ALBERT

Description: Key Points Increased immune suppressors and PD-1 abrogates effector responses in CML patients at diagnosis. Enhanced net effector immune responses and decreased PD-1 and immune suppressors may promote sustained deep molecular response in CML.

Description: We hypothesized that immune responses contribute to deep BCR-ABL molecular responses in chronic phase chronic myeloid leukaemia (CML) patients on tyrosine kinase inhibitors (TKI). We studied 32 CML patients; 16 at diagnosis, patients treated with imatinib (n=20), nilotinib (n=9) or dasatinib (n=3). Methodology: The effector immune responses of Natural Killer (NK) cells were characterized by flowcytometry and functional analysis by CD107a degranulation assay. Cytotoxic T lymphocyte (CTL) responses to leukaemia-associated antigens (LAAs) WT1, BMI-1, PR3 and PRAME were quantified by interferon-gamma ELISPOT using peptide libraries of 15-mer peptides overlapping by 11 amino acids spanning the entire protein, or HLA-A0201 specific peptides in HLA-A0201+ patients. Immune suppressor regulatory T cells (Treg), Myeloid Derived Suppressor Cells (MDSC), Programmed cell death-1 (PD-1) expression on T cells, NK cells, B cells and monocytes, and major B cell subsets were extensively characterized by flowcytometry. Results: Patients in deep molecular response (MR4.5; BCR-ABL

Description: Introduction:An attempt at tyrosine kinase inhibitor (TKI) withdrawal in deep molecular remission leads either to treatment free remission (TFR) or early molecular relapse (MolR) in chronic myeloid leukaemia (CML) patients. We hypothesise that immune responses promote sustained TFR and immunological markers may predict response following TFR attempt. Methodology: We studied 54 CML patients (from ALLG trials CML 8, median follow-up 66 mo, and CML 10, median follow-up 24 mo) at baseline on TKI (minimum 24 mo MR4.5) and 3 mo and 6 mo following TKI discontinuation. MolR was defined as any single sample on follow-up with BCR-ABL1 〉0.1% or two consecutive BCR-ABL1 positive samples at any value. Effector immune responses of CD56dim natural killer (NK) cells and NK cell receptor repertoire were characterised by flow cytometry and cytotoxic T lymphocyte (CTL) responses to leukaemia-associated-antigens (LAAs) WT1, BMI-1, PR3 and PRAME by interferon-gamma ELISPOT. Immune suppressor regulatory T cells (Treg; CD4+CD25brightCD127-FoxP3+), Granulocytic and Monocytic Myeloid-Derived Suppressor Cells (MDSCs; HLA-DR-Lin-CD11b+CD33+CD66b+CD15+ and HLA-DR-Lin-CD11b+CD33+CD66b-CD14+, respectively), Programmed cell death-1 (PD-1) expression on T cells, NK cells, B cells and Monocytes, and major B cell subsets were characterized by flow cytometry. Results: TFR patients displayed increased CD3-CD56dimCD16bright cytolytic NK cells as a proportion of total lymphocytes at baseline (n=23, 27.1% ± 2.9) vs MolR (n=23, 19.1% ± 2.0, p=0.02). TFR patients displayed a more mature CD56dim CD57+ NK cell phenotype at baseline (74.5% ± 2.2 of total NK cells) vs MolR (66.3% ± 2.7, p=0.04). Extensive characterisation of NK cell receptor repertoire revealed NKG2D activating receptor expression was increased in TFR patients (baseline= 56.8% ± 3.8, 3 mo= 61.4% ± 5.0, 6 mo= 49.9% ± 5.8) vs MolR (baseline= 44.2% ± 3.7, 3 mo= 42.2% ± 5.5, 6 mo= 22.0% ± 8.3, all p=0.02). KIR2DL2/DL3/DS2-positive NK cells were increased in MolR patients at 3 and 6 mo vs TFR. (MolR; 3 mo= 44.8% ± 4.6, 6 mo= 48.8% ± 4.9. TFR; 3 mo= 31.5% ± 4.0 p=0.05, 6 mo= 31.1% ± 2.1, p=0.001). No significant differences were observed in CD56brightCD16-/dim immunoregulatory NK cells, C-type lectin receptor expression (CD94/NKG2A/NKG2C, CD161, CD69), Natural cytotoxicity receptors (NKp30, NKp44, NKp46), CD62L (on T cells and NK cells) and KIR2DL5 expression. No difference in NK Cell-mediated K562 degranulation as a surrogate marker of NK cell function was observed between TFR and MolR patients. Functional CTL immune responses were observed in TFR and MolR patients. BMI-1 CTL responses were increased at baseline in TFR (23%) vs MolR (9%). PR3 CTL responses were not detected in TFR at baseline, 3 mo or 6 mo (0%) vs MolR (baseline= 18%, 3 mo= 50%, 6 mo= 50%). No difference was observed in WT1 or PRAME CTLs. Quantification of immune suppressor cell types revealed decreased Monocytic MDSCs in TFR patients at baseline (10.0% ± 2.3) vs MolR (17.7% ± 3.1, p=0.02). There was no difference in granulocytic MDSCs or Treg between TFR and MolR. No difference in PD-1 expression was observed on NK cells, T cells, B cells and Monocytes. Extensive characterisation of B cell subsets revealed no difference in TFR vs MolR (Table 1). Conclusion: In keeping with STIM and EURO-SKI trials, a threshold level of particular NK cell subsets may be important in maintaining TFR. We found additionally that enhanced NK and CTL effector responses and decreased inhibitory NK KIR2DL2/DL3/DS2 expression, in combination with reduced monocytic MDSC may promote sustained TFR. Methods to enhance nett immune effector responses, such as mature CD56dimCD57+ NK cells and BMI-1 CTL responses or targeting inhibitory KIR may increase TFR success rates. Disclosures White: Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Hughes:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria. Yong:Celgene: Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Description: Chimeric antigen receptor T-cells (CAR Tc) have yielded impressive remission rates in treatment-refractory B-cell malignancies (B-ALL and B-lymphomas) by targeting CD19, resulting in the first FDA approved CAR Tc therapies, Kymriah and Yescarta. However, the translation of these results for other cancer entities remains a challenge. Pre-clinical studies using second-generation CAR Tc against the interleukin-3 receptor alpha chain (CD123) engendered strong anti-leukemic activity. CD123 CAR Tc clinical studies resulted in transient responses, or complete remission but at the expense of on-target off-tumor toxicities. Our studies employing third-generation anti-CD123 CAR Tc demonstrate strong anti-leukemic activity with no adverse effects in vivo. However, the leukemia was not completely eradicated. Combining anti-CD123 CAR Tc with DNA hypomethylating (HMA) agents may enhance the anti-leukemic effect and survival. HMAs such as azacytidine (Aza) activate key epigenetically silenced pathways in AML cells, inhibiting cell proliferation while enhancing cell immunogenicity. We hypothesized that Aza will increase the expression of CD123 on AML cells resulting in long-term disease eradication by anti-CD123 CAR Tc. The anti-leukemic efficacy, survival advantage, safety and feasibility of the combination treatment with Aza and anti-CD123 CAR Tc were evaluated in vivo. HL-60 (CD123med), MLL-2 (CD123lo), MOLM-13 (CD123hi), primary de novo and relapsed/refractory (r/r) AML cells were cultured for 0-8 days in the presence of Aza (0µM-5µM) and analysed for their CD123 expression by flow cytometry, quantitative western blot and RNAseq. The anti-CD123 CAR was constructed with the humanized CSL362-based ScFv and the CD28-OX40-CD3ζ signaling domain, encoded in a third-generation lentiviral vector and expressed in CD3+ Tc from healthy donors. Rag2γc-/- mice (n=12-16/ group) were engrafted with 1x105 MOLM13/ffLuc AML cells and treated with PBS, 5x106 Non-transduced (NTD) Tc orCAR Tc, 4x 2.5mg/kg Aza, or 5x106 CAR Tc following 4x Aza (2.5mg/kg). Leukemic burden was assessed weekly by bioluminescence imaging. Tc activity and immunophenotyping was performed using flow cytometry at day 35 post engraftment, and survival was monitored. HL-60, MLL-2 and MOLM-13 cells showed significant increases in HLA-DR, PD-L1, STAT1 and IRF7 expression, as well as CD123 when exposed to Aza (Fig 1A,B). Interestingly, the increased effect was seen from day one regardless of concentration. This was similarly reflected in AML patient cells. Aza treatment also arrested cell proliferation and decreased viability in both cell lines and patient cells suggesting Aza can aid in the anti-leukemic effect. Rag2γc-/- mice engrafted with MOLM-13 and treated with Aza and CD123 CAR Tc demonstrated suppressed growth, and eradication of MOLM-13 cells compared to mice treated with CD123 CAR Tc or Aza alone. Additionally, a significant decrease in residual CD123+ cells in the bone marrow (BM) of dual treated mice was seen (Fig 1C). A higher frequency of residual CD8+ T-cells in the BM, and CD4+ Tc in the peripheral blood (PB) and BM of dual treated mice was observed compared to CAR Tc only treated mice. Most prominently, we found a significantly higher mean number of stem cell-like and central memory CD8+ Tc in the BM of dual treated mice (232 cells/µl and 208cells/µl, respectively) compared to the CAR Tc only group (55 cells/µl and 23 cells/µl, respectively). Assessment of immune checkpoint markers on residual CAR Tc of dual treated mice revealed significantly decreased levels of CTLA-4, PD-1 and TIM-3 in the BM, and CTLA-4 in the PB compared to the CAR Tc only group. While CAR Tc treatment alone demonstrated a survival advantage compared to PBS, NTD or Aza treated mice, Aza and CAR Tc treatment had a significantly higher survival rate compared to the CAR Tc only group (92% vs. 46% at day 50, p

Description: Key Points Immune responses to FVIII sequence variants encoded by ns-SNPs do not contribute appreciably to inhibitor development in African Americans. African American HA subjects with an intron-22 inversion had a 2- to 3-times-higher inhibitor incidence than whites with the same mutation.

Description: Background: Allogeneic SCT is considered standard treatment for patients with advanced phase CML (accelerated phase, blast crisis), de novo Ph+ ALL, or patients in chronic phase (CP) resistant or intolerant to at least 2 tyrosine kinase inhibitors (TKI). Ponatinib is FDA and EMA approved for the treatment of CML or Ph+ ALL in patients with the BCR-ABL1 T315I mutation or for whom no other TKI therapy is indicated. In patients harboring the T315I mutation, ponatinib currently represents a suitable alternative treatment option to allogeneic SCT. However, differences in outcomes between patients treated with ponatinib and allogeneic SCT have not been analyzed. Objective: To compare overall survival (OS) among CML and Ph+ ALL patients with the BCR-ABL1 T315I mutation treated with ponatinib (in PACE) versus allogeneic SCT (in the EBMT database). Methods: Data from a Phase II trial of ponatinib (PACE trial; Cortes et al., New Engl J Med 2013; NCT01207440) and European Bone Marrow Transplant (EBMT) registry were pooled to conduct an indirect comparison of ponatinib with allogeneic SCT. Both ponatinib and allogeneic SCT cohorts comprised patients with the T315I mutation age 18 years or older in any phase of CML or with Ph+ ALL. All patients harbored the T315I mutation detected by Sanger sequencing, DHPLC, PCR-RFLP, or other equivalent tests. Allogeneic SCT patients in their second CP phase were excluded, and no patients in the EBMT database were treated with ponatinib prior to receiving allogeneic SCT. The date of intervention (ponatinib or SCT) served as the index date. Baseline demographic and clinical characteristics were compared between the two intervention groups. OS was compared between the two groups using adjusted Kaplan-Meier (KM) survival curves and multivariate Cox proportional hazards models; all comparisons were adjusted for age (as a continuous variable), gender, geographic region (Europe, Asia, and Australia vs. North America), time from CML diagnosis to intervention, and CML phase or Ph+ ALL at intervention to control confounding by these variables. Results were presented overall and stratified by phase of CML or Ph+ ALL. Results: A total of 184 (128 ponatinib, 56 allogeneic SCT) patients were included in the analysis: 90 were in CP-CML, 26 were in accelerated phase (AP-CML), 41 were in blast phase (BP-CML), and 27 had Ph+ ALL. On average, ponatinib patients were older than allogeneic SCT patients on the date of intervention (median age 53 vs. 45 years, p=0.006). In addition, a larger proportion of patients in the ponatinib group were from North America than in the allogeneic SCT group (43.8% vs. 26.8%, p=0.030). Median time from diagnosis to intervention was longer for patients treated with ponatinib compared with those treated with allogeneic SCT in CP-CML (58 vs. 32 months, p=0.029), but not significantly different in AP-CML (80 vs. 49 months, p=0.075) nor Ph+ ALL (17 vs. 10 months, p=0.212). This period was nominally shorter for the ponatinib cohort in BP-CML (26 vs. 43 months, p=0.340). Over 93% of patients in both treatment cohorts in all disease phases reported previous use of imatinib. Adjusted median OS was significantly longer in CP-CML patients treated with ponatinib as opposed to allogeneic SCT patients (KM median: not reached [NR] vs. 103.3 months, p=0.013), with a hazard ratio (HR) of 0.37 (95% CI: 0.16, 0.84, p=0.017). Median OS was not significantly different between the two treatment groups in patients with AP-CML (NR vs. 55.6 months, p=0.889; HR=0.90 [95% CI: 0.20, 4.10, p=0.889]). However, among patients with BP-CML, ponatinib was associated with significantly shorter OS compared with allogeneic SCT: median 7.0 vs. 10.5 months (p=0.026), HR=2.29 (95% CI: 1.08, 4.82, p=0.030). Ph+ ALL patients treated with ponatinib had nominally shorter median OS than allogeneic SCT (6.7 vs. 32.4 months, p=0.119; HR=2.77 [95% CI: 0.73, 10.56, p=0.136]). See Figures 1a-1d for adjusted KM survival curves. Conclusion: AllogeneicSCT remains a potential curative therapy for patients with BP-CML. However, ponatinib was associated with significantly longer OS than allogeneic SCT in patients with CP-CML that harbor the T315I mutation and could represent a promising therapeutic alternative in this setting, although follow-up remains short to date. OS was similar between intervention groups in AP-CML and longer for allogeneic SCT patients in BP-CML and Ph+ ALL. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Basak:MSD: Consultancy, Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Pierre-Fabre: Honoraria. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:BMS: Consultancy, Speakers Bureau; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau. Apperley:ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Ariad: Consultancy; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chiltern International: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; ROCHE: Consultancy; BMS: Consultancy, Speakers Bureau; AMGEN: Consultancy. DerSarkissian:ARIAD: Research Funding. Kageleiry:ARIAD: Research Funding. Yang:ARIAD: Employment. Huang:ARIAD: Employment, Equity Ownership. McGarry:ARIAD: Employment, Equity Ownership. Cortes:Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Description: Introduction: Pain is the top concern of individuals with sickle cell disease (SCD). Acute painful vaso-occlusive episodes in SCD are the leading cause of emergency department (ED) encounters and frequent hospital admissions. Well-documented disparities include significant delay and under treatment of SCD patients with acute pain crisis in the ED. An acute care observation unit (ACOU) staffed with SCD specialists can help to address these disparities. SCD patients treated in a dedicated ACOU have a 40% lower admission rate than patients treated in the ED. An expedited transfer and treatment program at our dedicated sickle ACOU at the University of Illinois Hospital (UIH) was implemented with the goal of improving overall care and decreasing the hospital admission rate for SCD patients. Method: This is an outcome study of individuals with SCD 〉16 years of age who presented with an acute painful episode to UIH. A quality improvement project used the Plan-Do-Study-Act translation method. The following key areas were identified for intervention: 1) established criteria for direct ACOU admission, 2) expedited transfer to the ACOU from the ED, 3) addition of a third provider to expand hours, and 4) establishing a consistent but individualized pain treatment plan across the ED and ACOU. The number of admissions to hospital of patients with SCD was examined from September 2018 through August 2019. Applying the Donabedian triad of Structure, Process, and Outcomes, we demonstrated improved outcome and decrease hospitalization. Results: There were 877 admissions to the ACOU from January to July of 2019, which is an increase of 37% compared to the same period in 2018. Of the 877 admissions, 793 were discharged home (90.4%) as compared to 88.6 % in 2018. The average time to first dose of opioids in the ACOU in 2019 was 55 minutes with and average decrease in the pain score of 2.62 during an average length of stay of 4:18 hours. Conclusions: Expedited care and treatment with a focus on improving quality and improving access resulted in increased volume of patients treated and decreased rate of admission to the hospital. Allocating resources to a dedicated sickle acute care observation unit can significantly decrease inpatient hospitalizations. Table. Disclosures No relevant conflicts of interest to declare.

Description: Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for treatment of patients (pts) with relapsed/refractory marginal zone lymphoma (MZL) who have already received one or more anti-CD20 containing treatment regimens and require systemic therapy. Approval was based on a clinical trial in 60 pts that showed durable responses and a median progression-free survival (PFS) of 14.2 months (mos) (Noy et al., Blood 2017). Since pts outside clinical trials may have different disease and demographic characteristics, our study investigates the safety and efficacy of ibrutinib when implemented in a non-trial setting. Materials and Methods: This is a retrospective analysis of MZL pts who received ibrutinib monotherapy as part of their treatment at the University of Pennsylvania. Subjects were identified by a database search for any MZL pts prescribed ibrutinib. Primary endpoints were PFS and overall survival (OS) since initiation of ibrutinib. Secondary endpoints were overall response rate (OR) and complete response rate (CR), adverse events, and reasons for discontinuation. The first patient was treated on April 10, 2014, and the data cutoff was July 1, 2019. Analyses were performed using STATA 15.0 software. Results: There were 28 pts included in this study with a median age of 69 years (range 36-90) and median ECOG performance status at diagnosis of 0 (range 0-2). All pts had advanced disease (all stage III/IV & 68% with bone marrow involvement). The distribution of MZL subtypes was 43% extranodal, 25% nodal, and 32% splenic. Most pts (89%) had received one or more treatments prior to ibrutinib (32% received first-line rituximab only). The median number of previous therapies was 2 (range 0-5), and 43% of pts were refractory to the previous line of therapy. A minority of pts (11%) received rituximab or another anti-CD20 antibody concurrently with ibrutinib. Pts started ibrutinib a median of 56 mos after their initial diagnosis (range 0.5-221 mos) with a median duration of therapy of 7 mos (range 0.7-62 mos). The median starting dose was 420 mg daily (range 70-560 mg daily). In 26 pts with response data available, the OR was 73% with CR 15%. The 12-mo PFS and OS were 77% and 87% respectively (see Figures 1 & 2, median PFS and OS not yet reached). PFS and OS at median follow-up were 55% and 69% respectively. There was no significant difference in response or survival rates among MZL subtypes. Pts who received rituximab only prior to ibrutinib had an OR of 86% compared to 69% in those with more than one previous therapy (Χ2 = 0.73, p = 0.39). Ibrutinib was discontinued in 43% of pts after a median of 2.9 mos (range 0.7-13.7 mos) due to disease progression (50%), intolerance (42%), or other reasons (8%). Most (67%) pts subsequently received other therapies. All pts who stopped due to toxicity were responding at the time of discontinuation. Ibrutinib was also temporarily held or dose-reduced in 46% of pts due to toxicity (77%), preparation for surgery (15%), or drug interactions (8%). One patient experienced acute rebound of symptoms until ibrutinib was restarted. Most commonly reported toxicities are summarized in Table 1. Grade 3 toxicities included pneumonia (7%), sepsis (4%), hemorrhage (4%), arthralgia (4%), fatigue (4%), URI (4%), and hepatitis (4%). Toxicities responsible for cessation of treatment were arthralgia, hepatitis, thyroiditis, and hemorrhage. There were no reported treatment-related deaths. Conclusion: To our knowledge, this is the first study to report the efficacy and safety of ibrutinib in a large cohort of MZL pts treated outside of a clinical trial. We found that the therapy was well-tolerated and observed response rates that compared favorably to those shown in the prospective clinical trial. Disclosures Hughes: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Dwivedy Nasta:47 (Forty Seven): Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. OffLabel Disclosure: This paper looked at the effectiveness of ibrutinib, a Bruton's tyrosine kinase inhibitor, in treating patients with marginal zone lymphoma (MZL). Ibrutinib is FDA approved for MZL patients who have received at least one anti-CD20 containing therapy and now require systemic treatment. Some patients in the study had not previously received an anti-CD20-based therapy and received ibrutinib off-label.

Description: Introduction: Venous thromboembolism (VTE) is a significant adverse event in adults receiving pegaspargase (PEG) for acute lymphoblastic leukemia (ALL). PEG increases VTE risk by depletion of antithrombin III (AT). Heparin requires adequate AT for anticoagulation. Younger adults with T-cell ALL receiving prednisone may be particularly at risk. Retrospective series (most with L-asparaginase) suggest AT supplementation may decrease VTE, however prospective data in adults beyond induction is limited while the optimal dose of AT remains undefined and varies across series. We reviewed adults at our institution who received PEG for ALL to assess the incidence of VTE within our AT supplementation practice. Laboratory and cost data for AT repletion were also analyzed. Methods: Adults who received PEG for ALL between 11/2015 and 7/2018 were retrospectively identified. Institutional recommendations were to supplement AT if serum AT 〈 60% following PEG for at least the first 2 courses (induction/consolidation). AT levels were assessed twice weekly until normalized. AT supplementation following additional cycles was recommended for all patients receiving therapeutic anticoagulation. Pharmacists calculated the AT dose using a repletion factor of 80-120%, rounded to the nearest vial. After VTE, patients received therapeutic enoxaparin throughout all remaining PEG doses, with enoxaparin held only if platelets 〈 50,000/mcL or for procedures. After 3/2018, all patients receiving PEG also received enoxaparin prophylaxis when platelets 〉30,000/mcL. A retrospective analysis was done to assess the incidence of VTE. Secondary endpoints included an assessment of VTE risk factors, ability to achieve therapeutic AT levels with supplementation and to characterize drug therapy costs with AT supplementation. Results: Thirty-one patients (30 newly diagnosed, 1 in relapse) with ALL received ≥ 1 dose of PEG followed by AT supplementation. Seventeen of 31 patients were adolescent/young adults (AYA) and 13/31 had T cell ALL. Additional patient characteristics are summarized in table 1. The incidence of VTE was 19%, with 7 VTEs identified in 6 patients. Two patients developed CNS thrombosis (1 fatal), 1 had a pulmonary embolism, and the remainder were upper extremity VTE. Six of 7 VTE occurred during the first two courses at a mean of 66 days (range 6-225) following the first PEG dose. Patients with VTE had a median platelet count of 118/mcL (range 34-377) and a mean AT nadir of 53% (36-98) within 72 hours of VTE. Two of 7 events occurred despite enoxaparin prophylaxis. Five of 6 (83%) patients with VTE had T-ALL; which was more common in the VTE vs. no-VTE group (p = 0.01). The incidence of VTE within the T-ALL group was 38%. Patients with VTE were all AYA and were younger than those without VTE (median 31 vs. 42 years, p = 0.06). Patients with VTE received a higher mean PEG dose than patients without VTE (4589 vs. 3504 units, p 〈 0.0001), reflective of the more aggressive dosing in the AYA regimen. Six of 7 VTEs occurred during a course containing prednisone (p = 0.08 vs. dexamethasone). AT nadirs during cycles with VTE were similar to cycles without VTE. No clinically significant bleeding occurred. Characteristics of patients with VTE are summarized in table 2. Overall the mean time to AT nadir was 11 days. Therapeutic AT (〉 60%) following supplementation occurred 56% of the time. Most AT doses (89%) were calculated with a correction factor of 80-89%. The probability of obtaining a therapeutic AT increased when a higher repletion factor (〉 90%) was used (76% vs. 52%, p = 0.06). Patients received a mean of 1.9 (0-6) doses of AT per PEG dose, and a mean of 5.9 (1-21) AT doses throughout treatment. The mean AT supplementation cost per PEG dose was $11,663 with 186 doses administered ($3.22/unit). Conclusions: VTE occurred in 19% of patients receiving AT supplementation following PEG, with 2/7 events involving the CNS. The risk of VTE was greatest in younger adults with T-ALL receiving concurrent prednisone and higher doses of PEG. AT levels were low at the time of VTE in most patients, however nadirs were similar compared to courses not complicated by VTE. Routine or augmented VTE prophylaxis and a higher AT repletion goal (〉 90%) may further limit VTE risk but given the cost and patient inconvenience, prospective evaluation is needed to confirm the benefit. Disclosures Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board.

Description: Introduction: Venetoclax (VEN) is a highly effective agent for chronic lymphocytic leukemia (CLL) that targets BCL-2. Thus, it has been hypothesized to have efficacy in NHL and tested in phase-1/2 studies (Gerecitano JF, Blood 2015; de Vos S, Blood 2015; Davids MS, J Clin Oncol 2017). Overall response rates (ORR) observed in r/r NHL were 44% for all subtypes combined, 38% for follicular lymphoma (FL), 75% for mantle cell lymphoma (MCL), and 18% for diffuse large B-cell lymphoma (DLBCL). The adverse effect profile was consistent with the labeling despite dose escalation to doses higher than used in CLL. Additionally, VEN is a potential option in the r/r NHL setting, potentially providing less T cell toxicity compared to other agents used as bridging to T-cell therapies (Cummins NW, mBio, 2016; Dzhagalov I, J Immunol, 2008). We performed an analysis of all NHL patients (pts) treated with VEN at our institution to assess efficacy and safety of VEN in r/r NHL. Patients and Methods: We conducted a retrospective cohort study of all adult pts who received VEN for r/r NHL at the University of Pennsylvania between 4/2016 and 6/2018. Demographics, tumor lysis syndrome (TLS; events, prophylaxis and management), duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from VEN start to disease progression or regimen change, death due to NHL or last-follow-up in remission), and overall survival using the Kaplan-Meier method. All other analyses were descriptive. Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (35%; n=8), MCL (30%; n=7), Richter transformation (RT) (9%; n=2), transformed FL (tFL) (12%; n=4), post-transplant lymphoproliferative disease (PTLD) (4%; n=1), and marginal zone lymphoma (MZL; n=1) (4%). Median age at VEN start was 65 years; most pts were Ann Arbor stage IV (87%) and ECOG performance 2-4 (57%). NHL characteristics were MYC rearrangement (35%), BCL2 rearrangement (22%), double-hit lymphoma (26%), BCL2 IHC+ (22%), non-germinal center phenotype (13%). Median number of prior therapies was 4 (range: 2-13) with 17% having a prior autologous stem cell transplant. Median time to VEN initiation from prior therapy was 1 month (range, 0.5-9). Median VEN dose achieved was 400 mg (Range, 100-1200). Data for TLS are in Table 1. Median time on VEN was 2 months. While on VEN, 17% received radiation and 43% were on other anti-neoplastic therapy. Overall response rate (ORR) for the entire cohort was 26% (100% Partial Response [PR]). Subtypes with PR included MCL (13%), DLBCL (9%), and RT (4%). No PRs were observed with tFL, PTLD, nor MZL. Pts most commonly discontinued VEN for disease progression (74%); 2 pts (9%) remain on VEN therapy (range: 2-11 months). Median PFS and OS for the entire cohort were 2 months and 3 months, respectively, (Figure 1). Analyzed as histologic cohorts, large B-cell lymphomas (DLBCL, RT, PTLD, tFL) had similar median PFS and OS. However, small B-cell lymphomas (MCL, MZL) had median PFS and OS of 2.5 and 4 months, respectively. Two pts subsequently received CAR T-cell therapy post-VEN; one collected T-cells during VEN therapy and one collected T-cells prior to VEN start. Adverse events (AEs) occurred in approximately 65% while on VEN. AEs included: neutropenia (48%), thrombocytopenia (43%), TLS (30%), infection (26%), neutropenic fever (26%), and diarrhea (22%). One pt had an opportunistic infection (Pneumocystis jiroveci pneumonia) while on VEN and concurrent high-dose steroids. Conclusion: VEN monotherapy appears effective for NHL in phase I clinical trials. We describe our experience outside the setting of a clinical trial, including VEN used as part of multi-agent salvage therapy. Median PFS for our entire cohort is 2 months; AEs, while expected, were observed frequently, reflecting comorbidities. Clinical TLS events are attributed to pre-existing renal dysfunction (61% below 80 mL/min) during VEN escalation. The wide heterogeneity of VEN dose escalation, multi-agent combinations, and timing of initiation of VEN therapy are factors that require further investigation best designed as prospective clinical trials using other agents in combination with VEN. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Schuster:Genentech: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Physician's Education Source, LLC: Honoraria. Svoboda:Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Regeneron: Research Funding; KITE: Consultancy; Kyowa: Consultancy; Merck: Research Funding. Gill:Novartis: Research Funding; Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership. Mato:TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Johnson & Johnson: Consultancy; Regeneron: Research Funding; Acerta: Research Funding; Celgene: Consultancy; Prime Oncology: Honoraria; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Medscape: Honoraria. Altman:Epizyme: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Pfizer: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Other; GSK: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Other: Payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Pharmacyclics: Research Funding; Incyte: Research Funding; Roche: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Debiopharm: Research Funding; Merck: Other: DSMC; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.