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PURPOSE Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis. PATIENTS AND METHODS Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. RESULTS Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE. CONCLUSION Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.

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.

Purpose:Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental Design:To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].Results:We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.Conclusions:For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501

Supplemental Figure 2: Progression free survival of patients without prior BTKi exposure who had progressed on venetoclax and were then treated with BTKi.

Supplemental Figure 1: Overall survival of entire cohort from initiation of venetoclax.

The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

Background: Richter transformation (RT) is an aggressive diffuse large B-cell lymphoma that can occur in 10% of patients with chronic lymphocytic leukemia (CLL). RT has no approved therapies, poor prognosis, and an estimated median overall survival (OS) of 3-11 months. Pirtobrutinib is a well-tolerated highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) with favorable oral pharmacology and promising efficacy in patients with poor-prognosis B-cell malignancies following prior covalent BTKi therapy. We now report on RT patients from BRUIN. Methods: Patients previously treated for B-cell malignancies were eligible for pirtobrutinib monotherapy in dose escalation/expansion within the phase 1/2 BRUIN study. Key endpoints: investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response-evaluable cohort consisted of patients with RT who completed either first response assessment or discontinued therapy. The safety cohort consisted of patients who received ≥1 dose of pirtobrutinib monotherapy (n=725). Data cut was 31 January 2022. Results: Of 57 RT patients (median age: 67 years), 91% (n=52) received at least 1 prior RT-directed therapy. Median lines of prior RT therapy were 2: (anti-CD20 antibody [86%, n=49], chemotherapy [79%, n=45], BCL-2 inhibitor [35%, n=20], BTKi [28%, n=16], PI3K inhibitor [12%, n=7], CAR-T [9%, n=5], immunomodulator [5%, n=3], stem cell transplant [4%, n=2], other systemic therapy [33%, n=19]) and median lines of prior CLL were 2: (BTKi [60%, n=34], anti-CD20 antibody [60%, n=34], chemotherapy [47%, n=27], BCL-2 inhibitor [42%, n=24], immunomodulator [9%, n=5], PI3K inhibitor [7%, n=4], stem cell transplant [7%, n=4], CAR-T [2%, n=1], other systemic therapy [11%, n=6]). ORR for patients within phase 2 (n=56, 200mg once/day starting dose) was 54% (95% CI, 39-68): 5 complete responses, 22 partial responses. Median DoR was 8.6 months (95% CI, 1.9-NE, 63% censored) and median OS was 13.1 months (95% CI, 7.1-NE) at a median follow up time of 5.5 months and 9.7 months respectively. Six patients electively discontinued pirtobrutinib to pursue curative-intent therapy (allogeneic transplant, n=6, 3.8 months median time-on-therapy). The most frequent TEAEs were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). Of Grade≥3 TEAEs, neutropenia (20%, n=143) was the most frequent and hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were of low grade. Fifteen (2%) patients discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib demonstrated promising preliminary efficacy and was well tolerated for patients who received prior RT-directed chemoimmunotherapy and covalent BTKi. Presented:ASH2022. Citation Format: Joanna Rhodes, David Lewis, Paolo Ghia, Nirav N. Shah, Catherine C. Coombs, Chan Y. Cheah, Jennifer Woyach, Nicole Lamanna, Marc S. Hoffmann, Shuo Ma, Toby A. Eyre, Talha Munir, Manish R. Patel, Alvaro J. Alencar, Constantine S. Tam, John F. Seymour, Wojciech Jurczak, Ewa Lech-Maranda, Lindsey E. Roeker, Philip A. Thompson, Paolo B. Abada, Chunxiao Wang, Binoj Nair, Hui Liu, Donald E. Tsai, Anthony R. Mato, William G. Wierda. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT167.

Neuroscience models commonly have a high number of degrees of freedom and only specific regions within the parameter space are able to produce dynamics of interest. This makes the development of tools and strategies to efficiently find these regions of high importance to advance brain research. Exploring the high dimensional parameter space using numerical simulations has been a frequently used technique in the last years in many areas of computational neuroscience. High performance computing (HPC) can provide today a powerful infrastructure to speed up explorations and increase our general understanding of the model's behavior in reasonable times.

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.

The understanding of the B cell receptor (BCR) pathway and its contribution to chronic lymphocytic leukemia (CLL) pathogenesis have led to the development of targeted BCR inhibitors which have transformed the treatment paradigm of CLL. Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor which has demonstrated improvements in both progression free (PFS) and overall survival (OS) in both the treatment naïve and relapsed/refractory setting as compared to traditional chemoimmunotherapy. Despite its clinical efficacy, many patients discontinue treatment due to adverse events, which are thought to be mediated through off-target kinase inhibition. Zanubrutinib is a second-generation non-covalent BTK inhibitor with higher potency, allowing for inhibition of BTK with fewer off target effects. Early phase clinical trials have demonstrated excellent efficacy and a well-tolerated safety profile. Long-term follow-up is needed, but zanubrutinib holds promise to be an effective therapy for CLL with a manageable side effect profile and will be an exciting addition to our treatment paradigm.

The treatment of chronic lymphocytic leukemia (CLL) embodies one of the great success stories in translational research, with the development of therapies aimed at disrupting crucial pathways that allow for the survival and proliferation of the malignant clone. The arrival of targeted agents into our armamentarium, along with the advent of novel monoclonal antibodies that can achieve deeper remissions, has steered the field to a new treatment paradigm. Given the panoply of therapeutic options available, the question arises whether chemotherapy still has a role in the management of CLL. The novel targeted agents, which include the Bruton’s tyrosine kinase inhibitors, ibrutinib and acalabrutinib, along with the B-cell lymphoma-2 inhibitor, venetoclax, are highly effective in achieving a response with improved remission duration and survival, particularly in high-risk patients. Despite this major progress, the new agents bring a unique set of toxicities unlike those associated with cytotoxic chemotherapy. There is a paucity of head-to-head comparisons among all of the novel agents, because their approval was based on randomization against traditional chemoimmunotherapeutic regimens. Parallel to the increase in the number of available targeted agents, there has been a significant improvement in quality of life and life expectancy of the patients with a CLL diagnosis over the last decade. Our review will examine whether “chemotherapy-free” frontline treatment approaches are worth the associated risks. Our goal is to help identify optimal treatment strategies tailored to the individual by reviewing available data on monotherapy vs combination strategies, depth of response, treatment duration, and potential toxicities.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of two therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was one (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95% Confidence Interval: 62-83). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; P=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

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 is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Haplo/cord transplantation combines an umbilical cord blood (UCB) graft with CD34-selected haploidentical cells and results in rapid hematopoietic recovery followed by durable UCB engraftment. We compared outcomes of transplants in older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) who received either HLA-matched unrelated donor (MUD) cells or haplo/cord grafts. Between 2007 and 2013, 109 adults ages 50 and older underwent similar reduced-intensity conditioning with fludarabine and melphalan and antibody-mediated T cell depletion for AML (n = 83) or high-risk MDS (n = 26) followed by either a MUD (n = 68) or haplo/cord (n = 41) graft. Patient characteristics were similar for each graft source except for more minority patients receiving a haplo/cord transplant (P = .01). One half of the AML patients were not in remission. Two-year progression-free survival (PFS), overall survival (OS), and graft-versus-host disease–free relapse-free survival were 38%, 48%, and 32.1% for MUD and 33%, 48%, and 33.8% for haplo/cord transplants (P = .62 for PFS; P = .97 for OS; P = .84), respectively. Acute grades II to IV and chronic graft-versus-host-disease rates did not differ at 19.5% and 4.9% in haplo/cord compared with 25% and 7.4% after MUD (P = .53 and P = .62, respectively). Multivariate analysis confirmed no significant differences in transplant outcomes by donor type. Haplo/cord reduced-intensity transplantation achieves similar outcomes relative to MUD in older AML and MDS patients, making this a promising option for those without matched donors.

Background: The development of Richter Transformation (RT) in patients (pts) with chronic lymphocytic leukemia (CLL) while on targeted agents has been reported to have a median survival of 2.3-3.5 months (mo). Treatment is usually anthracycline-based combination regimens, though responses are short-lived. Phase 2 trial of combined venetoclax-REPOCH achieved a median progression free survival (PFS) of 16 mo. We studied the use of ibrutinib in combination with obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone (I-OCHOP) JUN2017-SEP2018 (ClinicalTrials.gov: NCT03145480). During the conduct of the study, ibrutinib plus RCHOP in untreated diffuse large B cell lymphoma (NCT01855750) reported more treatment-emergent serious adverse events when compared to RCHOP, leading to higher rates of treatment discontinuation with toxicity more prominent in elderly pts. Since the majority of pts with CLL are elderly, enrollment was stopped. We report the outcomes of 3 participants. Methods: Informed consent was provided through IRB-approved protocol. Subjects were enrolled in an open-label phase II trial combining ibrutinib with O-CHOP. Ibrutinib 560mg was taken daily starting cycle 1 day 1 (C1D1) continuously until progression or start of new anticancer treatment. Obinutuzumab was given per prescription insert starting on C1D1 with CHOP for up to 6 cycles. Pts were allowed to discontinue study drugs to pursue allogeneic stem cell transplant (allo-SCT). Pts aged 18-80 years old with adequate organ function, Eastern Cooperative Oncology Group performance status ≤ 2, and histologically confirmed evidence of RT from CLL were eligible to participate. Prior targeted agent use was allowed until 24 hours prior to dosing. Chemo- or immuno-therapy was not allowed within 21 and 10 days of C1D1 respectively. The primary endpoint was investigator-assessed overall response rate (ORR) per revised response criteria for malignant lymphoma. Secondary outcomes included hematological improvement, PFS, overall survival (OS), and quality of life. Pts were allowed to pursue allo-SCT after achieving a response and were followed for PFS/OS. Descriptive analyses were utilized, and PFS/OS was calculated from initial treatment to death or last follow-up. Results: Three pts consented and started therapy: two women and one man with a median [range] age of 53 [36-73] years, all had high-risk disease (Figure 1). Median Cumulative Illness Rating Scale at baseline 2 [0-4]. No large cell lymphoma involved the bone marrow. All pts developed RT while on a novel agent (ibrutinib, acalabrutinib, or venetoclax monotherapy respectively). All enrolled immediately after RT diagnosis and received I-OCHOP. Participants had overall good adherence to ibrutinib therapy (mean missed doses per 28-day treatment cycle was 0.88 doses) while on trial. Two pts developed neutropenia (n=1, grade 3 and n=1, grade 4; neither febrile) that resolved by time of withdrawal from study. 2 pts had anemia (grade 1 and 2), and one participant had thrombocytopenia (grade 2), neither requiring transfusion support. All 3 pts reported fatigue (all grade 2 or less) that on average improved during treatment as assessed by FACIT questionnaire (mean Δ from baseline to end of treatment: -5). Figure 1 lists other adverse events. Of 3 enrolled pts, 2 pts achieved remission (1 complete, 1 partial) and undetectable minimal residual disease (detection sensitivity 0.01%) in the bone marrow post 4 cycles I-OCHOP and underwent allo-SCT and were followed for progression. Figures 2 and 3 show the PET responses after 2 cycles of I-OCHOP in 2 participants with bulky lymphadenopathy. Time to allo-SCT for the 2 pts was 3.7 and 3.9 mo from C1D1. After transplant, one pt relapsed with RT in the central nervous system after 20 mo and died from pneumonia 5 mo later; the other pt is alive 49.5 mo later with no evidence of disease. The third pt had rapid progression and came off study. Median PFS for the 3 pts was 23.5 mo [1.9-NR] and OS 29.1 mo [6.7-NR] as of datacut July 30, 2021. Conclusions: Despite historically poor outcomes reported after RT while on a targeted agent, ibrutinib addition to anthracycline-based regimen seemed well tolerated. Two patients achieved a rapid and deep responses irrespective of prior BTK inhibitor use and were able to pursue allo-SCT which correlated with durable PFS/OS. Figure 1 Figure 1. Disclosures Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Background: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) accounting for ~35% of NHL and often have a clinically indolent course. PET/CT max SUV ≥10 and high proliferative index are associated with FL at high risk for transformation to aggressive lymphoma (Schöder, 2005; Rossi, 2020). A subset of patients (pts) with low histologic grade and high proliferation index (LG-HPI) have a more aggressive clinical course with inferior overall survival (OS) compared to low grade, low proliferation index (LG-LPI) FL patients (Wang, 2005). The aim of our study was to identify outcomes for patients with LG-HPI FL at our institution. Methods: We conducted a single center, retrospective study of FL diagnosed from 1/1/2015-1/1/2021. Demographic information, diagnoses, laboratory results, medications, pathology, and radiology reports were collected from pts' electronic medical records. Pathology specimens were de-identified and retrospectively reviewed by two pathologists. Review included comprehensive evaluation of histologic grade, proliferation index by Ki-67 percentage (Ki-67%), immunohistochemical staining, and c-MYC immunohistochemical staining. Biopsies were classified as LG-LPI if Grade 1-2 and Ki-67 was Results: 152 pts were diagnosed with FL and included for analysis. Patient characteristics are summarized in Table 1. Median age at diagnosis for all pts was 65.9 years. Sixty-three pts had LG-LPI, 61 LG-HPI, and 28 HG pts. Ten pts transformed to DLBCL (2 LG-LPI, 5 LG-HPI, 3 HG). Treatment regimens included initial observation (n = 44), anti-CD20 therapy alone (n = 24), chemo-immunotherapy (n = 53), and other (n = 31). Median TTFT was 1.27 mo (range 0-115.2 mo). There was moderate correlation between SUV of biopsied lesion ≥10 and Ki-67 percentage (ROC Area 0.6175). Median PFS was longer for LG-LPI compared to LG-HPI (78.6 vs 57.8 mo, p = 0.04, HR 2.37) but not between LG-HPI and HG (57.8 vs 61.3 mo respectively, p = 0.32) (Figure 1A). Median OS was not reached in any cohort with median follow up of 29.5 mo. There was no difference in OS between LG-LPI vs LG-HPI (p = 0.53) (Figure 1B). Histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity (max or of biopsied lesion), presence of c-Myc staining, or initial treatment regimen were not associated with median PFS or OS in either subgroup on univariate analysis. Conclusions: In our cohort, PFS was shorter for LG-HPI compared to LG-LPI but with a similar trajectory to that of HG FL, consistent with prior reports. No differences were seen in OS between LG-HPI and LG-LPI, and no covariates of interest including histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity, presence of c-Myc staining, or initial treatment regimen were associated with differences in PFS or OS. Our study is limited by a short follow up time compared to prior published cohorts (29.5 vs 98.4 mo). PET/CT SUV values of ≥10 have moderate predictive value for higher proliferative disease and can aid in identifying patients with higher proliferative disease. Longer follow up is needed to determine if LG-HPI impacts OS. References: 1. SchöderH, et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma. J Clin Oncol 2005;23:4643-51. 2. Rossi C, et al. Baseline SUVmaxis related to tumor cell proliferation and patient outcome in follicular lymphoma. Haematologica 2020;Online ahead of print. 3. Wang SA, et al. Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg Pathol2005;29:1490-6. Figure 1 Figure 1. Disclosures Allen: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: Equity Ownership; Bristol Myers Squibb: Other: Equity Ownership; Alexon: Research Funding. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Chronic lymphocytic leukemia (CLL) is a neoplasm of small mature B lymphocytes, and is the most common leukemia in the Western hemisphere with an estimated 18,650 cases diagnosed in 2016 and almost...

Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have dramatically changed outcomes for patients. Despite these improvements, CLL is still considered incurable. Chimeric antigen receptor-modified T cells have demonstrated the ability to produce long-term remissions in subsets of heavily pretreated patients with B-cell malignancies, including CLL. Unfortunately, the majority of patients with CLL do not attain durable responses. Recent studies have focused on understanding the mechanisms and predictors of response in these patients. In this review, we will discuss the literature for chimeric antigen receptor-modified T-cell therapy in CLL and highlight mechanisms of response and resistance as currently understood.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies. See related commentary by Rogers, p. 3501

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.

Giant cell hepatitis (GCH) is a rare diagnosis in adults that is found in 0.25% of liver biopsies. GCH has been associated with multiple causes including drugs (6-mercaptopurine, methotrexate), toxins, viruses and autoimmune. GCH has been described in few patients with chronic lymphocytic leukemia (CLL). Here we describe three patients diagnosed with GCH thought to be related to underlying CLL and its management. All of our patients were treated with a combination of immunosuppression as well as CLL-directed therapy to address CLL and concomitant liver disease. GCH is a rare manifestation of active CLL and should be ruled out with prompt liver biopsy in patients with CLL with persistent transaminitis without another attributable cause. Prompt treatment of GCH with immunosuppression is required to prevent long-term liver toxicity. If transaminitis does not improve with immunosuppression alone, the addition of CLL directed therapy should be considered in patients who carry this diagnosis to prevent long-term liver toxicity.

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin’s lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

BACKGROUND The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed “poor mobilizers” with granulocyte–colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. STUDY DESIGN AND METHODS To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. RESULTS Significant differences (p ≤ 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. CONCLUSION Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.

Introduction: T cell lymphomas are heterogenous with an overall poor prognosis. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T cell lymphoma (AITL) are the two most common subtypes in the US accounting for 45% of diagnoses. Based on overlapping recurrent molecular and cytogenetic abnormalities, the WHO created an umbrella category of nodal T-cell lymphomas with T-follicular helper phenotype (TFH lymphoma), which includes AITL and PTCL with TFH phenotype (Swerdlow SH, et al. Blood. 2016). 25-30% of patients (pts) are refractory to initial therapy and even amongst responders to initial therapy, relapse is common. Survival after relapse or progression (R/P) is typically measured only in months. Outcomes have not changed significantly even with the introduction of several new agents in the last 10 years (Chihara D, et al. Br J Haematol. 2017). There remains no standard 2nd line therapy or guidance on sequencing of therapies as interpretation of clinical data in T-cell lymphoma is frequently hampered by the heterogeneity of the patient population and small sample size. The aim of our study was to determine outcomes in a large, well-defined group of pts with either primary refractory PTCL-NOS or TFH lymphoma. Methods: We performed a multi-center retrospective study to determine outcomes to 2nd line therapy for adult pts diagnosed between 1.1.09-6.30.18 with PTCL-NOS or TFH lymphoma, who were primary refractory defined by either induction failure, less than CR to initial therapy, or relapse within 6 months (mo) of completion of initial therapy. We performed time to event analysis using Kaplan-Meier method and compared groups using log-rank test. All other statistics were descriptive. Results: Patient and disease characteristics at diagnosis and relapse are summarized in Table 1. We identified 80 eligible pts from 7 US academic centers. Median FU was 17.2 mo from diagnosis (0.5-70). Overall, pts had mostly advanced stage with multiple high-risk features including bone marrow (BM) or extranodal (EN) involvement and B symptoms at diagnosis and R/P. Most pts received CHOP (52%) or CHOEP (24%) as initial therapy. 60% of patients did not attain a CR, while 40% of pts relapsed after initial CR.14% had received a consolidative transplant in 1st CR prior to relapse (almost all autologous hematopoietic cell transplant [HCT]). At R/P, 48% received single agent therapy [mostly romidepsin (15/38)], while 36% received multi-agent salvage therapy [mostly ICE (9/29)]. 13/80 pts were placed on hospice or only received local therapy after R/P. Median OS from diagnosis and following R/P was 19 mo/12.9 mo respectively. Median PFS2 (defined as time from 2nd line therapy to 2nd progression) for pts receiving systemic therapy was 73 days (d) (range 41-175). On univariate and multivariate analysis, there was no significant difference in PFS2 by histologic subtype (74 d for PTCL and 73 d for TFH lymphoma; p=0.29), platelet count Conclusions: Outcomes in this large, well-defined population of primary refractory PTCL-NOS and TFH lymphoma were poor, but better compared to most other retrospective series in R/R T-cell lymphoma. EN disease and advanced stage were common in this cohort of primary refractory pts. Relapse after HCT in CR1 had a particularly poor prognosis. Our findings suggest that single agent therapy following R/P in primary refractory pts and transplant may be beneficial, though our statistical power was limited due to small sample size. In a next step, we plan to expand the cohort and perform genetic/molecular characterization of available biospecimens following central pathology review. Disclosures Rhodes: DAVA Oncology: Honoraria. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Ghosh:TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Dwivedy Nasta:Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding; Celgene: Honoraria; ATARA: Research Funding; Aileron: Research Funding; Debiopharm: Research Funding; Millenium/Takeda: Research Funding; Pharmacyclics: Research Funding. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding.

Introduction Patients (pts) diagnosed with double hit lymphoma (DHL) are reported to experience poor survival outcomes following first-line treatment with R-CHOP, although survival may be improved with receipt of intensive front-line immunochemotherapy. These results may be altered by selection bias, as prior retrospective series of DHL pts did not report performing routine cytogenetic testing to identify those with DHL. We hypothesized that outcomes might differ for DHL pts identified after the implementation of routine testing at our institution. Methods In January of 2015, our institution began routine testing for MYC-rearrangement (R) by fluorescence in situ hybridization (FISH) for all newly-diagnosed cases of DLBCL and HGBL/BCLU, with reflex testing for BCL2-R and BCL6-R by FISH if positive for MYC-R. Prior to this, FISH for MYC-R, BCL2-R and/or BCL6-R was performed at the discretion of the treating physician or interpreting hematopathologist. Pts included in our analysis were diagnosed with DHL from May 2009 through July 2018. Inclusion criteria were adults treated with first-line curative-intent immunochemotherapy. Exclusion criteria were HIV-associated lymphoma, primary CNS or testicular lymphoma, post-transplant lymphoproliferative disorder, and incomplete clinicopathologic and outcomes data. Primary outcome measures were progression free survival (PFS) and overall survival (OS) in the pre-January 2015 selective testing (ST) and post-January 2015 routine testing (RT) cohorts. Data were censored on 5/31/19. Results Sixty-five pts were included in the analysis. The ST and RT cohorts did not differ significantly on the baseline characteristics of age, sex, stage, performance status, B symptoms, elevated LDH, extranodal disease, stage III/IV, blood or bone marrow involvement, International Prognostic Index score, Ki67, cell of origin, expression of MYC or BCL2 protein or the combination, time from diagnosis to treatment >14 days, disease bulk > 7.5 cm, transformation from an indolent lymphoma, or front-line treatment with R-CHOP vs intensive immunochemotherapy. Eighty percent (n=52) of pts received intensive front-line immunochemotherapy, most with R-EPOCH (n=42). Median length of follow-up was 32 months (61 months for ST and 24 months for RT). The RT group had a longer 2-year PFS 70% vs 43%, p=0.02; univariate hazard ratio (HR) for progression 2.4, 95% confidence interval (CI) 1.1-5.4, p=0.03, (Figure 1A). The only other variable associated with progression was presence of extranodal disease (HR 2.35, 95% CI 1.0-5.4, p=0.047). In a multivariate model, both ST and the presence of extra-nodal disease were independently associated with progression at 2 years (HR 2.84, 95% CI 1.3-6.4, p=0.012 and HR 2.79, 95% CI 1.2-6.5, p=0.018, respectively). Longer OS was observed with RT (median OS NR vs 16 months, 2-year OS 72% vs 41%, p=0.008; HR 2.97 95% CI 1.3-6.9, p=0.012, Figure 1B). No other factors were associated with longer OS. For pts who relapsed after first-line therapy, survival was poor with a median OS after relapse of 6 and 5 months in the RT and ST groups (p=0.11). When limiting the analysis to only those pts treated with intensive immunochemotherapy, median PFS and OS remained significantly longer for the RT group (2-year PFS 70% vs 38%, p=0.01; median OS NR vs 16 months and 2-year OS 74% vs 38%, p=0.007). Post-relapse survival was similarly poor for those treated with intensive induction regardless of RT vs ST (median post-relapse OS 6 vs 5 months, p=0.1). Conclusions Long-term survival may be improved for DHL pts identified through routine as opposed to selective FISH testing. These data could serve as a new baseline for outcomes of DHL pts identified in this manner. Survival outcomes for our cohort of pts treated with intensive immunochemotherapy are similar to those for DHL pts reported in a recent prospective multicenter study of front-line R-EPOCH (Lancet Haematol. 2018 Dec;5(12):e609-e617). While we suspected that the poorer outcomes experienced by ST pts may have been due to high-risk clinicopathologic factors that contributed to selection bias in testing, this does not seem to be the case for any measured factors. It may be that variation in additional molecular features within this high-risk cytogenetic population could explain differences in survival, and next generation sequencing analysis of DHL patient tissue specimens is planned. Disclosures Dwivedy Nasta: Celgene: Honoraria; ATARA: Research Funding; Pharmacyclics: Research Funding; Rafael: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; 47 (Forty Seven): Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding. Schuster:Merck: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Loxo Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Nordic Nanovector: Honoraria; AstraZeneca: Honoraria; Pfizer: Honoraria; Acerta: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Chong:Merck: Research Funding; Tessa: Consultancy; Novartis: Consultancy. Rhodes:DAVA Oncology: Honoraria. Landsburg:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Triphase: Research Funding.

Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p Conclusions: In the largest experience of therapies following VEN dc in CLL, we demonstrated that therapy selection following VEN requires consideration of prior novel agent exposure and reasons for discontinuation. For BTKi naïve pts, selection of a covalently binding BTKi results in high ORR and durable remissions. PFS-2 data provide reassurance for using VEN prior to IBR. For BTKi exposed pts, BTK inhibition is not effective in the setting of BTKi resistance but should be considered if prior BTKi intolerance. PI3K inhibition following VEN does not appear to result in durable remissions even in PI3Ki naïve pts, suggesting possible overlap in resistance mechanisms (BTK or VEN with PI3K). We conclude that BTKi in naïve or previously responsive pts and alloHSCT following VEN appear to be the most effective strategies with durable responses. These data suggest that a number of effective regimens exist for post VEN pts, providing support for VEN use earlier in the course of CLL. Disclosures Mato: Acerta: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Janssen: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Eyre:Gilead: Consultancy, Other: Research support, Speakers Bureau; Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Janssen: Honoraria, Other: Travel to Conferences ; Takeda: Other: Travel to Conferences . Jacobs:Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; TG Therapeutics: Honoraria, Research Funding. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Brander:Tolero: Research Funding; MEI: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding. Shadman:AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; BeiGene: Research Funding; TG Therapeutic: Research Funding; ADC Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Verastem: Consultancy; Acerta Pharma: Research Funding; Sunesis: Research Funding; Mustang Bio: Research Funding; Celgene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Sound Biologics: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Ujjani:AstraZeneca: Consultancy; Genentech: Consultancy; Rigel: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Research Funding. Perini:Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board; AstraZeneca: Other: Advisory Board. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; 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. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. Coombs:H3 Biomedicine: Research Funding. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Merck: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Schuster:AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Pfizer: Honoraria; Nordic Nanovector: Honoraria; Pharmacyclics: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Merck: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Martinez-Calle:ABBVIE: Other: Travel support. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Nabhan:Aptitude Health: Employment. King:Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; DAVA Oncology: 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; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:Genentech: 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, Research Funding; 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; 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. Fox:Gilead: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy.

Introduction: The type II anti-CD20 monoclonal antibody, obinutuzumab (OBI) is an effective therapy approved for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL). Data are limited for use of OBI as monotherapy in CLL/SLL as well as across other lymphoma subtypes, other than the GAUSS, GADOLIN, and GAUGUIN trials. We describe our experience of OBI as monotherapy without chlorambucil in the CLL/SLL population and OBI as monotherapy or in combination regimens across non-Hodgkin lymphomas (NHLs). Patients and Methods: We conducted a retrospective cohort study of all adult pts who received OBI for CLL/SLL and NHL at the University of Pennsylvania between 2/2013 and 6/2019. Demographics, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from OBI start to disease progression or regimen change, death due to CLL/SLL or NHL or last-follow-up in remission), and overall survival (OS) using the Kaplan-Meier method. All other analyses were descriptive. Indolent lymphomas included follicular, marginal zone, and mantle cell lymphomas. Aggressive lymphomas included diffuse large B-cell lymphoma, Richter transformation, transformed follicular lymphoma, and transformed marginal-zone lymphoma. Results: We identified 78 pts for this analysis. Disease subtypes included CLL/SLL (58%; n=45), follicular lymphoma (13%; n=10), MZL (8%; n=6), MCL (5%; n=5), DLBCL/transformed disease (15%; n=12). Median age of OBI start was 67 years (27-89); CLL/SLL patients (pts) were median Rai Stage 2 and ECOG performance 0. NHL pts were median Ann Arbor Stage IV and ECOG performance 1. Median number of prior therapies was 1 (Range 1-7) in CLL/SLL and 3 in NHL (Range 0-9) with a median time to OBI initiation from last therapy of 12 months (mos) and 1 mos respectively. Of the CLL/SLL population 60% were rituximab naïve and 18% were rituximab refractory; 9% of NHL pts were rituximab naïve and 52% were rituximab refractory. Overall response rate (ORR) for the CLL/SLL cohort was 91%, 80% for FL, 83% for marginal zone lymphoma (n=6), 80% for mantle cell lymphoma (n=5), and 25% for aggressive lymphomas (n=12). For NHL, 50% received OBI as monotherapy, with 33% ORR. Median PFS subdivided by histologic cohorts were: 35 mos for CLL/SLL, not reached in indolent lymphomas, and 4 mos for aggressive lymphomas. Median overall survival divided by histologic subtype were 17 mos for CLL/SLL, 14 mos in indolent lymphoma and 45 mos in aggressive lymphomas. (Figure 1). OBI monotherapy in the indolent lymphoma group (n=8) had a 75% ORR and aggressive lymphoma group (n=6) had a 33% ORR. Of note, 2 aggressive lymphoma pts were successfully bridged to CAR T-cell therapy. Adverse events (AEs) occurred in approximately 91% of CLL/SLL pts and 61% of NHL pts. AEs for the CLL/SLL group included: infusion related reactions (IRRs) (62%), neutropenia (16%), thrombocytopenia (40%), infection (22%), neutropenic fever (7%), and diarrhea (9%). AEs for the NHL group included: IRRs (24%), neutropenia (18%), thrombocytopenia (27%), infection (9%), and diarrhea (24%). In the CLL/SLL population 62% experienced an IRR on the first dose and 6 of those pts experienced a second infusion reaction in the first cycle of OBI. Despite a high rate of reactions in this population, most were confined to grade 2 reactions (93% grade 2; 7% grade 3). In the NHL population, all 8 pts (24%) experienced an infusion reaction on the first dose of OBI and one patient experienced a subsequent infusion reaction on the second dose. Conclusion: We describe our experience of OBI therapy across histological subtypes of NHL outside the setting of a clinical trial, including OBI used as part of multi-agent salvage therapy in indolent and aggressive NHL. We observed high ORRs and durable PFS and OS in both CLL/SLL and indolent lymphoma cohorts. As expected, the aggressive lymphoma cohort had an ORR of 25% with a median PFS of 4 mos. Neutropenia and thrombocytopenia were manageable with close supportive care, yet are critical parameters to monitor while on OBI regimens. IRRs were high in the CLL/SLL cohort and mainly confined to grade 2 reactions. OBI remains an effective and well tolerated agent in NHL and should continue to be considered for utilization in clinical trials to develop novel combination regimens for aggressive NHL as well as a partner to cellular therapy. Figure 1 Disclosures Hughes: Acerta Pharna/HOPA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees. Schuster:Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Celgene: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Rhodes:DAVA Oncology: Honoraria. Stadtmauer:Celgene: Consultancy; Abbvie: Research Funding; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Amgen: Consultancy. Dwivedy Nasta:Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding. OffLabel Disclosure: Obinutuzumab was investigated as a monotherapy agent as opposed to in combination for CLL. Additionally, obinutuzumab was only studied in follicular lymphoma and chronic lymphocytic leukemia. This retrospective analysis includes lymphomas outside of specified indications.

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2–37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

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 Transformation of chronic lymphocytic leukemia (CLL) into Hodgkin lymphoma (HL) is a rare, but recognized complication of CLL. The prognosis of CLL with HL Transformation (HT) appears significantly worse than de novo HL, but most series are small and there are limited published data. These reports have prompted several groups to recommend aggressive therapy with stem cell transplantation (SCT) in first complete remission (CR1). We describe the largest reported series of HT patients (pts) with analyses of the clinicobiologic characteristics, treatment patterns, and clinical outcomes based upon our multi-institutional clinical experience. Methods Pts diagnosed with HT from 01/2000 - 01/2018 were retrospectively identified in 13 tertiary cancer centers. Clinicobiologic characteristics, treatment type, and survival outcomes for each pt were analyzed. Overall survival (OS) was measured from the time of HT diagnosis until time of death. OS estimates were calculated using the Kaplan-Meier method. The log-rank test was used to calculate differences in survival. Results Ninety-four pts with HT were identified. Median age at HT was 67 years (yrs; range, 38-85) and 81% of the pts were male. Median time from CLL diagnosis to HT was 5.5 yrs (range, 0-20.2; 7 pts with simultaneous diagnosis of CLL and HL). At initial CLL diagnosis, 31%, 34%, 21%, 10%, and 4% were Rai Stage 0, 1, 2, 3, and 4, respectively. At CLL diagnosis, 67% (25/37) had an un-mutated IgVH gene, 36% (21/59) had del(13q), 32% (14/44) had trisomy 12, 24% (14/59) had del(11q), and 15% (9/61) had del(17p). Prior to HT diagnosis, pts had a median of 2 (range, 0-12) therapies for CLL. Seventeen (18%) had no prior CLL treatments. Forty-three (46%) and 25 (27%) patients had received purine analogue- and ibrutinib-based therapy prior to HT, respectively. Baseline characteristics at HT are described in Table 1. As initial therapy for HL, the majority of pts (61%, n = 62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine) at full (n = 48) or reduced (n = 14) doses. Of these, CD20 monoclonal antibody was added in 6 and Bruton-tyrosine kinase inhibitor was added in 2. Ten (11%) received a brentuximab-based regimen. Seven (7%) received an RCHOP-based regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Six patients (6%) received no therapy for HT due to frailty. Subsequent therapy included autologous SCT and allogeneic SCT in 7 (7%) and 11 (12%) of patients, respectively. Two (2%) and 5 (5%) pts received their autologous and allogeneic SCT while in CR1, respectively. The median number of treatments for HT per pt was 1 (range, 0-5) with 59 (61%) pts only receiving one line of therapy. After HT diagnosis, pts had a median follow-up of 1.6 yrs (range, 0.0 - 15.1). Two-yr OS after HT diagnosis was 72% (95%CI 62 - 83%). The pts who received any CLL directed therapy (n = 80) prior to HT had a significantly lower estimated 2-yr OS of 69% (95%CI 58 - 82%) compared with pts who did not receive any prior CLL-directed therapy (n = 17; 93%; 95%CI 82-100%; p 0.02; Figure 1). Pts who received purine-analogue-based therapy for their CLL prior to HT had a significantly lower estimated 2-yr OS of 60% (95%CI 46 - 79%) compared with pts who did not receive purine-analogue-based CLL-directed therapy prior to HT (n = 51; 83%; 95%CI 73 - 96%; p 0.009; Figure 2). Although limited by small sample size, the pts who underwent SCT for HT in CR1 had a similar 2-yr OS (n = 7; 67%; 95%CI 38-100%) to pts who did not undergo SCT for HT in CR1 (n = 87; 72%; 95%CI 63 - 84%; p 0.46; Figure 3). Conclusions In this retrospective analysis, we describe the largest reported series of pts with HT from CLL. Two-yr survival in pts with HT was shorter than what is historically expected in patients with de novo HL, but longer than what is expected in CLL pts who transform to diffuse large B-cell lymphoma. Pts with HT who have received prior CLL-directed therapies (specifically purine-analogue-based treatments) are estimated to have a shorter 2-yr OS, likely due to underlying immunosuppression. The majority of pts (61%) only received 1 line of HL therapy and only 20% went on to receive SCT (7% while in CR1), indicating that these patients can have prolonged OS after achieving response to first-line therapy for HT and may not require SCT in CR1. Further study of this rare population is required to determine optimum management. Disclosures Kander: AstraZeneca: Consultancy. Parikh:Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Shadman:Acerta Pharma: Research Funding; Verastem: Consultancy; Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mato:Portola: Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Celgene: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Johnson & Johnson: Consultancy; AbbVie: Consultancy, Research Funding. Hill:Amgen: Research Funding; Abbvie: 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; 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Abbvie: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov:Verastem: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding. Phillips:Abbvie: Research Funding; Bayer: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: 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; Novartis: Consultancy, Other: DSMB; Teva: Consultancy, Honoraria; TG Therapeutics: 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; Genentech: Consultancy, Honoraria, 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. Smith:BMS: Consultancy; Portola: Honoraria. Davids:Surface Oncology: Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MEI Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: 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; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: 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, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, 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; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Celgene: Consultancy; BMS: Research Funding; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding.

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.

Introduction: Musculoskeletal toxicities are common in CLL patients (pts) treated with ibrutinib (Ibr) in both upfront and relapsed/refractory (R/R) settings. Importantly, arthralgias/myalgias (A/M) are among the most common reasons for discontinuation of Ibr due to toxicity in reported series (Mato, Ann Oncol, 2017; Mato, Haematol, 2018). Despite this, there are no detailed descriptions and limited guidance for management of A/M. Methods: To characterize this syndrome and its management, we retrospectively analyzed a cohort of 128 pts treated with Ibr at a single academic center from 2011-2017. Demographics, prognostic factors, concomitant statin use, as well as Ibr dose reductions/dose holds, use of NSAIDs/corticosteroids, and the supplement CoQ10 were collected. A/M were graded using CTCAE v4.0 when available, or per physician description as mild, moderate, or severe. Due to clinical difficulty in separating joint and periarticular soft tissue and/or muscle symptoms, we combined arthralgias and myalgias into a single toxicity defined by the most severe grade. Log rank (LR) test was used for comparison of covariates with outcomes. All other statistics were descriptive. Results: Demographics are summarized in Table 1. The cohort was predominantly male (75%) and Caucasian (95%); 50% received Ibr as front-line therapy and starting dose was 420 mg in 92% pts. 29 pts (24%) had 17p deletions and 26 (20%) had 11q deletions. 48 pts (38%) were on a concurrent statin. 48 (35%) pts developed A/M (20 frontline treatment, 28 R/R). Mean time to development was 349 days (range 7 -1162). 27/48 (56%) developed A/M >6 months from start of Ibr. 39/48 (82%) A/M events were described as mild or moderate (71% Grade 1/2; 19% Grade 3 per CTCAE). 37/48 (77%) of pts had a partial response or partial response with lymphocytosis at the onset of symptoms. 19/48 (39%) pts developed A/M while on a statin. Management and outcomes are described in Table 2. 15/48 (31%) were managed by Ibr hold and 20/48 (42%) by dose reduction; 9/48 (19%) had both. Mean hold duration was 17.5 days (range 2-67). Dose hold was successful in 6/15 (40%) pts, while dose reduction alleviated symptoms in 6/20 (30%); statins were discontinued in 5/17 (29%) pts. Corticosteroids (4 pts) and CoQ10 (4 pts) were used in conjunction with dose holds and dose reductions with symptomatic improvement in 2 and 4 pts, respectively. 4 pts used NSAID or acetaminophen without improvement in symptoms. 2 pts required opiate analgesics for pain management. 29/48(60%) had resolution of A/M during follow up. Overall, no changes in therapy were made in 19 (48%) pts and 13 (68%) had spontaneous resolution of symptoms. Of these patients, 12 had Grade 1 A/M. 40% of pts' A/M persisted, 13/19 (68%) had dose reduction, 8/14 (57%) had a dose hold, 7/16 had both, and 5/19 (26%) had no intervention. Management and outcomes did not differ if A/M occurred before or after 6 months. In this cohort, 46/128 (36%) of pts discontinued Ibr: 11/128 (9%) for toxicity related to A/M; 19/128 (15%) for other toxicity; 10/128 (8%) for disease progression; 5/128 (4%) for transformation; 2/128 (2%) other reasons. Median time to discontinuation of Ibr for A/M was 23.3 mo (1-56.8 mo). Concurrent statin use and statin dose intensity were not associated with increased risk of developing A/M by LR test. Based on our observations, we suggest the following algorithm for the management of Ibr-associated A/M (Figure 1): if A/M do not interfere with ADLs, continue Ibr at current dose and monitor closely for symptom progression, as cases can resolve without intervention. If symptoms affect ADLs, hold or dose reduce until improvement/resolution of symptoms. If managed using Ibr hold, pts can be re-challenged at a lower dose once symptoms improve. If there is recurrence on a lower dose, we recommend observation or consideration or an alternative agent if CLL-directed therapy is still required. Conclusions: In this cohort, A/M was a frequent event and occurred both as an early or late toxicity, though generally developing after 6 months of Ibr therapy. Dose holds and dose adjustments are the most frequent approach to management, and are the most successful. The role of supportive care agents including corticosteroids and CoQ10 is less clear; however not enough data are currently available to suggest efficacy for any single supportive care agent. Further studies are needed to better understand this toxicity and develop best practice management. Disclosures Mato: Celgene: Consultancy; Regeneron: Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Johnson & Johnson: Consultancy; TG Therapeutics: Consultancy, Research Funding; Prime Oncology: Honoraria; Medscape: Honoraria; Portola: Research Funding. Kennard:AbbVie, Gilead, Verastem: Consultancy. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Dwivedy Nasta:Roche: Research Funding; Incyte: Research Funding; Debiopharm: Research Funding; Merck: Other: DSMC; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Takeda/Millenium: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding. Svoboda:Kyowa: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG Therapeutics: Research Funding; KITE: Consultancy. Schuster:Dava Oncology: Consultancy, Honoraria; 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; Genentech: Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding.

Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P