (HR=0.586) using two one-sided log-rank tests with type I error rate of 2.5% and 90% power. The Alliance Data and Safety Monitoring Board approved the data release after meeting the protocol-defined efficacy threshold at a planned interim analysis with a one-sided critical value of 0.001538. These data were locked July 2, 2018; updated results will be presented at the meeting. Results: Between 12/9/2013 and 5/16/2016, 547 pts were registered and randomized (Arms 1: 183, 2: 182, and 3: 182). Median age was 71 years and 67% of pts were men. High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28%. Local vs centralized FISH was performed for del(11q) and del(17p) with agreement between local and central results in 94% (Kappa=0.80) and 97% (Kappa=0.76) of pts, respectively. 525 (96%) pts were eligible and included in the primary PFS analysis (Arms 1: 176, 2: 178, and 3: 171). With median follow-up of 32 months (mo), median PFS was 41 mo in Arm 1 and has not been reached in Arms 2 or 3 (HR comparing Arm 2 to 1 is 0.40 with one-sided p Conclusions: This international phase 3 trial demonstrates that ibrutinib produces superior PFS to standard CIT in older pts with CLL and justifies it as a standard of care treatment for pts age 65 and older. The addition of rituximab does not prolong PFS with ibrutinib. While ibrutinib represents a major therapeutic advance, toxicities and also cost justify future efforts to reduce the need for long-term continuous treatment. Support: K23CA178183, R01CA183444, U10CA180821, U10CA180882, U24CA196171, Clinicaltrials.gov identifier: NCT01886872 Figure. Figure. Disclosures Ding: Merck: Research Funding. Bartlett:Astra Zeneca: Research Funding; ImaginAB: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Bristol-Meyers Squibb: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Parikh:Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Coutre:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Research Funding; Beigene: Consultancy; AbbVie: Consultancy, Research Funding. Lozanski:Novartis: Research Funding; BI: Research Funding; Genentech: Research Funding; Stem Line: Research Funding; Coulter: Research Funding; Beckman: Research Funding. Larson:Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Erba:Amgen: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Juno: Research Funding; Janssen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Juno: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee. Owen:Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Teva: Honoraria. Abramson:Bayer: Consultancy; Novartis: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Introduction and Objective: Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Data on the impact of graft composition, namely CD34 and T-cell subsets, and aGVHD is conflicting. We hypothesized an upper cell dose limit of CD34 would exist predictive of aGVHD without affecting engraftment and sought to explore T-cell subsets and their impact on aGVHD outcomes amongst peripheral blood progenitor cell (PBPC) HLA-identical sibling transplants (Allo-Sib). Methods: In an IRB approved protocol, consecutive Allo-Sib patients underwent HSCT for hematologic malignancy at our center from 1/2004 to 12/2012. Demographic and clinical data were prospectively collected and retrospectively confirmed. Patients received the entire D1 CD34 PBPC collection from their donors and from a second day of collection if necessary to achieve a dose of 4 x 106 CD34/kg cells. aGVHD prophylaxis was uniformly tacrolimus and mini-methotrexate. Tacrolimus was monitored to achieve a trough of 10-15 ng/ml. aGVHD was graded as per the International Bone Marrow Transplant Registry System. Exact binary logistic regression models were used to estimate the odds of aGVHD as a function of patient demographic and clinical data. For the association between cell counts and aGVHD, binary cut scores were determined by finding the point along the receiver operating characteristic curve that maximized sensitivity and specificity. Non-parametric Spearman correlation coefficients were used to estimate the association between CD34, CD3, CD4, and CD8 cell counts. Results: We analyzed 160 consecutive patients. In this mostly male (63%) population, median age was 51 and most patients underwent a myeloablative transplant (93%). Disease risk as per Armand et al 2012 was low 45%, intermediate 13.2%, and high 41.7%. Co-Morbidity Index by Sorror et al (HCT-CI) was 30.5% for 0, 33.8% for 1-2, and 35.8% for > 2. Sixteen patients (10%) developed grade II-IV aGVHD while 9 (6%) developed grade III-IV aGVHD. Median CD34 cell dose infused was 6.27 X 106/kg. Median CD3, CD4, and CD8 cell doses infused were 2.51 X 108/kg, 1.80 X 108/kg, and 0.66 X 108/kg, respectively. In univariate analysis, patients (n=67) receiving > 9.94 x 106 CD34/kg were 12 times more likely to develop grade III-IV aGVHD (odds ratio =12.308; p=0.01)(figure 1). Conversely, patients receiving > 0.50 x 108 CD8/kg were less likely to develop grade II-IV aGVHD (odds ratio = 0.30; p=0.049)(Figure 2), but not Grade III-IV aGVHD. The only other factor associated with aGVHD was a diagnosis of AML, which was protective (p=0.01). CD3 and CD4 cell counts did not correlate with aGVHD in our patient cohort. There was no correlation between engraftment and CD34, CD3, CD4, or CD8 cell dose. Finally, we found no direct correlation between CD34 cells counts and CD3, CD4, or CD8 cell counts. Conclusion: This study represents the largest evaluation examining the correlation between both infused CD34 cells and T-cell composition with aGVHD among patients undergoing strictly matched related donor HSCT. Importantly, the data demonstrates patients receiving > 10 x 106 CD34/kg have increased risk of developing clinically significant aGVHD, a dose that far exceeds adequate engraftment doses and serves now as a cap on CD34 cell dose in our program. Interestingly, our data suggests infusion of > 0.50 x 108 CD8/kg may protect from severe aGVHD whereas prior reports have demonstrated no association between CD8 cells and aGVHD. Further investigation is needed to better characterize the relationship between CD8 cells and aGVHD and better define the correlation between CD8 and CD34 cell doses in the development of aGVHD. Disclosures No relevant conflicts of interest to declare.

Dasatinib with corticosteroid yields high complete remission (CR) rates in Ph+ ALL with minimal induction death. Optimal post-remission therapy is not known. We report a prospective study evaluating dasatinib/dexamethasone induction then consolidation with reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), autologous HCT (autoHCT), or chemotherapy alone (chemo), followed by dasatinib-based maintenance. Methods: We conducted a phase II, 3-arm, non-randomized trial (NCT01256398, Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171) at 17 US centers with primary objectives to determine 3-year overall survival (OS) and disease-free survival (DFS) of adults ≥18 years (yrs) old with untreated Ph+ ALL treated with dasatinib/dexamethasone induction, CNS prophylaxis with systemic and intrathecal methotrexate, consolidation with alloHCT, autoHCT, or chemo, then dasatinib maintenance. Induction (Course I) used dasatinib 140 mg orally daily and dexamethasone 10 mg/m2/day orally or IV days 1-7. If ≤20% lymphoblasts in marrow at Day 15, Course II continued dasatinib with 7 days of dexamethasone. If >20% lymphoblasts, patients (pts) also received vincristine and daunorubicin. Pts not in CR/CRi received a second induction (Course III) with dasatinib, cyclophosphamide, vincristine, daunorubicin, and dexamethasone. CNS prophylaxis (Course IV) used dasatinib, IV vincristine and IV, oral, and intrathecal methotrexate. Course V consisted of HCT or chemo. Pts 18-70 yrs old underwent RIC alloHCT if they had a HLA-matched donor; otherwise they underwent autoHCT. AlloHCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 IV once on day -2. GVHD prophylaxis with tacrolimus began day -2. Pts undergoing autoHCT received etoposide 10 mg/kg/day (age >65, 5 mg/kg/day) CIV for 4 days and cytarabine 2 g/m2 (age >65, 1 g/m2) IV every 12 hours for 8 doses then G-CSF for mobilization. AutoHCT conditioning was melphalan 100 mg/m2/day IV on days -2 and -1. Pts >70 yrs old or unable to undergo HCT received etoposide/cytarabine alone. Dasatinib maintenance (Course VI) began day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse. BCR-ABL1 isoform and ABL1 kinase domain (KD) mutation determination were done locally. Results: From 12/15/2010 to 11/14/2014, 64 eligible pts enrolled. Median age was 60 yrs (22-87); median WBC 23.2 x 103/μl (0.3-454). The dominant BCR-ABL1 isoform was p190 in 59%, p210 in 17%, and not reported in 23%. The CR rate was 97% with no induction deaths. Fifty-five pts completed CNS prophylaxis (Course IV). Twenty pts underwent protocol-specified alloHCT, 7 autoHCT, and 9 chemo. Nine pts underwent off-study alloHCT and 5 skipped Course V. Dasatinib maintenance was tolerable with 72%, 80%, and 80% receiving >50% of planned maintenance doses in alloHCT, autoHCT, and chemo arms, respectively. With a median follow up of 48 months (37-78) for survivors, 3-yr OS and DFS were 55% (median OS 45 months) and 43% (median DFS 30 months), respectively. For pts undergoing consolidation with protocol-specified alloHCT, autoHCT, or chemo, 3-yr OS was 75%, 71%, and 55% respectively with median OS not reached (NR) for all groups. DFS at 3-yrs was 55%, 43%, and 46% respectively. Median DFS for alloHCT was 42 months vs 15 months for autoHCT and 34 months for chemo (Log-Rank P=0.4). Outcomes were similar with inclusion of off-study alloHCT and chemo patients skipping Course V. Relative to p190 BCR-ABL1 isoform, p210 was associated with shorter median OS (NR vs 16 months, P=0.04) and median DFS (35 months vs 10 months, P Conclusions: Dasatinib and dexamethasone followed by alloHCT, autoHCT, or chemo yield similar 3-yr survival comparable to approaches using intensive induction chemotherapy. Pts with the p210 BCR-ABL1 isoform had dismal outcomes and may benefit from alternate approaches. T315I mutation was the major cause of relapse and should be addressed in future studies. Disclosures Wieduwilt: Amgen: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria. Liedtke:Caelum: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Research Funding; Genentech/Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBirdBio: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Devine:Kiadis Pharma: Consultancy. Larson:BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Chemoimmunotherapy in follicular lymphoma is associated with significant toxicity. Targeted therapies are being investigated as potentially more efficacious and tolerable alternatives for this multiply-relapsing disease. Based on promising activity with rituximab and lenalidomide in previously untreated follicular lymphoma (overall response rate [ORR] 90%-96%) and ibrutinib in relapsed disease (ORR 30%-55%), the Alliance for Clinical Trials in Oncology conducted a phase 1 trial of rituximab, lenalidomide, and ibrutinib. Previously untreated patients with follicular lymphoma received rituximab 375 mg/m 2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, and 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #NCT01829568.

This phase II study evaluated YM155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received YM155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients.

We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.16-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% CI, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001).

Summary Data on outcome, prognostic factors, and treatment for very elderly nonHodgkin lymphomas (NHL) is sparse. We conducted a multicentre retrospective analysis of NHL patients ‡80 years (at diagnosis) treated between 1999 and 2009. Detailed characteristics were obtained including geriatric syndromes, activities of daily living (ADLs), and co-morbidities using the Cumulative Illness Rating Scale-Geriatrics (CIRS-G). We identified 303 patients: 170 aggressive NHL (84% B cell/16% T cell) and 133 indolent NHL (82% B cell/18% T cell). Median age was 84 years (80‐95). A geriatric syndrome was present in 26% of patients, 18% had ‡1 grade 4 CIRS-G, and 14% had loss of ADLs. At 49-month median follow-up, 4-year progressionfree (PFS) and overall survival (OS) for aggressive NHLs were 31% and 44% respectively (stage I/II: PFS 53% and OS 66%; stage III/IV: PFS 20% and OS 32%; P

We analyzed 93 couples undergoing male screening with the Sperm Penetration Assay (SPA) before in vitro fertilization and intracytoplasmic sperm injection (ICSI), to determine the accuracy of SPA for subsequent embryonic development, incidence of pregnancy and miscarriage rates (SAB). ICSI patients with the lowest SPA scores had significantly higher incidences of Sthan did patients in the other SPA groups. Sperm quality is higher with better SPA scores. Poor sperm quality has increased incidence of chromosomal abnormalities and is associated with early fetal loss. Couples with negative SPA are candidates for preimplantation genetic diagnosis, to reduce the incidence of SAB.

e20004Background: A variety of tumor markers have been identified to define risk and predict and monitor treatment response in multiple myeloma (MM). Circulating endothelial cells (CECs) and circul...

Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P.001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim.