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Supplemental Table 1 and Supplemental Figure Legends

Purpose:Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental Design:This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.Results:The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.Conclusions:These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Introduction: Venetoclax has demonstrated deep responses and sustained progression-free survival and is well tolerated in patients (pts) with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) in clinical trials. Some early studies provided initial insight of venetoclax utilization in the real-world (RW), but RW evidence focusing on venetoclax effectiveness and safety is still limited. This study assessed venetoclax effectiveness, safety, and treatment patterns in CLL pts treated in clinical practice. Methods: The CLL Collaborative Study of Real-World Evidence (CORE), a large multicenter chart review across 21 institutions in 4 countries, enrolled adult pts who initiated a first line (1L) therapy on/after 01/01/2012 or a new line of therapy (LOT) for R/R CLL/SLL on/after 02/12/2014 (current data cut through 06/08/2020). Clinical responses were abstracted from the medical records as assessed by treating physicians or investigators (iwCLL criteria were provided as reference). Overall response rate (ORR) was calculated as the proportion of pts with complete response (CR) or partial response (PR) out of pts with documented response assessments. Treatment patterns included choice of regimens and sequences, dose interruption, dose reduction, and discontinuation. Treatment discontinuation was defined as ending therapy for any reason(s) other than the completion of planned duration of therapy. Interruption was defined as a gap in the same LOT. All analyses were descriptive. Results: Of the 1231 CLL pts in the CORE data, 155 received venetoclax (21 in 1L and 134 in R/R) and were included in this study. Most of the sample were male (65%) and the median age at venetoclax initiation was 67.5 (range 37-91). For high-risk features among pts with available data, 33% (43/132 pts) had del(17p) or TP53 mutation, 24% (31/131 pts) had complex karyotype (≥ 3 abnormalities), and 77% (61/79 pts) had unmutated IGHV. At venetoclax initiation, 46%, 40%, and 14% of 151 pts with available data had low, medium, and high tumor burden, respectively. Median follow-up time from venetoclax initiation across all lines was 7.0 (0.1-43.1) months. Median number of prior LOT for R/R pts was 2 (1-5); the largest proportion of pts (36%) received venetoclax in 2L followed by 3L (26%). In 1L, venetoclax was most frequently used (62%) in combination (Figure 1), while in R/R setting venetoclax monotherapy was more commonly used (61%) followed by venetoclax + rituximab (25%; Figure 2). Majority of R/R pts (63%) received Bruton's tyrosine kinase inhibitors (BTKi) prior to venetoclax (Figure 2). Response was assessed and documented for 114 pts (74%). Among these, ORR was 75% (CR=40%, PR=35%) overall. Pts ≥65 years old had an ORR of 79% (CR=41%, PR=38%, n=74), and pts Overall, 48% of pts had adverse events (AEs) recorded. Five R/R pts (3.2%) had TLS events (defined by Howard or Cairo-Bishop criteria), of which 3 (1.9%) were clinical. Of the 5 pts, 2 had high tumor burden, and 3 had medium burden. Other AEs of interest include neutropenia (17%), thrombocytopenia (9%), and diarrhea/colitis (5%). Overall, 32% of pts discontinued venetoclax; 13% of all pts discontinued venetoclax due to AEs (primarily neutropenia [n=2] and thrombocytopenia [n=2]), followed by disease progression (8%). Venetoclax interruption rate was 14%, and dose reduction rate was 22% overall. Conclusions: Consistent with trial experiences, venetoclax demonstrates high response rates, including high-risk groups, and a manageable safety profile with low rates of TLS in clinical practice. Despite limitations of RW research, this study provides useful insights into treatment practices with venetoclax. Future research with longer follow-up is warranted to better understand the long-term clinical outcomes associated with venetoclax regimens. Disclosures Zheng: AbbVie: Current Employment. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Roeker:Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding; AbbVie: Other: spouse with minority ownership interest . Manzoor:AbbVie: Current equity holder in publicly-traded company. Tuncer:AbbVie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Ujjani:Gilead/Kite: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. Barr:Genentech: Consultancy; Merck: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; TG therapeutics: Consultancy, Research Funding; Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding. Brown:Novartis: Consultancy; Nextcea: Consultancy; Octapharma: Consultancy; MEI Pharma: Consultancy; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo: Consultancy, Research Funding; Sun: Research Funding; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Janssen: Honoraria; AbbVie: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Acerta: Consultancy. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support. Skarbnik:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Verastem: Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bannerji:Regeneron Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; AbbVie: Research Funding. Eichhorst:BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; DTRM: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pena:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Emechebe:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pivneva:Novartis: Consultancy, Other: Irina Pivneva is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Burne:Analysis Group, Inc., which has received consultancy fees from AbbVie: Current Employment. Guerin:Abbvie: Consultancy, Other; Novartis Pharmaceuticals Corporation: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Davids:Celgene: Consultancy; Research to Practice: Honoraria; AbbVie: Consultancy; Sunesis: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; BeiGene: Consultancy; Novartis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Adaptive Biotechnologies: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy; Eli Lilly: Consultancy; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Mato:AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Introduction Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age. Methods Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices. Results Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3). Conclusion These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice. Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected. Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose. Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Ibrutinib demonstrated superior response rates and survival for treatment-naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; P = .7) and HR 1.2 (95% CI, 0.6-2.3; P = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; P = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; P = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.

The value of combination therapy for refractory ITP is not well defined. We present the case of a 29-year-old male with severe ITP refractory to initial standard therapy including steroids, IVIG, and subsequent splenectomy, who was treated with the combination therapy of rituximab, romiplostim, and mycophenolate and eventually developed thrombocytosis requiring plateletpheresis. Our case highlights the importance of the need to understand predictors of response to standard upfront treatment of acute ITP.

BACKGROUND Novel agents have changed the treatment landscape in chronic lymphocytic leukemia (CLL), however little has been reported about real-world treatment sequence patterns and associated outcomes post-introduction of novel agents. Studies have demonstrated that venetoclax is effective for patients (pts) who have discontinued ibrutinib, however treatments and outcomes post-venetoclax discontinuation remain unclear. The objective of this study was to examine real-world treatment sequence patterns post-introduction of novel agents and specifically understand treatment sequencing following venetoclax. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) is a retrospective, multicenter, collaborative observational study of pts with CLL/small lymphocytic leukemia (SLL). For this analysis, adult pts were eligible for inclusion if they started therapy for CLL/SLL in the relapsed/refractory setting after February 12, 2014 (FDA approval date of first novel agent for CLL/SLL). Interim data are presented; data collection for this analysis is ongoing and is expected to be completed by October 31, 2019. Treatment sequences were characterized specifically focusing on treatment sequencing following venetoclax and other novel agents (i.e., BCRi: e.g., ibrutinib, idelalisib or acalabrutinib). Clinical response, as assessed by physician, was also reported from medical charts (iwCLL criteria were provided as a reference only). RESULTS Of the 267 pts available at the time of interim data analysis, 231 pts (87%) received a novel agent in at least one line of therapy (first-line: 35 pts [15%]; second-line: 133 pts [58%]; third-line or later: 63 pts [27%]). Among novel agents, ibrutinib was the most commonly used first novel agent for 198 pts (86%) followed by venetoclax for 18 pts (8%) and idelalisib for 12 pts (5%). Of those 267 pts, 143 pts (54%) received chemotherapy/chemoimmunotherapy (CT/CIT) followed by a novel agent; 63 pts (24%) received a novel agent followed by a novel agent; 17 (7%) received a novel agent followed by CT/CIT; and 47 (18%) received a CT/CIT followed by CT/CIT. At the time of this interim data cut there were 220 pts (82%) who received BCRi-based regimens (first-line: 33 pts [15%]; second-line: 123 pts [56%]; third-line or later: 64 pts [29%]) and 62 pts (23%) who received venetoclax-based regimens (first-line: 2 pts [3%]; second-line: 22 pts [36%]; third-line or later: 38 pts [61%]). Of the 220 pts who received BCRi-based regimens, 50 (23%) achieved complete remission (CR) and 83 (38%) achieved partial remission (PR) (responses based on physician assessment). Of the 220 pts, 88 (40%) went on to receive a subsequent line of therapy. The most common subsequent treatments administered were venetoclax containing regimens (n= 34, 39%). Of the 88 pts who received a subsequent line of therapy after BCRi-based regimens, 22 pts (25%) achieved CR and 24 pts (27%) achieved PR. Of the 62 pts who received venetoclax-based regimens, 20 pts (32%) achieved CR and 14 pts (23%) achieved PR. Of the 62 pts, 15 pts (24%) went on to receive a subsequent line of therapy. The most common subsequent treatment administered were BCRi containing regimens (n= 10, 67%) primarily ibrutinib-based. Of the 15 pts receiving a subsequent line of therapy after venetoclax-based regimens, 3 pts (20%) achieved CR and 4 pts (27%) achieved PR. While preliminary results are encouraging, further data collection efforts are ongoing and will be included for presentation to confirm the results and outcomes associated with different sequencing options. CONCLUSIONS The treatment paradigm is evolving with the introduction of novel agents. Results from this study will provide a baseline description of treatment sequence patterns enabling clinicians to benchmark the impact of the introduction of novel agents and associated outcomes. Early evidence from these results also suggests that novel agents are most commonly introduced during second line treatment and that other novel agents, including ibrutinib, following venetoclax treatment are being utilized in the real-world settings. Table. Disclosures Mato: Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy. Sail:AbbVie: Employment, Other: may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shadman:Bigene: Research Funding; TG Therapeutics: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Gilead: Research Funding; Merck: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Celgene: Research Funding; Sunesis: Research Funding. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ujjani:PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Atara: Consultancy; Astrazeneca: Consultancy; Gilead: Consultancy. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy. Brown:Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Schuh:Pharmacyclics: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Verastem: Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Eyre:Janssen: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support. Wierda:Pharmacyclics LLC: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Miragen: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; AbbVie: Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Gilead: Other: travel support; Celgene: Consultancy; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy; Pharmacyclics: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy, travel support; Merck: Other: travel support, Patents & Royalties: IP rights. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Schuster:Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau. Cheson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, 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; Trillium: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Gilead: Research Funding; Epizyme: Research Funding. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:Genentech: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; MEI: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Lamanna:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

BACKGROUND The recent approval of novel agents (NAs) has changed the treatment landscape in chronic lymphocytic leukemia (CLL), however, there remains uncertainty regarding treatment discontinuation patterns in real-world (RW) settings. This study assessed patterns of and reasons for discontinuation for patients (pts) treated with chemotherapy/chemoimmunotherapy (CT/CIT) and NAs in first (1L) and second (2L) lines of therapy in CLL. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, observational study. Adult CLL patients (pts) were included if they were diagnosed with CLL, initiated 1L or 2L therapy for CLL on/after 01/01/2012 (excluding lines of therapy received as part of clinical trials). Discontinuation patterns were assessed among CT/CIT and NAs, more specifically in four treatment cohorts: fludarabine+cyclophosphamide+rituximab (FCR), bendamustine+rituximab (BR), B-cell receptor inhibitors (BCRi)-based (e.g., acalabrutinib, ibrutinib, or idelalisib) and venetoclax-based regimens. Treatment discontinuation was operationally defined as ending therapy for reason(s) other than completion of planned duration of therapy. RESULTS Of 671 pts receiving 1L therapy, 81 (12%) received FCR (median age=58, 70% males); 153 (23%) BR (median age=63, 61% males), 255 (38%) BCRi-based (median age=65, 65% males); and 13 (2%) venetoclax-based (median age=59, 54% males). The remaining 169 pts received other regimens (e.g., other CT/CIT). The most common BCRi-based therapy in 1L was ibrutinib-containing regimens (97%). Median duration of follow-up was 24, 27, 11 and 8 months for FCR, BR, BCRi-based and venetoclax-based regimens, respectively. Treatment discontinuation occurred in 18 (22%), 41 (27%), 51 (20%) and 4/13 pts receiving FCR, BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuation in FCR (11/18 pts; 61%), BR (15/41 pts; 37%) and BCRi-based (24/51 pts; 47%) cohorts was adverse events (AEs), with >70% being severe AEs in each cohort. Common AEs leading to discontinuations were hematological abnormalities (e.g., neutropenia, thrombocytopenia) in the FCR (6/18 pts; 33%) and BR (6/41 pts; 15%) cohorts. In the BCRi-based cohort the most common AEs leading to discontinuations were cardiac (4/51 pts; 8%), skin and subcutaneous tissue disorders (e.g., rash; 6/51 pts; 12%), hemorrhage/bleeding (3/51; 6%), and musculoskeletal and connective tissue disorders (3/51; pts; 6%). For the relatively small number of pts treated with venetoclax-based regimens and discontinued, disease progression was the common reason for discontinuations (3/4 pts); no pts discontinued venetoclax-based regimens due to adverse events. In the relapsed/refractory setting specifically in 2L, 15 (7%), 113 (56%) and 16 (8%) pts received BR, BCRi-based and venetoclax-based regimen respectively, of which the most common BCRi-based therapy regimen was ibrutinib-based (95%). Treatment discontinuation occurred in 5/15 pts (33%), 27/113 pts (24%) and 4/16 pts (25%) receiving BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuations were severe AEs for BR (3/5 pts) and BCRi-based (13/27 pts) cohorts and disease progression for venetoclax-based regimens (2/4). CONCLUSIONS Despite the relatively short follow-up, in both 1L and 2L, similar discontinuation patterns emerge. CT/CIT is often discontinued prior to completion of planned cycles of therapy, suggesting that these regimens are difficult to tolerate. Additionally, treat to progression BCRi-based regimens are also discontinued for severe AEs, discordant to results from clinical trials. With a small cohort and limited information collected, results on venetoclax discontinuation warrants additional studies. Well tolerated chemotherapy-free combinations with finite treatment duration in treatment naïve and relapsed/refractory settings may limit continuous exposure to treatment and prevent discontinuations due to AEs. Table Disclosures Shadman: Atara: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Mustang Biopharma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; ADC Therapeutics: Consultancy. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:AstraZeneca: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Ujjani:Atara: Consultancy; Gilead: Consultancy; Astrazeneca: Consultancy; Genentech: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding. Emechebe:AbbVie: Employment, Other: and may hold stock or stock options. Kamalakar:AbbVie: Employment, Other: and may hold stock or stock options. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Brown:Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy. Schuh:AbbVie: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Verastem: Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Eyre:Janssen: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Wierda:Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding. Skarbnik:Jazz Pharmaceuticals: Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Celgene: Consultancy; Celgene: Consultancy; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Gilead: Other: travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy, travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Gilead: Other: travel support. Pauff:AbbVie: Employment, Other: and may hold stock or stock options. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Follows:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cheson:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, 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; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:BeiGene: Research Funding; ArQule: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:DTRM Biopharma: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Tolero: Research Funding; Acerta: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Guerin:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member, Research Funding.

Introduction: The number of patients with sickle cell disease (SCD) approaches 100,000 in US after adjusting for early mortality (Hassell Am J Prev Med 2010). Management of SCD and its complications require frequent access to healthcare system lifelong, thus impacting patients' quality of life and cost of healthcare. Chronic pain inducing illnesses are known to increase susceptibility to mental health disorders (Rayner Pain 2016). Psychosocial disorders are common in this population and impact the course of hospitalization, however we have limited published data in this area. Hence, we performed a large retrospective study utilizing the National Inpatient Sample (NIS) data to evaluate the prevalence of mental health disorders in hospitalized sickle cell patients, and their influence on length of hospitalization. Methods: We identified hospitalized sickle cell patients using ICD 9 codes (282.5,282.6X -282.6X ) in the National Inpatient Sample (NIS) database. Similarly, ICD-9 codes were used to identify patients with mental health disorders of interest. The demographics and length of hospital stay of patients with and without mental health disorders were then compared. Surveyfreq was used to calculate proportions and surveymeans was used to calculate median length of stay and hospital charges. Cochran-Armitage test was used for analyzing trends. We used chi-square for categorical data frequency, P value of < 0.05 was considered statistically significant. All analysis was performed using SAS 9.4. Results: We identified a total of 1,349,701 hospitalizations for sickle cell patients between 2003-2014, of which 221,279 (16%) had associated mental health disorders. Mood disorders were most common (40%), followed by substance abuse (28%) and anxiety disorder (16%) (Table 1). Over the timeline of our study, we found a longitudinal trend towards higher prevalence of mental health disorders in hospitalized sickle cell patients (Figure 1). There was higher prevalence of mental health disorders among patients aged between 21-40 years (24%). No difference in the rate of mental health disorders was noted in patients admitted with or without acute sickle cell pain episode. Median length of hospital stay (LOS) was 4 days in patients with mental health disorders (95% CI 4.04-4.12) compared to 3 days in those without (95% CI 3.17-3.20). Conclusion: The prevalence of mental health disorders in hospitalized sickle cell patients has been gradually increasing from 2003 to 2014 and approaches 16% overall. The length of hospital stay is longer for the individuals with these disorders than those without hence, increasing the cost of health care and reducing patient satisfaction. Therefore, early recognition and intervention for mental health disorders is paramount to promote quality of life and reduce health care costs. This demands for a multidisciplinary approach to provide better access to mental health resources to this population in the outpatient setting. Disclosures No relevant conflicts of interest to declare.

Introduction: Venetoclax (Ven), an oral BCL2 inhibitor, is approved for the treatment (tx) of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Ven is generally well tolerated, and side effects observed in clinical trials have been consistent with other CLL tx. Clinical trials using the approved dose escalation schedule report negligible rates of clinical tumor lysis syndrome (TLS). We aimed to understand rates of select adverse events (AEs) including cytopenias, infections, and TLS in CLL patients (pts) treated with Ven in community and academic settings. To do so, we examined 297 pts with CLL who received Ven, either alone or paired, in this multicenter, international study. Methods: We conducted a retrospective cohort study of Ven treated pts with CLL across at 15 academic (n=169) and 51 community (n=128) centers outside of the clinical trial setting. This study represents a collaboration between US centers, CLL Collaborative Study of Real World Evidence (CORE), and UK CLL Forum. Demographics, baseline disease characteristics, Ven dosing, TLS risk (per FDA Ven label) and prophylaxis, and AEs were collected. Lab vs. clinical TLS was defined by Howard criteria. PFS was estimated by Kaplan Meier methodology. All comparisons were descriptive. Results: Of the 297 pts examined, median age at Ven initiation was 67 (range 37-91). The group was 69% male, 96% had R/R CLL, and 45% had del17p. Baseline characteristics stratified by practice setting are included in Table 1. 80% received Ven as monotherapy while 20% received it paired with another agent (anti-CD20 mAb (75%), ibrutinib (8.5%), other (16.5%)). All pts were treated outside of clinical trials. During dose escalation, 81% achieved a 400 mg dose and 65% maintained 400 mg following escalation (cyp3A4 use unknown). TLS risk was low in 40%, intermediate (int) in 32%, and high risk in 28%. CT scan prior to Ven initiation was performed in 62%. At least one hospitalization occurred for 56% of low, 80% of int, and 88% of high risk pts (63% of the total cohort). Table 1 describes the distribution of TLS risk and frequency of hospitalizations in academic, community centers. TLS prophylactic measures were available for a subset of pts. Allopurinol was used for 91% (n=68/75) of low, 93% (n=52/56) of int, and 94% (n=29/31) of pts at high risk for TLS. Rasburicase was used for 27% (n=28/102) of low, 42% (n=34/81) of int, and 72% (n=57/79) of high risk pts. Normal saline was used in 85% (n=62/73) of low, 88% (n=49/56) of int, and 97% (n=30/31) of high risk pts. TLS occurred in 8.4% of pts (n=25/297). Three lab and 2 clinical events occurred in low risk pts, 7 lab and 3 clinical events in int risk pts, and 7 lab and 3 clinical events in high risk pts. Of pts with TLS, 1 has discontinued Ven. Of pts with clinical TLS, all were hospitalized, received allopurinol and normal saline, and 28% received rasburicase. 72% with TLS had creatinine clearance Select AEs were neutropenia (ANC7 stools/day) 6.9%. For the subset who received Ven paired, AEs were not increased: 35% neutropenia, 29% thrombocytopenia, 22% infection, 6.3% neutropenic fever, and 6.4% diarrhea. TLS was observed in 3.4% of pts who received Ven paired vs. 9.3% who received Ven monotherapy. 29% pts required ≥1 dose reduction and 32% had ≥1 dose interruption. Median length of dose interruption was 7 days (range 1 - 132). 22 pts (7.4%) discontinued Ven due to an AE. PFS was similar in pts with ≥1 dose interruption vs. 0, pts who required dose interruption ≥8 days vs. Conclusions: Ven was well tolerated in this cohort; AE rates were similar to those reported in clinical trials. Both academic and community sites employed TLS prophylaxis consistent with FDA/EMA recommendations resulting in a small proportion of clinical TLS events ( Disclosures Fox: Sunesis: Consultancy; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau. Eyre:Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Roche: Consultancy; Janssen: Consultancy, Other: travel support; Celgene: Other: travel support. Allan:Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees. Schuster:OncLive: Honoraria; Physician's Education Source, LLC: Honoraria; Dava Oncology: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nabhan:Cardinal Health: Employment, Equity Ownership. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Geron: Equity Ownership. Lamanna:Jannsen: 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; Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Coombs:AROG: Other: Travel fees; H3 Biomedicine: Honoraria; Abbvie: Consultancy; DAVA Oncology: Honoraria; Incyte: Other: Travel fees. Barr:AbbVie, Gilead: Consultancy. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shadman:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Celgene: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Mustang Biopharma: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy. Ujjani:AbbVie: Consultancy, Speakers Bureau. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Jacobs:Genentech: Honoraria. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Brander:Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; BeiGene: 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; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; 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. Mato:Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Regeneron: Research Funding; Sunesis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Acerta: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Prime Oncology: Speakers Bureau.

Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date. Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive. Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p Conclusions: In this heavily pretreated, poor risk group, Ven showed favorable outcomes with comparable toxicity and efficacy on or off clinical trial. Similar outcomes were observed for Ven mono and Ven paired; longer follow up is needed from studies of Ven paired to understand depth and durability of response. Complex karyotype independently predicted inferior PFS and OS. Without complex karyotype, del(17p), multiple lines of prior tx, and prior ibrutinib tx were independent predictors of inferior outcomes. Outcomes of retreatment with KI in Ven-failure previously treated with KI were poor. Data on sequencing cellular therapies post Ven is forthcoming. Disclosures Mato: AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria; Portola: Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy. Eyre:Abbvie: Consultancy, Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Nabhan:Cardinal Health: Employment, Equity Ownership. Lamanna:Acerta: Research Funding; TG Therapeutics: Research Funding; Jannsen: 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; Verastem: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; AbbVie: 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; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Shah:Geron: Equity Ownership; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Kennard:AbbVie, Gilead, Verastem: Consultancy. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Physician's Education Source, LLC: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; OncLive: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau. Coombs:AROG: Other: Travel fees; Abbvie: Consultancy; Incyte: Other: Travel fees; DAVA Oncology: Honoraria; H3 Biomedicine: Honoraria. Ujjani:AbbVie: Consultancy, Speakers Bureau. Jacobs:Genentech: Honoraria. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Shadman:Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Research Funding; Genentech: Research Funding; Genentech: Consultancy; Acerta Pharma: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy. Fox:Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Sunesis: Consultancy.

6577Background: Differences in outcomes have been reported in CLL pts receiving chemo±immunotherapy with non-Caucasians and males having inferior outcomes. Less is known if such disparities exist f...

Background and Objectives ABO blood group accounts for up to 40% of the variability in plasma von Willebrand factor (VWF) levels, which vary in the rank order AB > B > A > O > Bombay. This may be due in part to the influence of ABOassociated oligosaccharides on the proteolysis of VWF by the metalloprotease ADAMTS13, which is markedly deficient in thrombotic thrombocytopenic purpura (TTP). Using ABO blood group as a surrogate for baseline VWF levels as well as susceptibility to proteolysis by ADAMST13, we set out to determine whether ABO blood group influences the clinical course of TTP. Methods We conducted a retrospective analysis of the clinical course of 76 patients with primary, sporadic TTP treated at two institutions over the past 10 years. Results We found no significant differences between group O and non-O patients with respect to presenting platelet count and lactate dehydrogenase concentration, maximum serum creatinine concentration, and total number of therapeutic plasma exchanges per episode. Conclusions Substrate-related contributors to the highly variable phenotype and clinical course of TTP warrant further investigation.

Natural killer (NK) cell-mediated cytotoxicity can control leukemia relapse while protecting patients from graft-versus-host disease (GVHD) after allogeneic stem cell transplant. Cord blood (CB) is rich in NK cell progenitors with similar properties of proliferation and cytotoxicity as adult blood NK cells. Hence, it is attractive to expand and potentially utilize these cells for adoptive immunotherapy. In this study, CB mononuclear cells were CD3-depleted by immunomagnetic microbead selection to remove T cells. This CD3(dep) CB-MNC fraction was then plated for ex vivo expansion, with or without a feeder layer of irradiated umbilical cord mesenchymal stem cells (UC-MSC), with or without cytokines that have been shown to be critical for NK expansion: IL-2, IL-15, IL-3, and FLT-3L. At an average of 2 weeks of culture, there was significantly higher expansion (64.7 +/- 8.4-fold) of CD56(+)/CD3(-) NK cells in the presence of the UC-MSC feeder layer and cytokines compared to controls (no increase with feeder layer only and 6.4 +/- 1.5-fold increase with cytokines only, P.05). Contact between CD3(dep) CB-MNC cells and UC-MSC augmented NK expansion. The combination of all 4 cytokines was superior to IL-2 alone or 2 cytokines combinations: mean 64.7 +/- 8.4-fold expansion with 4 cytokines combination versus IL-2 alone, IL-2 + FLT-3L, IL-2 + IL-15 or IL-2 + IL-3 (12.2 +/- 2.0, 14.4 +/- 2.4, 10.4 +/- 4.1, 25.2 +/- 8.1 respectively). We also observed that only fresh CD3(dep) CB-MNC preparations could be expanded reliably, whereas frozen and thawed CD3(dep) CB-MNC cells did not expand consistently (mean fold increase 6.5 +/- 3.2). Cytotoxicity of expanded NK cells was compared with NK cells from fresh and overnight IL-2 activated CD3(dep) CB-MNC. Whereas fresh cells displayed no discernible killing, strong cytotoxicity against K562, Raji, REH, and SUP-B15 cells lines was noted after overnight activation in IL-2. Cytotoxicity of expanded NK cells against Raji, REH, and SUP-B15 was lower, which, however, correlated with a predominant expansion of CD56(+)/CD16(-) cells known to have less cytolytic activity than CD56(+)/CD16(+). To test the transfection efficiency in NK cells, fresh or expanded CD3(dep) CB-MNC cells were electroporated with either DNA or mRNA constructs for GFP. DNA had a low transfection efficiency (10%), whereas the one for mRNA reached 52%, but at the cost of significant cell death. Our results suggest that CB NK cell progenitors can be expanded to obtain large numbers by using an irradiated feeder of UC-MSC. They maintain an elevated cytotoxic profile, and may be genetically manipulated-all characteristics that make them suitable for cellular therapies.

The Wharton's jelly of the umbilical cord is rich in mesenchymal stem cells (UC-MSCs) that fulfill the criteria for MSCs. Here we describe a novel, simple method of obtaining and cryopreserving UC-MSCs by extracting the Wharton's jelly from a small piece of cord, followed by mincing the tissue and cryopreserving it in autologous cord plasma to prevent exposure to allogeneic or animal serum. This direct freezing of cord microparticles without previous culture expansion allows the processing and freezing of umbilical cord blood (UCB) and UC-MSCs from the same individual on the same day on arrival in the laboratory. UC-MSCs produce significant concentrations of hematopoietic growth factors in culture and augment hematopoietic colony formation when co-cultured with UCB mononuclear cells. Mice undergoing transplantation with limited numbers of human UCB cells or CD34+ selected cells demonstrated augmented engraftment when UC-MSCs were co-transplanted. We also explored whether UC-MSCs could be further manipulated by transfection with plasmid-based vectors. Electroporation was used to introduce cDNA and mRNA constructs for GFP into the UC-MSCs. Transfection efficiency was 31% for cDNA and 90% for mRNA. These data show that UC-MSCs represent a reliable, easily accessible, noncontroversial source of MSCs. They can be prepared and cryopreserved under good manufacturing practices (GMP) conditions and are able to enhance human hematopoietic engraftment in SCID mice. Considering their cytokine production and their ability to be easily transfected with plasmid-based vectors, these cells should have broad applicability in human cell–based therapies.

BACKGROUND: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a diagnosis of exclusion when a patient presents with the sine qua non findings of thrombocytopenia and microangiopathic hemolytic anemia without an identifiable cause. Although most patients respond to therapeutic plasma exchange (TPE), a significant number of patients relapse. The aim was to determine if clinical, laboratory, and/or treatment features could predict response and/or relapse. STUDY DESIGN AND METHODS: This study was a retrospective review of adults with TTP-HUS treated with TPE at our institution from January 1996 to February 2004. RESULTS: The study population consisted of 90 patients (69% female) with mean age of 45 years and mostly obese (65%). The majority of cases were considered idiopathic. Ten patients died (11%) from the disease before achieving a response, whereas 79 percent were considered responders. Obesity and severe anemia at presentation were predictors of response to TPE (p = 0.0126 and p = 0.0071, respectively). Among the responders, 28 percent relapsed in a median of 14 months. Male sex, severe thrombocytopenia (mean ± SD, 13 × 109 ± 8 × 109/L), and higher lactate dehydrogenase pre-/posttreatment ratio were associated with relapse (p values of 0.0141, 0.0199, and 0.0407, respectively). ADAMTS-13 values were not obtained on enough number of patients to provide important data. CONCLUSION: Although patient and laboratory characteristics associated with response and relapse were identified, there was significant overlap between patient groups. Thus, our findings offer preliminary evidence and do not yet justify short- or long-term changes in the management of patients with TTP-HUS.

Photopheresis has become a key component in the therapeutic armamentarium of cutaneous T-cell lymphoma, graft-versus-host disease following stem cell transplant, and allograft rejection of solid organs such as heart. Although it is considered a new treatment modality in its present form, the field of phototherapy dates back thousands of years. In this review, the reader will learn more about the history of photopheresis and how it became a therapeutic alternative for patients with solid organ transplants. An extensive literature search will highlight the evidence-based benefits of photopheresis (or lack thereof). A discussion of the mechanism of action of photopheresis and the technical aspects of the procedure will also be covered. Since photopheresis may be the best tolerated form of immunomodulation, current promising, albeit preliminary data on its efficacy warrant further investigation and understanding. J. Clin. Apheresis 21:72–77, 2006. © 2006 Wiley-Liss, Inc.

An emerging treatment option for chronic lymphocytic leukemia (CLL) is to make cytotoxic immune cells express a chimeric antigen receptor (CAR) that recognizes specific surface molecules on CLL cells. Here an mRNA coding for an anti-CD19 CAR was transfected into the NK-92 cell line by electroporation. In contrast to cDNA, mRNA resulted in high transfection efficiency (47.2 +/- 8% versus5% for cDNA) with minimal effect on cell viability. NK-92 cells expressing anti-CD19 CAR killed previously resistant CD19+ B-ALL cell lines, as well as primary CLL cells and therefore may present a safe, cell-based, targeted treatment for patients with CLL.

Recognition and management of gastrointestinal and hepatic complications of hematopoietic stem cell transplantation has gained increasing importance as indications and techniques of transplantation have expanded in the last few years. The transplant recipient is at risk for several complications including conditioning chemotherapy related toxicities, infections, bleeding, sinusoidal obstruction syndrome, acute and chronic graft-versus-host disease (GVHD) as well as other long-term problems. The severity and the incidence of many complications have improved in the past several years as the intensity of conditioning regimens has diminished and better supportive care and GVHD prevention strategies have been implemented. Transplant clinicians, however, continue to be challenged with problems arising from human leukocyte antigen-mismatched and unrelated donor transplants, expanding transplant indications and age-limit. This review describes the most commonly seen transplant related complications, focusing on their pathogenesis, differential diagnosis and management.

Abstract 1400 Introduction: Hemostatic abnormalities are frequently encountered during initial presentation of acute myeloid leukemia (AML) as well as during induction treatment. Patients often present with decreased platelet counts and sometimes with abnormalities of the coagulation parameters with or without bleeding manifestations. In the absence of overt disseminated intravascular coagulopathy (DIC), transfusion practices during treatment are essentially based on the platelet count. Fibrinogen is an important element of the clotting mechanisms, constituting a template for both thrombin binding and the fibrinolytic system. We sought to determine the prevalence of altered serum fibrinogen levels during induction treatment in AML and its clinical significance. Methods: We prospectively measured serum fibrinogen on a daily basis in patients with newly diagnosed AML treated with induction anti-tumor chemotherapy at our institution from February 2007 to July 2010. Inclusion criteria included the diagnosis of AML and no overt DIC. Results: The study population included 17 patients (47% females) with mean age of 55.3 years (range 18 –80 years). At presentation, the mean platelet count was 62 × 109/L (range 3 – 252 × 109/L), the mean prothrombin time was 11.4 seconds (range 9.6–13.4 secs, normal range 10—13.7 secs), the mean international normalized ratio was 1.1 (range 0.9–1.3; normal range 0.9–1.1) and the mean activated partial thromboplastin time was 26.56 seconds (range 20.1–41 secs, normal range 22.3–34.0 secs). All patients had normal serum fibrinogen levels at presentation (mean 380.6 mg/dl; range 258–567 mg/dl; normal range 200–400 mg/dl). Thirteen patients were treated with idarubicin and cytarabine, 3 patients received a FLAG (fludarabine, cytarabine and G-CSF) regimen and one patient had amonafide and cytarabine. Serum fibrinogen levels were recorded on all patients on a daily basis (Figure 1). Nine (53%) developed hypofibrinogenemia on the fourth day of induction, 2 (12%) on day 5, 3 (17%) on day 6, 2 (12%) on day 7, and one (6%) on day 8 of the induction. Eight patients (47%) received prophylactic cryoprecipitate when the serum fibrinogen levels fell below 150 mg/dl. We did not observe a significant trend difference in serum fibrinogen levels between patients who received cryoprecipitate and those who did not. Serum fibrinogen levels were back to normal without transfusion support by day 6 for one patient (5.88 %), day 7 for 2 patients (11.76 %), day 8 for 3 patients (17.65 %), day 9 for one patient (5.88 %), day 10 for one patient (5.88 %), day 11 for 3 patients (17.65 %), day 12 for 6 patients (35.3 %). Conclusion: Patients with acute myeloid leukemia receiving induction chemotherapy may frequently develop isolated hypofibrinogenemia without evidence of disseminated intravascular coagulation. This finding is usually self-limited and disappears shortly after the completion of antitumor chemotherapy, usually by day 12. The mechanism of this under-recognized phenomenon is unclear. Its common occurrence raises questions about the appropriateness of transfusion practices in AML based solely on the platelet count and argues in favor of the need of more global tests such as thromboelastography. Disclosures: No relevant conflicts of interest to declare.

High dose chemotherapy followed by autologous stem cell transplantation (SCT) prolongs survival and is the standard of care for eligible multiple myeloma patients. Approximately 50 % of patients presented with renal insufficiency and 20% have renal failure at diagnosis. Transplant eligibility of patients with renal insufficiency is controversial due to the concerns of increased toxicity. We retrospectively evaluated 80 patients with multiple myeloma who underwent either single or tandem SCT at Rush University Medical Center between January 1999 and December 2003. Median OS was 51 months and PFS was 26 months for all patients. All patients with renal insufficiency except those who did not have change in renal function had SCT within 12 months of initial diagnosis. Ten (12 %) patients had serum creatinine of at least 1.5mg/dl immediately before the transplantation. (mean creatinine: 2.88 mg/dl, range 1.4–4.9mg/dl) All patients with renal insufficiency except one had positive urine immunofixation for free light chains (6 kappa and 3 lambda) and all had normal serum calcium level at the time of SCT. GFR was estimated by MDRD equation. Three out of ten (30%) patients had at least 100% improvement in GFR by day 30 post-transplant (mean decrease in serum creatinine 1.26 mg/dl, range 1.1–2.9 mg/dl). Four (40%) patients had at least 50% increase in GFR after day 100. (mean decrease in serum creatinine 1.48mg/dl, range 1–2.9 mg/dl ). Two (20%) patients had no significant change in renal function (pre-transplant mean serum creatinine 2.4 mg/dl, post-transplant creatinine at day 100 2.1mg/dl. One patient (pre SCT serum creatinine 4.9mg/dl) required hemodialysis throughout the transplant period. Table 1 compares the patient characteristics and clinical outcomes in patients with and without renal insufficiency. PFS and OS rates of patients with renal insufficiency at the time of SCT were similar to those with normal renal function. There was no significant difference in transplant related toxicity between two groups. In conclusion, the outcomes of myeloma patients with renal insufficiency who underwent autologous SCT were not significantly different from those who had normal renal function at the time of transplant. Moreover, we observed a measurable improvement in the renal function after autologous SCT. Table 1. Stratification of patient characteristics and clinical outcomes by renal insufficiency. Serum creatinine ≥ 1.5mg/dl Serum creatinine < 1.5mg/dl p value * Follow-up available in all but 1 patient. † Follow-up available in 59 (83%) patients. ‡ Follow-up available in 65 (92%) patients. Patients, no. 10 (12 %) 70 (88 %) Age (mean, years) 60 56 NS Male (%) 50 50 NS Patients receiving transplant ≤ 12months 8 (80%) 53 (76%) NS > 12months 2 (20%) 17 (24%) NS ISS stage (%) 1 10 43 2 0 34 < 0.01 3 90 23 B2microglobulin (mean, μg/ml) 15.26 3.24 < 0.01 Patients receiving melphalan 200 mg/m2 5 (50%) 69 (98%) < 0.01 ≤140 mg/m2 5 (50%) 1 (2%) PFS (median, months) 28* 25† NS OS (median, months) 53* 51‡ NS

The role of PET scans in Hodgkin Lymphoma (HL), especially after autologous HCT, is undefined. Positron emission tomographic (PET) scanning has increasingly become a promising non-invasive modality for the monitoring of patients with HL. Whole body PET scans have been reported to have increased sensitivity and accuracy as compared to conventional staging methods for the initial staging of HL. The sensitivity of PET is reported as 86% compared to 37% for CT, while the specificity has been reported as 96.5% compared to 99.7% for CT. The purpose of this study was to investigate the utility of PET scanning in relapsed HL s/p autologous HCT as a prognostic indicator of transplant outcome. Here, we describe a single institution retrospective analysis of 55 patients with HL who had FDG-PET scans after stem cell transplantation. Patients/Methods: Between 1/94 and 12/06, 55 patients with refractory or relapsed Hodgkin Lymphoma underwent an autologous HCT at our institution. They each had a FDG-PET approximately one month following stem cell transplant to evaluate for response following HCT. Patients were placed into two separate categories depending on results of the PET scan. The incidence and timing of relapse, disease free survival, and overall survival were assessed. Results: A total of 55 patients were evaluated post autologous HCT with a median age of 32 years (ranging from 15–66) with a median follow-up of 26 months. The patients were divided into two groups based on FDG-PET activity. Twenty-nine patients had no evidence of activity post transplant, while twenty-six patients had evidence of activity. The median DFS and OS of the PET negative group were 35.8 months and 35.8 months, respectively. The median DFS and OS of the PET positive group were 18.1 months and 10.1 months, respectively. There were statistically significant differences between the two groups when comparing their DFS and OS (p=0.0035 and p=0.004), in favor of the PET negative group. There were 2 relapses in the PET negative group and 9 relapses in the PET positive group (see figures). Conclusion: We conclude that FDG-PET scan performed after autologous HCT for patients with relapsed or refractory Hodgkin lymphoma strongly predicted transplant outcome. Patients with any significant PET uptake are at high risk of treatment failure and should be considered for additional treatment with strong contemplation for participation in clinical trials. Figure Figure

B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world and is characterized by monoclonal proliferation of functionally deficient lymphocytes, with relative decrease in T and Natural Killer (NK) cells. Available monoclonal antibody (mAb) therapies elicit a response in almost half of the patients, but durable remissions are rare. B-CLL cells are virtually impervious to T and NK cell-mediated cytotoxicity. However, a feasible approach to overcome this resistance is to redirect the specificity of T or NK cells by making them express chimeric antigen receptors (CAR). Such a method has been successfully tested in NK cells against a number of CD19-expressing cells; however the loading of cells with CD19-CAR relied on retrovirus-based transfection methods. We describe here a non-retroviral method for obtaining NK cells expressing high levels of CD19-CAR, based on electroporation of messenger RNA (mRNA). We used a CAR that is comprised of the single chain Fv portion of a mouse mAb against CD19 fused to the signaling intracellular domain of CD3ζ subunit. The corresponding cDNA was subcloned by PCR into a plasmid allowing T7-dependant mRNA synthesis. In vitro synthesis of the CD19-CAR mRNA was followed by a poly-adenylated tail elongation step in order to improve in vivo stability and translation of the messenger. Electroporation of NK-92 cells with this construct, using a Biorad GenePulser II apparatus, yields up to 78% expression efficiency and as high as 90% cell survival. Cytotoxicity of transfected NK-92 cells was tested against 3 target cell lines (NK sensitive, CD19 negative K562; CD19 expressing, NK resistant REH and SUPB15) as well as primary CLL cells from 6 untreated patients. A non-radioactive fluorochrome-based flow cytometric assay was used to determine NK-mediated cytotoxicity, at effector to target (E:T) ratios ranging from 1:1 to 10:1. Expression of the CD19-CAR on the surface of NK-92 cells do not change their cytolytic properties against K562: 70% ±5% killing compared to 74% ±2% killing for non-transfected NK-92, (E:T ratio of 10:1). Expression of CD19-CAR in NK-92 cells completely overcomes the resistance of REH and SUPB15 cell lines: 76% ±7% and 73% ±5% killing respectively, compared to 21% ±10% and 18% ±7% killing respectively with non-transfected NK-92 (E:T ratio of 10:1). Moreover, previously resistant primary CLL cells became highly sensitive to lysis by NK-92 expressing CD19-CAR: 46–82% killing, as opposed to 7–22% killing for non-transfected NK-92 (E:T ratio of 10:1). These results show that NK cells can be engineered using mRNA transfection by electroporation to target and effectively kill resistant primary CLL cells.

Natural Killer (NK) cell-mediated cytotoxicity can control leukemia relapse while protecting patients from graft-versus-host disease (GVHD) after allogeneic stem cell transplant. Cord blood (CB) is rich in NK cells with similar properties of proliferation and cytotoxicity as adult blood NK cells. Hence these cells are attractive for developing strategies to eliminate residual disease after cord blood transplant. In this study, CB mononuclear cells were cryopreserved after CD3 depletion performed by immunomagnetic microbead selection (Miltenyi Biotec, Auburn, CA). After thawing, cells were plated for NK expansion, with or without a feeder layer of irradiated cord mesenchymal (UCM) cells either from the same (autologous) or from an unrelated (allogeneic) cord donor, with or without IL-2 (1000 IU/ml), IL-15 (10 ng/ml), IL-3 (10ng/ml) and Flt3 (10ng/ml). At a median of 19 days of culture (range 14–21), there was significantly higher expansion (range 3.5–72 fold) of CD56+/CD3− cells with the UCM feeder layer and cytokines compared to controls (mean 21.2 ± 20.8 fold increase vs 1.6 ± 0.9 fold increase with feeder layer only and 1.8 ± 0.89 fold increase with cytokines only, p=0.039 and p=0.041 respectively). There was no significant difference in NK expansion between autologous and allogeneic UCM feeder layers (29.6 ± 26.8 vs. 12.8 ± 8.9 fold, p=0.243). Expanded CB-NK cells were then tested for cytotoxicity against K562 cells using a calorimetric assay with PKH67-GL. CB-NK cells expanded either with autologous or allogeneic UCM feeder layers displayed enhanced cytotoxicity compared to controls plated with cytokines only (91.78±0.7% vs. 82.5±1.8%, p=0.003 and 89±2.3% vs. 83.7±0.18%, p=0.056, respectively). In order to test whether expanded CB-NK cells can be transfected for ultimately targeting malignant cells, we electroporated expanded CB-NK cells with mRNA produced from plasmid GFP-DNA by in vitro transcription. Flow cytometry was used to detect viability, which was 94%, 92% and 93% for non-transfected, GFP-DNA and GFP-mRNA samples respectively. GFP-mRNA expression at 24 hours was significantly higher (range 36.6–50.8%, mean 42.8±5.2%) compared GFP-cDNA controls (mean 4.2±0.35%, p

Umbilical cord blood (UCB) is a viable source of hematopoietic stem cells for transplantation of children and adults undergoing treatment for hematological malignancies. However only 4% of adults 70kg and over have a UCB unit available which contains the widely accepted minimum cell dose of 1.5x107 mononuclear cells per kilogram. Co-transplantation of hematopoietic stem cells with mesenchymal stem cells may enhance engraftment and therefore decrease transplant-related morbidity and mortality from delayed leukocyte recovery associated with a low pre-transplant cell dose. Umbilical cord matrix (UCM) cells, found in the Wharton’s Jelly, were easily and reliably extracted from minced pieces of cord by culture in RPMI + 20% fetal bovine serum at 37° and 5% humidified CO2. UCM expand best in 20% FBS but can also be expanded in human serum, autologous serum, and X-VIVO10. Small (1–3mm) minced pieces of umbilical cord can be cyropreserved at the time of delivery in 10% DMSO solution. UCM cells exhibit a fibroblast morphology and express markers common to mesenchymal stem cells: CD73 (SH3), CD105 (SH2), CD 29, CD44, CD49b, CD117, CD166, STRO-1 and HLA-DR. UCM are negative for CD14, CD 19, CD34, and CD45. Morphology and cell surface marker expression is stable after greater than fifteen passages. UCM cells grown in culture were shown to produce more GM-CSF and G-CSF than similar numbers of adult bone marrow mesenchymal stem cells, GM-CSF 178 pg/mL versus 77 pg/mL and G-CSF 82.6 pg/mL versus 7.9 pg/mL. NOD/SCID mice treated with anti-NK 1.1 antibodies and irradiated with 350 cGy were injected with suboptimal (1x104) numbers of cord blood CD34+ cells with and without 1x106 autologous UCM cells, extracted from the same umbilical cord as the cord blood CD34+ cells. Bone marrow was harvested at six weeks post transplant from both femurs and tibias and peripheral blood obtained via cardiac puncture. The percentage of human CD45+ cells in the bone marrow and the peripheral blood was assessed by flow cytometry. NOD/SCID mice transplanted with 1x104 cord blood CD34+ cells alone had 3.0% human CD45+ cell engraftment in the bone marrow and 3.6% human CD45+ cells in the peripheral blood, while NOD/SCID mice transplanted with 1x104 CD34+ cells and 1x106 UCM cells had an average of 27.3% human CD45+ cell engraftment in the bone marrow and 3.9% human CD45+ cells in the peripheral blood. These results indicate a trend towards improved engraftment in vivo with co-transplantation of suboptimal numbers of umbilical cord blood CD34+ cells and autologous umbilical cord matrix cells versus transplantation of suboptimal numbers of umbilical cord CD34+ cells alone.