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Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

PURPOSE The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

7511 Background: Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment (tx) of CLL and are associated with partial restoration of immune function with ongoing tx. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized. Methods: CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline (bl) and outcome data were collected including incidence (inc) of Richter’s transformation (RT), non-melanoma skin cancer (NMSC), and SPN. Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model. Results: 691 pts were included; median age was 64 years (y), median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At median f/u of 44 months, 68 pts (10%) were diagnosed (dx) with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6) cancers. CIR of SPN at 3 y was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p < .01) and low bl CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p < .01) were associated with higher inc of SPN. RT was dx in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 y overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%). Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi. [Table: see text]

In chronic lymphocytic leukemia (CLL) and very likely all cancer types, extracellular vesicles (EVs) are a common mechanism by which intercellular messages are communicated between normal, diseased, and transformed cells. Studies of EVs in CLL and other cancers have great variability and often lack reproducibility. For CLL patient plasma and cell lines, we sought to characterize current approaches used in isolating EV products and understand whether cell culture–conditioned media or complex biological fluids confound results. Utilizing nanoparticle tracking analysis, protein quantification, and electron microscopy, we show that ultracentrifugation with an OptiPrep cushion can effectively minimize contaminants from starting materials including plasma and conditioned media of CLL cell lines grown in EV-depleted complete RPMI media but not grown in the serum-free media AIM V commonly used in CLL experimental work. Moreover, we confirm the benefit of including 25 mM trehalose in PBS during EV isolation steps to reduce EV aggregation, to preserve function for downstream applications and characterization. Furthermore, we report the highest particles/μg EVs were obtained from our CLL cell lines utilizing the CELLine bioreactor flask. Finally, we optimized a proliferation assay that offers a functional evaluation of our EVs with minimal sample requirements.

Background: Acalabrutinib (A) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for marketing by the US FDA in patients (pts) with chronic lymphocytic leukemia (CLL). While responses to A monotherapy are durable in CLL, response depth may be enhanced with combination therapy and potentially allow treatment discontinuation. The safety and efficacy of A plus a CD20 antibody (obinutuzumab [O] or rituximab [R]) and the BCL-2 inhibitor venetoclax (V) were examined in a phase 1b study (CL-003; NCT02296918) in relapsed/refractory (R/R) or treatment-naïve (TN) CLL pts. Methods: Pts were aged ≥18 years with intermediate or high-risk CLL (R/R or TN) and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Prior BTK inhibitor treatment was allowed for R/R pts if discontinuation was not due to CLL progression. R/R CLL pts received oral (PO) A 100 mg twice daily (BID) until progression, plus intravenous (IV) R 375 mg/m2 for 9 infusions (cycles 2-7), plus V PO daily per standard dosing (cycles 3-15). TN CLL pts received PO A and V (as above) plus IV O per standard dosing (cycles 2-7). The primary endpoint was safety. Secondary endpoints included investigator-assessed overall response rate (ORR, partial response [PR] or better) at cycle 16, complete response (CR) rate, undetectable minimal residual disease (uMRD) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics (PK). Results: Twelve pts were included in each cohort (R/R: male, n=9 [75%], median [range] age: 66 [55-72] y; TN: male, n=9 [75%], median [range] age: 61 [42-73] y). All pts had ECOG PS ≤1; 6/8 (75%) R/R and 8/10 (80%) TN pts had unmutated IGHV ( At a median follow-up of 23.2 mo (range: 19.8-25.3) in R/R pts and 22.0 mo (range: 19.5-24.4) in TN pts, 11 (92%) and 10 (83%) pts remained on treatment, respectively. Reasons for treatment discontinuation were adverse events (AEs) in 1 pt (8%) in each cohort (R/R: grade 1 purpura; TN: grade 2 head discomfort), and withdrawal by 1 pt (8%) in the TN cohort. The median number of treatment cycles in R/R pts was 23 (range: 14.9-27.5) for A, 6 (6-6) for R, and 13 (10.0-13.7) for V, and in TN pts was 23 (18.0-24.8) for A, 6 (6-6) for O, and 13 (13.0-13.5) for V. Reported AEs were similar to the individual agents' toxicity profiles (Table 1). Among AEs of interest, 7 R/R pts (58%) and 4 TN pts (33%) had cardiac AEs; grade ≥3 cardiac AEs were reported in 1 pt (8%). Atrial fibrillation was reported in 1 pt (grade 3; R/R pt with prior atrial fibrillation history). No ventricular arrhythmias were reported. Three R/R pts (25%) and 7 TN pts (58%) had hypertension AEs; none were grade ≥3. The most frequent infections (≥40%) were upper respiratory tract infection (URTI; 50%) in R/R pts and URTI (67%), sinusitis (42%), and nasopharyngitis (42%) in TN pts. Grade ≥3 infections occurred in 3 TN pts (lung infection, n=2 [17%]; prostate infection, staphylococcal bacteremia, staphylococcal sepsis, n=1 [8%] each) and no R/R pts. Six R/R pts (50%) and 3 TN pts (25%) had infusion-related reactions; none were grade ≥3. One R/R pt (8%) and 6 TN pts (50%) had decreased neutrophil counts; all were grade ≥3. No tumor lysis syndrome AEs, Richter transformations, or deaths were reported. After 16 cycles, ORR was 92% (95% CI: 62-100) in R/R pts and 100% (95% CI: 74-100) in TN pts. At the time of data cutoff, 50% of pts in each cohort had achieved CR or CR with incomplete marrow recovery (CRi). All pts with CR or CRi achieved uMRD (10-4) in peripheral blood (PB) at the time of CR/CRi or earlier. Overall, 8 (67%) R/R and 9 (75%) TN pts achieved uMRD (10-4) in PB at cycle 10 (Table 2). Median DOR, PFS, and OS were not reached in either group. Estimated 18-mo PFS and OS rates were 100% (95% CI: not estimable) in both cohorts. The PK of A and its active metabolite, ACP-5862, were consistent when given as monotherapy or with V, R, or O. The PK of V remained within the range observed with monotherapy (Salem et al. J Clin Pharmacol. 2017;57:484-492) when given with A. Conclusions: Combination therapy with A plus an anti-CD20 antibody and BCL-2 inhibitor leads to a tolerable safety profile with high CR and uMRD rates in both R/R and TN CLL pts, with minimal to no drug-drug interactions. Disclosures Woyach: Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria; Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:Janssen: Research Funding; AstraZeneca: Consultancy, Other: Travel Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Lozanski:Genentech, Novartis, Beckman Coulter: Research Funding. Andersen:Ohio State University: Current Employment, Research Funding. Patel:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Munugalavadla:Acerta Pharma/AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company, Other: Family Association. Butturini:Puma Biotechnology: Divested equity in a private or publicly-traded company in the past 24 months; Dynavax, Puma Biotechnology: Ended employment in the past 24 months; Roche/Genentech, Pfeizer, AstraZeneca, Amgen: Current equity holder in publicly-traded company; Acerta Pharma: Current Employment. Xu:Acerta Pharma: Current Employment, Research Funding; AstraZeneca: Research Funding. Wang:Acerta Pharma: Current Employment. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Vincera: Research Funding.

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, ibrutinib is linked with potentially-limiting cardiotoxicity, including emerging reports of profound hypertension. However, the long-term incidence, severity, and impacts of hypertension development during ibrutinib-use are unknown. Therefore, from 562 consecutive patients treated with ibrutinib for B-cell malignancies between 2009-2016 we assessed the incidence of new/incident or worsened hypertension [systolic blood pressure (BP) cutoff of 130mmHg]. Observed incident-hypertension rates were compared to Framingham-heart predicted incident-hypertension rates. We also evaluated the relationship of hypertension on ibrutinib to the development of other major-adverse-cardiovascular-events (MACE), including arrhythmias, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the preventative and modulatory effects of antihypertensives, by medication-class, on ibrutinib-related hypertension. Overall, 78.3% of ibrutinib-users developed new or worsened hypertension [mean systolic BP increase 5.2mmHg ({plus minus}20.7)] over a median of 30months. New hypertension developed in 71.6% of ibrutinib-users (467 observed vs. 39 Framingham-predicted cases per 1,000 person-years), with a time-to-50% cumulative incidence of 4.2months. Among those without preceding hypertension, 17.7% developed high-grade (BP g160/100mmHg) hypertension. In multivariable regression containing known predictors of MACE, new or worsened hypertension was associated with increased MACE [hazard ratio (HR) 2.17, 95%CI 1.08-4.38]. No single-antihypertensive class was associated with prevention or control of ibrutinib-related hypertension. However, antihypertensive initiation was associated with a lower risk of MACE (HR 0.40, CI 0.24-0.66). Collectively, these data suggest ibrutinib is associated with substantial increase in the incidence and severity of hypertension, and that hypertension development may suggest a higher risk of subsequent cardiotoxic events.

COVID-19 is a respiratory infectious disease caused by a novel coronavirus-II. COVID-19 has affected a few millions of people across the globe with alarming death toll rate. Chest X-rays are widely available modality for immediate care in diagnosing COVID-19. X-ray images inherently possess significant amount of noise, and image resolution depends on radiation dosage. Diagnosis of COVID-19 chest X-rays would be more precise with high-resolution images. The aim of the current work is to explore selected super-resolution techniques for COVID-19 chest X-ray images. The samples are taken from COVID-19 chest X-ray public dataset. We conducted the experiments on COVID-19 chest X-ray public dataset. The super-resolution methods produced high resolution chest X-ray images the clear view of the pulmonary opacities in chest x-ray images. Evaluation metrics used in the experiments demonstrated improvement in overall quality enhancement of the chest X-ray images.

Stroke is a leading cause of death and disability worldwide. The reasons for increased stroke burden in developing countries are inadequately controlled risk factors resulting from poor public awareness and inadequate infrastructure. Computed tomography and MRI are common neuroimaging modalities used to assess stroke with diffusion-weighted MRI, in particular, being the recommended choice for acute stroke imaging. However, access to these imaging modalities is primarily restricted to major cities and high-income groups. In the case of stroke, the time-window of treatment to limit the damage is of a few hours and needs a point-of-care diagnosis. A low-cost MR system typically achieved at the ultra-low- and very-low-field would meet the need for a geographically accessible and portable solution. We review studies focused on accessible stroke imaging and recent developments in MR methodologies, including hardware, to image at low fields. We hypothesize that in the absence of a formal, rapid stroke triaging system, the value of timely on-site delivery of the scanner to the stroke patient can be significant. To this end, we discuss multiple recent hardware and methods developments in the low-field regime. Our review suggests a compelling need to explore further the trade-offs between high signal, contrast, and accessibility at low fields in low-income communities. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 6.

Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis); however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose. Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. This limitation can potentially be overcome with rapid dose escalation (RDE). We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. Median time to target dose was 9 days. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. TLS was seen in more patients with a higher initial tumor burden. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre–venetoclax dose to 24 hours post–venetoclax dose of 10 × 103/μL was associated with an increased risk of TLS (hazard ratio, 1.32; P = .02), after controlling for venetoclax dose level. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.

Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2–6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. Significance: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity–enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL. This article is highlighted in the In This Issue feature, p. 327

Background To explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20+ B-cell non-Hodgkin lymphoma (B-NHL). Patients and Methods Twenty patients with indolent B-NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL.

Background: Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib. Methods: We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model. Results: We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9). Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither. Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A). To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither. Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01). Conclusions: Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. Figure 1 Figure 1. Disclosures Kittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Background: Acalabrutinib is a more selective, second generation covalent binding Bruton tyrosine kinase (BTK) inhibitor. It was designed with the intent to mitigate adverse events (AEs) associated with ibrutinib, such as bleeding and cardiovascular events. In the phase 3 trial that that led to acalabrutinib approval in the front line setting for chronic lymphocytic leukemia (CLL), 37% and 2% of patients who received acalabrutinib monotherapy experienced grade 1-2 or ≥3 bleeding events, respectively. Currently, there are no long term studies evaluating the incidence of bleeding events associated with acalabrutinib. Therefore, the purpose of this study was to assess the incidence of bleeding events, and risk factors associated with bleeding events for patients treated with acalabrutinib for hematologic malignancies. Methods: This was a single center retrospective study conducted at The Ohio State University. Patients were included if they were ≥18 years old, diagnosed with a hematologic malignancy, and initiated on acalabrutinib (monotherapy or combination therapy) between January 1, 2010 and August 31, 2019. The International Society on Thrombosis and Haemostasis (ISTH) bleeding scale (no bleed, clinically non-relevant bleed, and clinically relevant/major bleed) and Common Terminology Criteria for Adverse Events V5.0 (CTCAE) were used to evaluate the grade and class of bleed events. Descriptive statistics were used to summarize demographic information and bleed events; univariable analysis was used to assess risk factors. Results: We analyzed 289 patients who received acalabrutinib for a hematologic malignancy. The main source of acalabrutinib was from clinical trials (85%) and the median acalabrutinib exposure time for all patients was 40.8 months (range: 0-81.6 months). 89% of patients had CLL, 2% had mantle cell lymphoma, and 9% had other non-Hodgkin's lymphoma. Additionally, 18% of patients had a prior bleed history and 51% were continued on concomitant medications that increase bleeding (Table 1). There were a total of 241 (83%) patients who experienced at least one bleed event. Per ISTH categorization, 143 (59%) patients' most severe bleed event was clinically non-relevant and 98 (41%) patients' was clinically relevant/major; cutaneous bleeds were most common in both groups, 71% and 31%, respectively. Only 6% of patients had a major bleed, hence, clinically relevant and major bleeds were analyzed together for the purpose of this study. There were a total of 633 bleed events that occurred in this study population; 76% were clinically-non relevant and only 3% (n=17) were CTCAE grade ≥3. Acalabrutinib was not discontinued or held for any clinically non-relevant bleeds, was discontinued for six (1%) clinically relevant/major bleeds, and held for 44 (7%) clinically relevant/major bleeds. Clinically relevant /major bleeds also resulted in discontinuations of concomitant anticoagulation and antiplatelet therapy in only 4% (n=24) of cases. 1263 procedures were identified and the incidence of clinically non-relevant and clinically relevant/major bleeds related to surgeries/procedures was 1% (n=12) and 1.3% (n=16), respectively. 10% of clinically non-relevant and 57% of clinically relevant/major bleeds led to hospitalizations, emergency room visits, or physician office visits; including two major CNS bleed events which resulted in death. The overall survival (OS) was not reached in the clinically non-relevant and clinically relevant/major bleed groups and was 14 months (95% CI 6-40) in the no bleed group (p=0.021). Univariate analysis showed that risk factors associated with a clinically relevant/major bleed included concomitant medications (OR 3.06, 95% CI 1.49-6.26) and prior bleed history (OR 4.40, 95% CI 1.45-13.40) (Table 3). Conclusions: Overall, our study had a long acalabrutinib exposure time and demonstrated a low incidence of grade ≥3 bleeds. There was also a low risk of bleeds related to procedures. The majority of bleeds were clinically non-relevant that did not result in significant treatment adjustments, hospitalizations, or death. This study identified prior bleed history and concomitant medications that increase bleeding as risk factors for bleeds and should be evaluated prior to starting acalabrutinib therapy. Our data supports acalabrutinib as a safe long-term treatment in regards to bleeds for patients with hematologic malignancies. Figure 1 Figure 1. Disclosures Wiczer: BTG Specialty Pharmaceuticals: Consultancy. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; AstraZeneca: Consultancy; Onclive: Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rogers: Janssen Pharmaceuticals, Inc: Research Funding; Pharmacyclics LLC: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Innate Pharma: Consultancy; ovartis Pharmaceuticals Corporation: Research Funding; AbbVie Inc.: Consultancy, Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

Background Acalabrutinib is a highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Ibrutinib, the first-generation nonselective BTK inhibitor, has been associated with cardiovascular (CV) complications including atrial fibrillation and ventricular arrhythmias, potentially related to off-target effects. In prior studies, the incidence of major adverse cardiovascular effects (MACE) with ibrutinib was 16.5-38%. With acalabrutinib being more selective, we postulate that less of these off-target effects would be seen. Although early experience with acalabrutinib suggests improved tolerability compared to ibrutinib, the long-term CV risks are unknown. Therefore, we sought to characterize the incidence, risk factors, and management of CV complications associated with acalabrutinib across long-term follow-up. Methods We performed a retrospective single-center cohort study of adult patients treated with acalabrutinib for a hematologic malignancy from January 2010 to August 2019. Patient demographics, CV and cancer variables, and CV complications were collected throughout the duration of acalabrutinib therapy. MACE was defined as cardiac arrhythmias (including atrial and ventricular arrhythmias), myocardial infarction, stroke, heart failure, and CV death. CV events, including arrhythmias, were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), and adjudicated with an independent cardiologist. Descriptive statistics were used to summarize patient characteristics, using the mean ± standard deviation (SD) or median (interquartile range) for continuous variables and frequency counts with percentages for categorical variables. Time-to-event analysis methods were used to summarize MACE outcomes and evaluate associations with these outcomes. Results Overall, 290 patients treated with acalabrutinib were identified, majority had CLL (89%), and were male (72%) with a median age of 64 years. Seventy-seven (27%) patients were previously treated with ibrutinib. Sixty-seven percent of patients had a prior cardiac history, including 49% with baseline hypertension (HTN). MACE occurred in 18 patients (6%). Atrial fibrillation was the most common event occurring in 12 patients, followed by diastolic heart failure in 3 patients. There was one ventricular arrhythmic event (0.3%). Forty-four percent of patients temporarily held acalabrutinib during the MACE event, while 50% had no change to their acalabrutinib therapy. After the event, 6% of patients discontinued acalabrutinib and 11% of patients had dose reduced to 100mg daily. Age, gender, diabetes, kidney disease, and smoking status were found to be significantly associated with MACE. The odds of MACE were 1.8 times higher for every 7-year increase in age; when looking at just atrial fibrillation, the odds were 1.58 times higher for every 7-year increase in age. The effect of current smokers compared to never smokers was not significantly associated with MACE, however the odds of MACE were 3.4 higher in former smokers compared to never smokers. In comparison to ibrutinib (Dickerson, et al. Blood, 2019), the rate of MACE was lower- 66 vs 21 events per 1,000 person-years (P Conclusion In summary, acalabrutinib was associated with a lower, but significant risk of MACE compared to ibrutinib. The occurrence of these cardiac events appears to associate with worse survival outcomes. Further research into the mechanism(s) of these events, their implications, and the optimal preventative strategies for adverse CV complications after BTK inhibitor initiation is needed. Figure 1 Disclosures Blachly: AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:Genentech: Research Funding; Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy, Other: Travel Funding; Janssen: Research Funding; AbbVie: Consultancy, Research Funding. Byrd:Kartos Therapeutics: Research Funding; Trillium: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Acerta Pharma: Research Funding; Syndax: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. Woyach:AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Research Funding.

CD19 is an attractive therapeutic target as it is highly expressed in CLL. Tafasitamab (Taf) is an Fc-engineered, humanized anti-CD19 monoclonal antibody with efficacy in CLL as a single agent. Compared to non-engineered antibodies, Taf shows significantly increased antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and direct cytotoxic effects (apoptosis) on tumor cells. With the addition of lenalidomide (Len), ADCC can be further augmented in vitro. Given the potential synergy of these agents, acceptable individual safety profiles, and efficacy as single agents, we conducted a study of Taf in combination with Len in patients (pts) with treatment-naïve (TN) and relapsed/refractory (RR) CLL, and included a pilot cohort of ibrutinib (IB)-treated pts with resistance mutations, but no clinical relapse, with Taf added to IB. We present the final results of this single institution phase II trial. In combination with Len, Taf was given at a dose of 1 mg/kg on cycle(C) 1 day(D) 1, 9 mg/kg on C1 D 2, 8, 15, and 22, and D1 of C2-12. Len 2.5 mg began daily on C1D8 and was given continuously. Len was escalated to 10 mg daily in pts without toxicity. After C12, Len could continue indefinitely in responding pts. In combination with IB, Taf was given at 1 mg/kg on C1D1, 12 mg/kg on C1 D2, 8, 15, and 22, weekly during C2-3, and every other week through C12. IB continued at 420 mg daily. The primary endpoint for Phase II was overall response rate (ORR) after C6. Based on previous studies with single agent Len, we tested whether the combination could improve ORR, from 50% to 80% in the TN cohort, and from 30% to 60% in the RR cohort. Using single stage designs, 19 pts per cohort provided at least 90% power to detect an increase in ORR (type I error rate 10%). By design, 13 and 9 responses were needed in the TN and RR cohorts, respectively, to warrant further study. A secondary endpoint was ORR after 12 cycles of therapy. Twelve pts were enrolled in the TN cohort; median age was 62 (range 44-75). Six pts were Rai stage III/IV, and 1 had both del(17p) and del(11q). Nine pts had ZAP 70-methylated disease. After C6, ORR was 67% [1 complete response (CR), 7 partial responses (PR); 90% confidence interval (CI): 39-88]; responses remained the same after C12. Three pts completed treatment per protocol, 3 discontinued treatment for progressive disease (PD) and 6 for AEs. Thirteen pts were enrolled in the RR cohort, median age was 70 (range 62-75). Eight pts were Rai stage III/IV, 4 had del(17p) and 2 had del(11q). Eleven pts had ZAP 70-methylated disease. After C6, ORR was 15% (all PRs - 90% CI: 3-41), and responses improved to 38% after C12 (90% CI: 17-65). Additional 1 pt had stable disease (SD). Five pts completed treatment per protocol, 6 discontinued treatment for PD, 1 for alternative therapy, and 1 continues on treatment. Nine pts with molecular progression on IB were enrolled; median age was 62 (range 45-87). Seven pts had del(17p) and 1 pt had del(11q). Eight pts had ZAP 70-methylated disease. After C6, only 1 pt (11%) responded with a PR; 3 additional pts had SD. Two pts completed treatment per protocol criteria, 3 discontinued treatment for AEs, 2 for alternative therapy and 1 pt each for PD and increased C481S allelic frequency. Figure shows Progression-free Survival (PFS) and Overall Survival (OS) for the 3 cohorts. Taf plus Len was well tolerated. Grade(gr)≥3 AEs included: infections [4: I each of lung infection, sinusitis, upper respiratory tract infection (URTI) and appendicitis], decreased neutrophil count (3) and infusion related reactions (2) in TN pts and decreased neutrophil count (10), infections [7: 2 catheter related urinary tract infections, 1 each with URTI, lung infection and soft tissue infection, 2 unspecified], diarrhea (3), hyponatremia (3) and hypophosphatemia (3) in RR pts. In the Taf plus IB cohort most common gr≥3 AEs included infections (4: 2 lung infections, 1 URTI and I unspecified), hyperglycemia (3) and hyponatremia (3). Gr≥3 atrial fibrillation was seen in 1 pt. In conclusion, although the trial did not fully accrue as planned, Taf in combination with Len appeared safe and demonstrated promising activity in TN CLL, warranting further investigation, and has similar efficacy to rituximab plus Len in RR CLL. Taf plus IB was less effective in pts with resistance to IB. Disclosures Blachly: AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy, Other: Travel Funding. Lozanski:Genentech, Novartis, Beckman Coulter: Research Funding. Byrd:Syndax: Research Funding; Vincera: Research Funding; Acerta Pharma: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. Woyach:Karyopharm: Research Funding; Morphosys: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Loxo: Research Funding. OffLabel Disclosure: Lenalidomide off label use for CLL

The therapeutic landscape for chronic lymphocytic leukemia has significantly evolved in recent years as our understanding of the biology of this disease has advanced. Chemoimmunotherapy has been the standard frontline treatment for patients of all age groups with chronic lymphocytic leukemia over the last decade. B-cell receptor signaling pathway plays a central role in the pathogenesis of chronic lymphocytic leukemia. The advent of novel small-molecule therapy for the treatment of chronic lymphocytic leukemia targeting the B-cell receptor signaling pathway has dramatically changed the therapeutic landscape with recent studies establishing ibrutinib, a Bruton's tyrosine kinase inhibitor, as the frontline treatment of choice regardless of patient's age, performance status or risk-category. Although these current advances along with the approval of other newer agents for the treatment of chronic lymphocytic leukemia is a significant step forward, newer challenges have emerged on how to best utilize these new treatment options.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare dendritic cell tumor with slightly more than 100 cases reported in the English literature. This report discusses a case of localized IDCS involving cervical lymph nodes and provides a literature review of clinicopathologic aspects and treatment outcomes.

RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx)-induced PAH model was used to evaluate twice-daily (b.i.d.) RP5063 at 10mg/kg (RP-10) and 20mg/kg (RP-20), as compared with positive (sildenafil 50mg/kg b.i.d.; Sil-50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar-Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP-10) pressures, and improvement in oxygen saturation (RP-20). It significantly reduced small-vessel wall thickness (RP-20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late-phase PAH.

Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A and 5-HT2B. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60mg/kg dose of MCT, rats were gavaged twice-daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10mg/kg), or sildenafil (50mg/kg) for 28 days. RP5063 at a dose as low as 1mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fulton's index (ratio of right to left ventricular weight). Doses as low as 3mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT-treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fulton's index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose-dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT-induced increases in the plasma cytokines TNFα, IL-1β, and IL-6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT.

Background B-cell receptor signaling inhibition (BCRi) is an effective treatment (trtmt) for patients (pts) with chronic lymphocytic leukemia (CLL), but resistance develops. Venetoclax selectively inhibits anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and has demonstrated efficacy in relapsed/refractory CLL pts, particularly after BCRi. Venetoclax is started at 20 mg daily and escalated weekly over 5 weeks to the goal dose to avoid acute tumor lysis syndrome. However, we observed that many pts with relapsed/refractory CLL relapsing on BCRi progress more quickly than this schedule allows; they may progress while still taking BCRi or vigorously after its discontinuation. Given the need to promptly attain goal venetoclax dose in this population, we developed a rapid dose escalation scheme for venetoclax and reviewed our experience to understand the feasibility, safety, and efficacy of this approach in a properly equipped university setting. Methods We retrospectively evaluated adult pts with relapsed/refractory CLL presenting to The Ohio State University who were treated with a "rapid dose escalation" of venetoclax. Charts were reviewed for previous and concomitant CLL treatments, tumor burden, prognostic factors, performance status, and co-morbidities. Venetoclax dosing was planned for a shorter time period than the 5 weeks described in the label dosing. The dose was increased as quickly as tolerated following the customary doses (20mg, 50mg, 100mg, 200mg, then 400mg). We reviewed the evaluated safety and efficacy outcomes with this approach. Results We treated 34 pts with rapid venetoclax dose escalation. Median age at venetoclax start was 54 years old and were 73.5% men. Pts had a median of 5 previous CLL trtmts (range 2-18). The most recent trtmt was single-agent BCRi in 18 cases, which overlapped with venetoclax in the majority. Only 6 pts had high tumor burden and the majority had low or medium tumor burden. Cytogenetic abnormalities at venetoclax start included: 17 (50.0%) pts with 17p deletion, 5 (14.7%) with 13q deletion, 6 (17.6%) with 11q deletion, and 3 (8.8%) with trisomy 12. Fifty percent of pts had a complex karyotype, and 76.5% had unmutated IGVH status. 24 (80%, n=30 pts that had testing done) pts had confirmed BTK/PLCу2 mutations. The mean time to goal venetoclax dose was 9.6 days (range 4-31); all but 1 pt reached goal dose. Eighteen (52.9%) pts developed tumor lysis syndrome (TLS) by lab criteria at doses from 20-400 mg, 5 pts developed TLS by clinical criteria, and 1 pt experienced grade 3 severity TLS (per Cairo-Bishop definition). Only 4 pts had an elevated uric acid requiring rasburicase. Seventy-three percent of pts achieved at least a partial remission, and 4 pts each had stable or progressive disease. Three pts died within 30 days: 1 from uncontrolled bleeding and neutropenia, 1 due to neutropenic sepsis with invasive fungal infection and gastric perforation, and 1 due to neutropenic septic shock and respiratory failure. Time to best response was mean 50.7 days (range 2-428). Median time to subsequent trtmt was 279.5 days (range 73-430). 23 pts (67.6%) had not progressed at 1 year, and 26 (76.5%) were surviving at 1 year. Conclusion/summary Rapid dose escalation of venetoclax in this pt population is safe and feasible. Despite a high percentage of patients developing TLS (52.9%), all patients recovered without lasting complications and all but one were able to achieve the goal dose of venetoclax. This dosing scheme achieved disease control with 67.6% remaining progression-free at 1 year and the majority of pts surviving. It is reasonable to implement venetoclax rapid dose escalation in the proper hospital setting with ample ancillary support. This approach may be needed for CLL patients with rapidly progressive disease on BCRi. Disclosures Dotson: Abbvie: Consultancy. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Awan:Genentech: Consultancy; Sunesis: Consultancy; Gilead: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau. Rogers:AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Acerta Pharma: Consultancy. OffLabel Disclosure: Venetoclax- we will be suggesting a faster increase from starting to maximum/goal dose than the dosing label recommends. This is in order to achieve faster disease control.

Introduction Blocking Bruton tyrosine kinase (BTK) with ibrutinib has demonstrated efficacy in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) patients (pts). However, resistance to therapy is common. Preclinical data suggest selinexor (oral selective inhibitor of nuclear export) downregulates BTK (Hing 2015). We hypothesized that dual BTK blockade by combining ibrutinib and selinexor would be tolerable and efficacious in CLL/NHL pts. Herein, we report the phase I combination study with expansion cohorts. Methods Pts with histologically confirmed CLL/NHL were enrolled (n=33). Eligible pts were age ≥18 years (yrs), had ≥1 prior therapy and ECOG performance status of 0-1. CLL pts met iwCLL 2008 criteria for therapy. Pts received selinexor orally 1-2 times weekly (3 weeks of 4-week cycle) and daily oral ibrutinib (420mg) starting Cycle 1 Day 8. Treatment cycles were repeated until disease progression, intolerance, death or discontinuation of trial participation. Primary endpoint was determination of maximum tolerated dose (MTD). Dose-finding proceeded using a modified continual reassessment method targeting a probability of dose limiting toxicity (DLT) Results Median age was 66 yrs (50-80). Included pts had CLL (n=16), Richter's transformation (RT=8), diffuse large B-cell lymphoma (DLBCL, n=6), and mantle cell lymphoma (MCL=3). Median number of prior therapies was 4 (1-14) and 58% had received ibrutinib. Baseline characteristics are detailed in Table 1. The combination was tolerated. MTD was 40mg of selinexor (D1, 8, 15) and 420mg daily ibrutinib [dose level 1 (DL1)]. Two pts were treated with selinexor 30mg twice weekly and 420mg of daily ibrutinib (DL2) and both experienced significant fatigue and discontinued therapy. These adverse events (AE) were considered DLTs. The remainder of pts received DL1. Grade ≥3 hematologic AEs were rare with 3 (9%) and 1 (3%) pt experiencing neutropenia and anemia, respectively. Most common non-hematologic AEs of any grade were nausea (39%) diarrhea (33%), fatigue (33%), and anorexia (27%). Grade ≥3 non-hematologic AEs were uncommon with 2 pts (6%) experiencing hypertension and 1 pt each (3%) experiencing diarrhea, nausea, elevated alkaline phosphatase, cataract, weight gain, upper respiratory tract infection, pancreatitis, pneumonitis, and multi-system organ failure. Other AEs of interest were weight loss, bleeding, and tachycardia, experienced by 5 (15%), 4 (12%), and 3 (9%) pts, respectively. There were 5 pt deaths while on study; 3 related to disease progression and 2 related to infection. In total, 81% achieved disease control with 33% achieving CR or PR (partial response) and 48% achieving stable disease (SD; Table 2). All CLL pts who received prior ibrutinib or had complex karyotype achieved at least SD, and all who did not receive prior ibrutinib had CR or PR. Two CLL pts with known BTK mutation had response to therapy and 7 had SD. One CLL pt who received 1 prior therapy achieved CR with no detectable residual disease. One of the 8 RT pts achieved CR and 5 achieved SD. In the 11 pts who achieved at least PR, the median duration of response was not reached (NR). In the 15 pts with SD and >2 mos of follow-up, 20% (3/15) maintained SD for >6 mos. Median PFS for pts with CLL and NHL was 8.9 (95%CI:4.6-NR) and 2.7 (95%CI:0.7-NR) mos, respectively (Figure 1). For CLL pts who received and did not receive prior ibrutinib, 64% (7/11) and 20% (1/5) progressed, respectively. For CLL pts who received 1-2 and ≥3 prior therapies 20% (1/5) and 64% (7/11) progressed, respectively. With median follow-up of 5.3 (range:1.2-22.5) and 5.5 (range:0.7-33.1) mos, median OS for CLL and NHL pts was NR (95%CI:15.4-NR) and 5.4 (95%CI:2.6-NR) mos, respectively (Figure 2). Conclusions Ibrutinib (420mg daily) and selinexor (40mg weekly) was tolerable and demonstrated efficacy in this heavily pretreated, high-risk population of CLL/NHL pts. Efficacy may be greater in earlier lines of therapy. Further investigation is needed to optimize response rates and durability. Disclosures Stephens: Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Rogers:Janssen: Research Funding; Acerta: Consultancy; Abbvie: Research Funding; Genentech: Research Funding. Bhat:Janssen: Consultancy; Pharmacyclics: Consultancy. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Glenn:BMS: Research Funding; Merck: Research Funding; Genentech: Research Funding. Byrd:Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. OffLabel Disclosure: Selinexor is an oral inhibitor of nuclear export. This presentation will describe the combination of ibrutinib and selinexor, which is an off-label use for the drug.

Background: Ibrutinib (ibr) for the treatment of chronic lymphocytic leukemia (CLL) has improved progression-free survival (PFS) compared to other treatments, especially in high-risk patients (pts). However, resistance occurs and is associated with mutations in the drug binding target (BTK) and its immediate downstream target (PLCg2). These ibr resistance mutations (IRmut) are detectable months prior to developing progressive disease (PD) and predict clinical relapse. Prospectively determining the time from starting ibr to development of IRmut and from IRmut detection to PD will improve our understanding of how to manage these patients. Venetoclax (ven) is highly effective after ibr and decreases IRmut. Adding ven to ibr for ibr resistance is a rational choice as this combination is safe and effective in CLL. Adding an agent rather than stopping ibr avoids disease flare associated with ibr discontinuation. This phase 2 study was designed to follow CLL pts taking ibr and at high risk for resistance (observation cohort) and to test ven in combination with ibr for those who develop PD (intervention cohort). This will determine: the incidence of IRmut and PD in this population, the ORR with ibr/ven, and the ability of this combination to eliminate IRmut. Trial Design and Methods: This multisite study will open at 4 centers initially. Eligible pts are adults with CLL taking ibr for ≥12 months and at high risk for ibr resistance defined as having ≥2 prior treatments and del(17p)(p13.1) on FISH panel and/or a complex karyotype. Pts with known IRmut or who cannot continue ibr for any reason are excluded. Enrolled pts enter the observation cohort and are followed every 3 months with a clinic visit, blood counts, and testing for IRmut. Pts who develop IRmut will also have CT scans at their visits to detect PD. Those with IRmut who develop PD by iwCLL 2018 criteria will enter the intervention cohort. Pts in the intervention cohort will start ven in addition to ibr. Ven will be ramped-up over 5 weeks to a target dose of 400mg. Pts will take combination ibr/ven for 12 cycles of 28 days in length. After 12 cycles they will undergo response assessment and those achieving a complete remission (CR) with no detectable leukemia (uMRD) in both the blood and bone marrow will stop ven and continue ibr alone. Those who do not achieve CR with uMRD will continue ibr/ven until cycle 24 and undergo a second response assessment. If in a CR with uMRD after 24 cycles they continue on ibr alone. If a CR with uMRD is not achieved after 24 cycles patients continue ibr/ven until PD, intolerance, death, or end of study which is 30 months after the last patient enters the intervention cohort (Figure). In the intervention cohort all pts will be tested for IRmut in the blood every 3 months with bone marrow testing at response assessments. The study has co-primary endpoints of ORR to combination ibr/ven after 12 cycles and the rate of IRmut negative status at that time in the intervention cohort. ORR will be tested first using a single-stage phase 2 design with a null hypothesis that the rate is ≤50% versus the alternative hypothesis that it is ≥75%. Only if the combination is effective in ORR will the rate of IRmut negative status be formally tested. Constraining overall Type I and II errors to 0.10 using this sequential testing strategy, 26 evaluable pts are required and 28 will be accrued. Secondary endpoints for the intervention cohort are the PFS and overall survival since starting the combination ibr/ven and the incidence and type of adverse events with ibr/ven. Secondary endpoints in the observation cohort are the incidence of IRmut during ibr treatment and the PFS after developing an IRmut. We estimate that 180 pt-years of follow up for the observation cohort will be needed. The yearly rate of mutation development in this population is approximately 20%, therefore this will identify 36 pts with IRmut. Of those with IRmut, approximately 80% will remain eligible to enter the intervention cohort. Accrual to the observation cohort will stop once 28 pts enter the intervention cohort. Conclusion: This multicenter phase 2 trial examines the development of IRmut and clinical resistance to ibr in a cohort of high-risk CLL pts and will determine the efficacy of adding ven to ibr in those who develop PD. We expect to determine the natural course of molecular and clinical ibr resistance in CLL and if adding ven is an effective treatment strategy. Figure Disclosures Rogers: Acerta: Consultancy; Genentech: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Ye:Janssen: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Sanofi: Research Funding. Byrd:Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. OffLabel Disclosure: This abstract discussion the use of combination ibrutinib and venetoclax in CLL.

Introduction Acalabrutinib (A) is a selective, second-generation irreversible Bruton's Tyrosine Kinase inhibitor (BTKi) that has shown outstanding clinical activity in chronic lymphocytic leukemia (CLL) and other hematologic malignancies. Acquired resistance to the first-generation BTKi, ibrutinib (I), is mediated most commonly by C481S mutations in BTK, which decrease binding affinity and change binding from irreversible to reversible. The mechanism of resistance to A has not been investigated. Patients and Methods All patients (pts) treated at The Ohio State University and enrolled on an IRB approved phase 1b/2 study in CLL were included in this analysis. Beginning 12 months (mos) after the initiation of A, pts underwent deep sequencing every 3-6 cycles using a digital droplet PCR assay for BTK C481S or Ion Torrent Sequencing for any BTK or PLCG2 mutations. At relapse, samples from each pt underwent full BTK and PLCG2 sequencing. Correlation between baseline characteristics and relapse was assessed using proportional sub-distribution hazards model, pts who were still on treatment were censored at last follow-up. Results 105 pts were included in this analysis. 38 (36%) were treatment-naïve (TN), 50 (48%) were relapsed/refractory (RR), and 17 (16%) were previously intolerant of I (intol). The median age was 62 (range 33-84) and median number of prior therapies was 1 (range 0-11). The pts were generally high-risk, with 66% having unmutated IGHV, 24% with del(11)(q22.3), 15% with del(17)(p13.1), and 28% with complex karyotype (≥ 3 abnormalities). With a median follow-up of 47.5 mos (range 37.7-58.5) 30% of pts (n=31) have discontinued therapy, 17 for progression of disease (CLL in 16 pts, Richter's transformation in 1), and 14 for other reasons. Cumulative incidence rate (CIR) of progression varied significantly by cohort. At 12 mos, CIR of progression ranged from 0% in both the TN and RR cohorts to 11.8% (95% CI 1.8-32%) in those who were intol. By 36 mos, CIR of progression was 5.3% (95% CI 0.9-15.7%) in TN cohort, 6% (95% CI 1.5-15%) in the RR cohort, and 35.3% (95% CI 13.7-58%) in the intol cohort (Figure 1). In univariable analysis, higher risk of progression was associated with del(17)(p13.1) on baseline FISH (p All 16 pts with CLL relapse had a sample evaluated for BTK C481S at relapse, and 14 had samples evaluated for full BTK and PLCG2 mutations using Ion Torrent deep sequencing. BTK C481 mutations were found in 11/16 (69%; C481S in 10, C481R and C481Y in 1). One pt with a BTK C481S mutation also had a BTK T474I gatekeeper mutation, and one had co-existing C481R mutation. Two pts with BTK C481S mutations had co-existing PLCG2 mutations previously associated with I resistance at 103/105 pts were screened every 3-6 cycles for BTK mutations. 22 pts have had mutations detected at a median of 31.6 mos from A initiation. TN and RR pts had median time to mutation of 38.8 and 32.9 mo, respectively. For intol pts median time to mutation detection was 24.8 mos from start of A, 33.8 mos from start of any BTKi. Median time from BTK mutation detection to clinical relapse is 12 mos (95% CI: 4.8-not reached), with no significant difference among cohorts in time from mutation to disease progression. Conclusions Here we show for the first time that CLL relapse on A is mediated predominantly by mutations in BTK similar to I. While not unexpected, this is significant as resistant patterns could be different given the more selective nature of A as well as potentially higher BTK occupancy over time due to twice daily dosing. Monitoring for BTK resistance offers the opportunity to intervene clinically before symptomatic disease. Disclosures Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Bhat:Janssen: Consultancy; Pharmacyclics: Consultancy. Grever:Acerta Pharma, LLC: Membership on an entity's Board of Directors or advisory committees. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding.

Introduction: The Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib (IB) is a standard therapy for previously untreated CLL patients. While therapy is currently indicated only for patients with progressive, symptomatic disease, the introduction of targeted therapies in CLL has re-opened the question of whether asymptomatic high risk patients would benefit from early intervention. As well, even in early stages CLL is associated with profound cellular, humoral and innate immune suppression and patients with CLL respond poorly to routine vaccinations. IB has been shown to reverse disease mediated immune dysfunction partly through Th1 skewing. We undertook a phase 2 study of IB in asymptomatic high risk CLL patients who did not otherwise require therapy to evaluate: 1) the safety and efficacy of 2 years of IB in this clinical setting and 2) ability of IB to improve the efficacy of routine vaccines. Methods: This is a single-stage phase II study of IB in previously untreated asymptomatic, genetically high-risk patients with CLL, who did not meet IWCLL treatment criteria. High risk genomics were defined as del(11)(q22.3), del(17)(p13.1), unmutated IGHV, and/or complex karyotype (≥3 cytogenetic abnormalities). Patients were randomized to receive IB 420mg PO daily either concurrent with the pneumococcal (PCV13), influenza and TdaP vaccines (Arm A) or following vaccination (Arm B) for a total of 27 cycles (2 years). The primary objective of the study was to determine the safety and 2-year progression-free survival (PFS) of asymptomatic, high-risk CLL patients treated with IB. Secondary objectives include determination of safety and immune responses to vaccines in relation to IB administration, development of resistance, and quality-of-life (QOL). QOL measures assessed general QOL (SF-12, EORTC), anxiety (GAD-7) and depression (PHQ-9). Results: Forty-four patients (pts; 21 in Arm A, 23 in Arm B) were enrolled from 1/2016 to 6/2017, with a median age of 58 (range 35-82). Sixty-six percent of pts were male and all were high-risk: 91% with unmutated IGHV, 14% with del(17)(p13.1), 34% with del(11)(q22.3), and 24% with complex karyotype (≥ 3 abnormalities). Median follow-up is 2.6 years (range: 0.2-3.2). Excluding 2 patients in Arm B who progressed prior to receipt of IB, 2-year PFS was 92%. From a landmark of 2-years and including 33 patients who reached this point and discontinued IB, 6-month PFS was 87% (95% CI: 69-95%; Figure 1). Of 9 pts who progressed after IB discontinuation, 3 have not required further treatment, 5 restarted IB or acalabrutinib, and 1 started venetoclax/rituximab, and all responded. For PCV13, in Arm A, 15/16 patients showed a significant increase in antibody titer 2 cycles following vaccination, but response disappeared by cycle 12. In Arm B, 3/13 patients had an increase in antibody titer, with no increase following second vaccination. For influenza, patients in Arm B showed a significant response to influenza A vaccination, while patients in both arms responded to influenza B vaccination. IB was generally well tolerated, and only one pt discontinued treatment due to toxicity (atrial fibrillation). Grade 3+ toxicities that occurred in >2% of patients included anemia (7%), atrial fibrillation (11%), dental caries (7%), hyperglycemia (7%), hypertension (43%), and neutropenia (7%). At baseline, patients' reports of physical health-related (M=48.52, SD=7.96) and mental health-related quality of life (M=52.20, SD=8.57) similar to U.S population norms, along with moderately high global health (M=78.49 of 100, SD = 20.51). Additionally, patients' anxiety (M=3.56, SD=4.71) and depressive symptom reports (M=3.65, SD=4.46) were in the "none/mild" range. There was no significant change in the latter measure from baseline to 12 months (p>0.25), excepting anxiety which slightly decreased (M=1.31, SD=2.33; F(3,44)=5.94, p Conclusions Early intervention with IB was well tolerated and significantly improved patient disease status. Vaccine response to PCV13 was improved by concurrent ibrutinib, but lost at 12 months, suggesting re-vaccination might be helpful. Quality of life remained good throughout treatment, with improvement in patient anxiety. Extended follow-up will be required to determine how long remissions can be maintained after drug discontinuation in this population. Disclosures Woyach: Verastem: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Grever:Acerta Pharma, LLC: Membership on an entity's Board of Directors or advisory committees. Lozanski:Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentec: Research Funding. Byrd:TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. Awan:Gilead: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Clinical trial of ibrutinib used in an off-label setting

Introduction: Resistance to covalent BTK inhibitors such as ibrutinib and acalabrutinib is a common mechanism of resistance that portends a poor long-term clinical outcome. ARQ 531 is a potent, reversible inhibitor of both wild type and ibrutinib-resistant C481S-mutant BTK. ARQ 531 suppresses oncogenic BCR signaling in CLL cells resistant to ibrutinib and has demonstrated antitumor activity superior to ibrutinib in CLL, Richter's transformation, and DLBCL mouse models. Methods: The primary objectives of the clinical study were to assess the safety and tolerability of ARQ 531, and to determine the recommended Phase 2 dose (RP2D) and schedule. The secondary objectives were to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity. Eligible patients had relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom's macroglobulinemia, had received at least 2 prior lines of systemic therapy and had good organ function including creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL and hemoglobin ≥ 8.0 g/dL. Prior therapy for CLL must have included an irreversible BTK inhibitor. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines. Results: As of July 19, 2019, a total of 40 patients have been treated: CLL/SLL (n=26), Richter's transformation (n=6), DLBCL (n=3), FL (n=4), MCL (n=1). Baseline demographics were: median age 65.5 (range 47-82) years, male/female 36/4 and median number of prior lines of therapy 4 (range 2-12). BTK-C481S mutation was documented in 22/26 (85%) CLL patients. Enrolled patients received ARQ 531 orally once daily, continuously, in 28- day cycles at doses of 5, 10, 15, 20, 30, 45, 65 and 75 mg QD. The most common drug-related TEAEs that occurred in > 2 patients were nausea (n=4), diarrhea (n=4), fatigue (n=3), neutrophil count decreased (n=3), dysgeusia (n=3) and rash (n=3). The majority of the drug-related TEAEs were grade 1 or 2. Drug-related grade 3 or 4 TEAEs included neutrophil count decreased (n=3), as well as febrile neutropenia, cellulitis, platelet count decreased, lipase increased, and rash (one each). One subject treated at 65 mg experienced a DLT of grade 3 rash. The 65 mg cohort was expanded to a total of 10 patients, and no other DLTs were observed. At the 75 mg QD dose level (n =4), drug-related grade 2 adverse events were reported which led to dose reduction to 65 mg QD (n=3) or treatment discontinuation (n=1). Preliminary PK data show that patients receiving ARQ 531 at 65 mg QD exhibit steady-state trough concentrations (Cmin) above 1 µM; the estimated plasma half-life generally ranged from 20-30 hours and was associated with complete pBTK inhibition. Clinical responses to ARQ 531 were observed in multiple patients with B-cell malignancies. Ten partial responses (PRs) were achieved mainly in the higher dose cohorts, and included patients with CLL (n=7), Richter's transformation (n=1), DLBCL (n=1) and follicular lymphoma (n=1). Of the 7 CLL patients who attained PRs, 5 were initiated at 65 mg, 1 was initiated at 45 mg and was dose escalated to 65 mg and 1 was initiated at 75 mg and dose reduced to 65 mg. Together, the safety, PK/PD and clinical activity results suggest that ARQ 531 at 65 mg QD is safe, well tolerated and has clear signs of anti-tumor efficacy. Thus, 65 mg QD dose has been selected as the RP2D in patients with B-cell malignancies. Conclusion: ARQ 531 has a manageable safety profile and shows anti-tumor activity as single agent therapy in heavily pre-treated patients with B-cell NHL and in patients with CLL resistant to covalent BTK inhibitor. The Phase 1 dose escalation portion of this study is complete. Enrollment of patients with multiple B-cell malignancies is ongoing at 65 mg QD in the phase 1b expansion portion of the study. Updated safety, PK, biomarker and anti-tumor activity data will be presented. Disclosures Woyach: Morphosys: Research Funding; Verastem: Research Funding; Loxo: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Bhat:Pharmacyclics: Consultancy; Janssen: Consultancy. Savage:ArQule, Inc.: Employment. Chai:ArQule, Inc.: Employment. Eathiraj:ArQule, Inc.: Employment. Granlund:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment. Byrd:Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding.

Introduction: Targeted irreversible Bruton's Tyrosine Kinase (BTK) inhibitors ibrutinib and acalabrutinib, have revolutionized treatment for chronic lymphocytic leukemia (CLL). While BTK inhibition (BTKi) achieves durable responses in 90% of patients, only 10% achieve minimal residual disease (MRD) negative status. MRD positive patients have persistent residual CD5+CD19+ tumor B cells at approximately 1-5 /mm3 in peripheral blood. These cells may represent a subpopulation of B-cell lymphocytosis pre-malignant cells or may carry a BTK C481, PLCG2, or other CLL mutation that is ultimately responsible for disease relapse. Alternatively, MRD could be derived from the original clones present at initial disease presentation that are not dependent on BTK signaling. Readily available clinical DNA sequencing and MRD monitoring techniques lack the ability to characterize these cells adequately due to their rarity in peripheral blood. To address this problem, we developed a novel method for limited-cells using fluorescence activated cell sorting in tandem with next generation sequencing (LC-FACSeq) to characterize rare tumor subpopulations in the blood and bone marrow. LC-FACSeq may be useful not only for CLL but also other leukemias. Methods: LC-FACSeq uses fluorescent activated cell sorting (FACS) to isolate pure populations of rare tumor cells after which targeted deep sequencing is performed to monitor CLL-related mutations in NOTCH1, SF3B1, and TP53, as well as genes associated with BTKi relapse and resistance: BTK and PLCG2. For validation of this method, we generated libraries from DNA isolated from FACS isolated bulk (n >15000) versus n= 50, 100, 300, or 500 CD5+/CD19+ cells from CLL patients (n=5). Results: All samples analyzed had an average read depth of 1212 (SEM=56) per gene and an average coverage uniformity of 88.24% (SEM=.01). We show that showed that 300-cell LC-FACSeq libraries demonstrated comparable variant calling and minimal noise to standard libraries generated from purified DNA from bulk cells. Using samples from patients with previously identified BTK C481S mutations, we found that both sensitivity and specificity of LC-FACSeq for BTK C481S was 100%. Furthermore, LC-FACSeq reliably amplified BTK C481S signals from subclones as small as 6 in 300 total cells (2%) when mutated tumor cells were serially diluted into BTK wild type tumor cells. In using LC-FACSeq to retrospectively analyze four independent patients who developed Ibrutinib resistance, we found that we could see the emergence of small BTKi resistant subclones as early as 10 months before clinical detection. We next extended LC-FACSeq to examine the clonal architecture of long-term (> 12 months) ibrutinib-treated MRD positive patients. Median treatment time was 5 years. BTK C481S mutations were observed in the latest available on-treatment samples of only one patient. Using LC-FACSeq we observed canonical CLL-associated clonal mutations similar to those observed in previous studies. Of the 14 MRD positive patients, 7 showed subclonal changes in TP53, NOTCH1, POT1, SF3B1, and MYD88 over the course of ibrutinib treatment although we found no correlation or consensus in these clonal shifts. Conclusion: LC-FACSeq is a highly sensitive method of characterizing clonal evolution in rare cells. Our data shows that LC-FACSeq is useful for monitoring sequential acquisition of mutations conferring therapy resistance and clonal evolution in long-term ibrutinib treated chronic lymphocytic leukemia (CLL) patients. We also observe that in most cases, MRD clones after long-term ibrutinib treatment are genetically similar to disease clones from pretreatment baseline. Compared to current MRD monitoring strategies, the main advantages of LC-FACSeq are that 1) variants can be confidently called from rare sorted tumor populations and subpopulations, 2) library generation can be completed in less than a day in a diagnostic laboratory compared to the labor-intensive protocols of traditional NGS approaches, and 3) amplicon panels can be easily customized for application to other types of leukemia and lymphoma. (EH is supported by the Graduate Pelotonia Fellowship and the NIH F30) Disclosures Bhat: Janssen: Consultancy; Pharmacyclics: Consultancy. Rogers:Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Woyach:AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding; Boehringer Ingelheim: Research Funding. Muthusamy:Ohio State University: Patents & Royalties: OSU-2S. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Acerta: Research Funding.

A significant number of patients relapse or do not respond to rituximab due to intrinsic or acquired resistance. Hence, mAbs targeting other cell surface antigens on B-cell lymphomas are being studied. CD80 is a glycoprotein expressed on Hodgkin's lymphoma, mature B-cell lymphomas and immunoeffector cells which may have T-regulatory, in addition to direct antitumor activity. CD80 serves as an attractive target in the continued development of mAbs against lymphoma.Preclinical studies with galiximab, an anti-CD80 primatized mAb, have been encouraging and have demonstrated antitumor activity against various B-cell lymphoma models, both as a single agent as well as in combination with rituximab. Data were reviewed from a PubMed literature search from 1975 to 2009 and also included a review of abstracts from published proceedings of annual meetings from the American Society of Hematology and International Conference of Malignant Lymphoma, Lugano.Readers will gain a better understanding of mechanisms of action (both documented and proposed) of galiximab. An update of currently available clinical data will be presented.Data from completed clinical trials are promising and galiximab is being studied in both upfront and relapsed settings with the potential of being incorporated into the future treatment of B-cell lymphoma.

e19060Background: DLBCL is a heterogeneous group of aggressive lymphomas with distinct subtypes, and efforts to identify patients at high risk for treatment failure and poor clinical outcomes are o...

e19023Background: Adequate cytoreduction with cisplatin-based chemotherapy is commonly used prior to high dose chemotherapy and autologous stem cell support (HDC-ASCS) among R/R aggressive lymphoma...

Background: Pre-clinical studies have shown that host immune system activation by G-CSF/GM-CSF enhances the biologic activity of rituximab through up-regulation of CD11b/18 expression on neutrophils, increase in the number of circulating granulocytes and higher CD20 epitope density on tumor cells. To further explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted an open-label, single-arm, phase II study evaluating the safety and clinical efficacy of peg-filgrastim and rituximab in patients with low-grade CD20 positive B-cell Non-Hodgkin lymphomas (B-NHL) [chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and marginal zone lymphoma (MZL)]. (NCT01682044) Materials and methods: Twenty patients with untreated or relapsed/refractory indolent lymphoma were treated with rituximab (375 mg/m2) every other week for 4 doses, and after 8 weeks every 2 months for 4 additional doses (total 8 doses). Peg-filgrastim (6mg) was administered subcutaneously 3 days before each dose of rituximab. Clinical responses and tolerability were examined according to standard international criteria. Biologic monitoring included evaluation of phenotype characteristics of host neutrophils, changes in oxidative burst, and in vitro functional assays including CMC and ADCC at baseline and before each dose of rituximab. Results: Baseline patient characteristics were as follows: Median age: 64 (28-86) yrs; 70% male; FL: 70%, CLL: 20%, MZL: 10%; Ann-Arbor stage- II- 10%, III- 30% and IV- 60%; disease status- newly diagnosed: 1, rituximab refractory: 2, relapsed ≥1 line of therapies: 17. Median number of prior therapies was 2 (1-5); 75% had previously received rituximab and 90% had received prior anti-CD20 monoclonal antibody therapy. The addition of peg-filgrastim to rituximab was well tolerated, and did not increase the frequency or severity of rituximab-related toxicities. Most of the adverse events were grade 1-2 infusion-related toxicities. One patient developed grade 4 hyperuricemia. One patient with MZL died while on treatment due to disease progression. The overall response rate (ORR) was 60% (12/20) with a complete response (CR) rate of 35% (7/20). Median progression-free survival (PFS) was 17.9 months (95% CI- 9.9-27.6 months); median overall survival (OS) was not reached. A shorter time-to-peak oxidative burst after first dose of peg-filgrastim was associated with higher rates of CR (p= 0.04) and longer PFS (p=0.03, figure 1). Though intensity of peak oxidative burst did not correlate statistically with outcomes, patients who achieved CR (and OR) had consistently higher free radical levels compared to those who did not, especially during the first 2 months of treatment. This trend waned during the latter part of therapy suggesting neutrophil exhaustion. Further analyses are ongoing to evaluate the association between rituximab ex vivo immunological assays and clinical endpoints outcomes. Conclusion: The combination of peg-filgrastim and rituximab was well tolerated with favorable response rates and PFS compared to historical controls treated with single-agent rituximab. Augmented neutrophil function was associated with higher CR rates and OS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-cell lymphoma. Disclosures Off Label Use: Pegfilgrastim has been combined with rituximab in this phase 2 study for treatment of indolent B-cell Non-Hodgkin lymphoma.. Czuczman:Celgene: Employment; Immunogen: Other: Advisory board; MorphoSys: Consultancy; Boehringer-Ingelheim: Other: Advisory Board.

S72 HRCTs was fungal and no viral pneumonia was detected. Conclusion: It can supply useful additive for a better FEN management process if the medical centers follow their infection agents closely, perform CMV and SGA assays and modify their empiric antibiotic treatment policies in especially HSCT groups.

e17689 Background: Safety of splenectomy is of concern in hematological disorders (HD) due to compromised blood indices and platelet dysfunction. Methods: We conducted a retrospective review of cli...

Based on molecular studies, DLBCL is now further divided in three subtypes with distinct pathogenesis and clinical outcomes. Fluorescence in situ hybridization (FISH) studies identified a subgroup of DLBCL with a poor clinical outcome harboring concurrent gene rearrangements of the MYC, BCL2 and/or BCL6 proto-oncogenes leading to the over-expression of c-Myc, Bcl-2 and Bcl-6, inferior response rates to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS). This group of patients is now categorized as double-hit (DHL) or triple-hit (THL) DLBCL. Immunohistochemistry (IHC) studies suggested that DLBCL patients with over-expression of Bcl-2 and c-Myc proteins exhibit a similar clinical course than those patients with DHL/THL. Alternative transcriptional (i.e. gene amplification or chromosomal gain) or post-translational regulatory mechanisms (yet to be defined) may be responsible for the over-expression of c-Myc, Bcl-2, or Bcl-6 in some patients with DHL/THL phenotype. The appropriate therapy for DHL/THL remains to be defined, but retrospective studies had demonstrated that at standard doses of R+CHOP are suboptimal. In order to study the impact of more aggressive therapeutic approaches in the management of DHL/THL, we retrospectively evaluated our single institution outcome experience over the last 14 years. Using the lymphoma translational database that includes 611 DLBCL patients, we identified 24 patients (M=13/F=11) (4%) with FISH-confirmed DHL/THL DLBCL. Demographic characteristics, clinical data, treatment history in the front line (including the use of CNS prophylaxis, high-dose chemotherapy and autologous stem cell support [HDC-ASCS] or allogeneic bone marrow transplant [allo-BMT]) were collected. In addition, response rate, PFS and OS were calculated. Since the first case-reports were published, we observed a steady increase in the number of DHL/THL patients at our Institution (7 vs. 18 cases before or after 2011) which represents an increasing medical awareness of this new clinical entity. The mean age at diagnosis was 62 years (25 to 85 years), most of them Caucasians (N=22). The median Ki67 proliferation index was 90%. Using the Han’s algorithm, 11 of the DHL/THL were categorized as germinal center B-cell like (GCB), 6 patients as non-GCB, and 7 patients could not be classified. By FISH studies, 58% were DHL (involvement of MYC and BCL2 [N=22] or BCL6 [N=10]) and 42% THL (involvement of MYC, BCL2 and BCL6, N=10). Gene rearrangements involving MYC, BCL2, or BCL6 were observed in 18 patients and MYC, BCL2 or BCL6 gain in 6. Clinically, 95% of the patients presented with stage III/IV, 67% with High-intermediate/High IPI score, and 79% of the patients had extranodal disease. Front-line chemo-immunotherapy included 1) standard doxorubicin-containing regimens: R+CHOP (N=10) or R-EPOCH (N=7), or 2) intensified regimens: R-DHAC (N=2) and R+HyperCVAD/R+HDMTXCytarabine (N=4). Prophylaxis IT chemotherapy was administered to 16 (67%) patients. The complete remission (CR) rate was 62.5% and 29% of the patients underwent HDC-ASCS (N=4)/allo-BMT (N=2) in first (N=2) or second-remission (N=4). In this group of patients, the use of intensified regimens was associated with a non-statistically significant improvement is OS when compared to R+CHOP/R+DA-EPOCH (OS at 3 years of 85.7% vs. 58%). Similarly, an improvement in OS was observed among patients receiving HDC-ASCT/allo-BMT as consolidation (71% vs. 60%, P=0.27). Of interest, CNS prophylaxis was associated with an improvement in OS at 3 years (81% vs. 37%, P=0.032). No differences in clinical outcomes were observed between DHL/THL harboring gene-rearrangements vs. gene gain. In summary, our single institution experience suggests that DHL/THL are increasingly being recognized as more aggressive sub-types of DLBCL with a dismal outcome with conventional therapeutic approaches. A high-index of suspicion should be raised and testing for DHL/THL in those DLBCL presenting with advance stage, multiple extra-nodal site of disease, and an elevated Ki67 index should be done. The accurate identification of DHL/THL patients is necessary, as they appear to benefit from rituximab-based intensified cytarabine-containing regimens, CNS prophylaxis and HDC-ASCT/allo-BMT consolidation. Disclosures No relevant conflicts of interest to declare.