ALBERT

Description: Background: Mutations of MAP2K1, which encodes MEK1, have been identified in up to half of patients with variant Hairy Cell Leukemia (vHCL).[Waterfall et al., Nat Gen 2014, Mason et al., Leukemia & Lymphoma 2016], and have been associated with vHCL with IGHV4-34 gene usage, which This form of HCL tends to have a worse prognosis than classic HCL or wild type vHCL (Arons et al., Blood 2009), with inferior responses to chemotherapy and shorter durations of remission. Trametinib, an oral inhibitor of MEK1 and MEK2, is FDA approved for treatment of patients with BRAF p.V600E mutant melanoma. We hypothesized that this MEK inhibitor would have activity in MAP2K1 mutant vHCL. Case Report: The patient is a 52 year old man with a history of CD25+, BRAF wildtype, IGHV4-34 usage vHCL diagnosed in 2005. His previous treatments included cladribine, BL22, pentostatin/rituximab, splenectomy, single agent rituximab, ibrutinib, bendamustine/rituximab, and allogeneic transplantation from a matched unrelated donor. The patient experienced disease relapse day +350 post transplant when he developed skin nodules as well as a generalized skin rash. The skin rash appeared clinically consistent with acute GVHD. However, when biopsies of both the skin nodules and skin rash were performed he was found to have relapsed vHCL. He was consented for paired tumor and germline next generation sequencing with a 25-gene amplicon panel which revealed a somatic MAP2K1 K57N mutation that has been shown to constitutively activate MEK [Marks et al., Cancer Res 2008]. As the patient had exhausted the majority of available treatment options, he was prescribed trametinib 2 mg po daily (commercial supply, according to approved melanoma dosing). Within a week of therapy initiation his skin nodules were markedly diminished in size and his generalized rash had resolved. He did develop a new acneiform rash over his face consistent with drug toxicity. This was managed with topical agents with improvement and did not require a dose reduction. Disease restaging following cycle 2 of therapy showed near complete resolution of skin nodules, with disappearance of visible skin rash. Repeat bone marrow biopsy showed unchanged hairy cell index. Skin biopsies were repeated and phospho-ERK (T202/Y204) staining of skin biopsies pre- and post-trametinib were performed (Figure 1). This showed diminished lymphocyte involvement on H&E staining with a decrease in p-ERK expression on immunostaining, indicative of decreased signaling downstream of MEK and consistent with on target trametinib effects. As of this writing, the patient has remained on trametinib for 12 weeks with no recurrence of leukemia cutis rash. Discussion: MEK inhibition with the oral MEKi trametinib is a well tolerated therapy with clinical activity in MAP2K1 mutant vHCL. Additional studies of this agent are warranted. Optimal dose and duration of therapy will need to be explored in prospective clinical trials. Figure 1 Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Figure 1. Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Geriatric deficits in patients with malignancy are predictive of morbidity and mortality. Measuring geriatric deficits provides additional prognostic information not otherwise captured in routine oncology care. Currently, the gap in geriatric-care delivery is the paucity of data demonstrating effective interventions once geriatric deficits are identified. Older adults with hematologic malignancy are understudied and evaluating both the impact of geriatric factors and interventions to improve upon geriatric deficits are warranted. Here we demonstrate the impact of identifying functional impairment and an exercise program among older adults with hematologic malignancy. Methods: This was a single center prospective study of older patients (≥60 years) with hematologic malignancy. Patients actively receiving any therapeutic treatment (chemotherapy, immunotherapy, targeted agents) were enrolled in a six-month exercise program to attenuate functional decline. The Otago Exercise Program (OEP) has been found to be an effective exercise regimen to improve functional balance, muscle strength, and prevent fall-related injury and mortality.1 The OEP is a structured combination of physical therapist prescribed individualized exercise plans with home-based exercise targeted to improve balance and functional decline. Patients enrolled had mild or moderate impairments in physical function, as defined by a score ≤9 on the Short Physical Performance Battery (SPPB). Patients were evaluated at baseline for geriatric deficits (Visit 1), after four months of OEP training (Visit 2), and following two months of self-directed exercise (Visit 3 - end of study) using a standardized Geriatric Assessmpent (GA) tool (CARG GA). The relationship between geriatric deficits and mortality and hospital utilization were analyzed. The change in GA factors over 3 visits were evaluated through a linear mixed model. The proportional hazards model was built to assess the association between Visit 1 GA and overall survival (OS), where OS was defined as time from date of V1 to death, censoring patients who were still alive at time of last follow-up. The generalized linear models were used to link Visit 1 GA with other clinical outcomes such as hospital length of stay (LOS) and the probability of emergency room (ER) visit. Results: Older adults (median age: 75.5; range 62-83) actively receiving chemotherapy for hematologic malignancy were enrolled (n=30). Physical health scores as measured by the MOS-PFS increased significantly at the second visit. [Median MOS-PFS: V1=55 (0-100); V2=70 (30-100), p

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

Description: BACKGROUND: Ibrutinib is an irreversible inhibitor of BTK in the B-cell receptor signaling cascade and is widely used to treat chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits the tyrosine kinase Tec in platelets, which may be one of the mechanisms of its bleeding toxicity. This makes concomitant use of anticoagulation (AC) or antiplatelet agents challenging, which is a common delimma as many patients taking ibrutinib are elderly and have increased risks of venous and arterial thromboses. The incidence of thrombosis in patients taking ibrutinib is unknown, and we hypothesized that the risk of thrombosis may be reduced during ibrutinib treatment. Therefore, we conducted a single-institution retrospective cohort study to determine the incidence and type of both arterial and venous thromboses during ibrutinib treatment and their management. METHODS: We reviewed medical records of all patients treated with ibrutinib for a hematological malignancy at the Ohio State University between 6/1/2010 and 3/31/2016. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All thrombotic events occurring at any time during treatment with ibrutinib and within three days of its discontinuation were recorded. Time to thrombosis was calculated from the date of starting ibrutinib to the date of thrombosis or censored at the last assessment date, treating discontinuation of ibrutinib or death prior to thrombosis as competing risks. The cumulative incidence of thrombosis was estimated and the Fine and Gray regression models accounting for competing riskes were used to examine the association between patient characteristics and risk of thrombosis. RESULTS: The cohort included 565 patients. Median age was 65 (range 23-〉89) years and 70.3% (397/565) were men. The majority of patients had CLL (73.6%, 416/565). Other diagnoses included mantle cell lymphoma (9.9%, 56/565), indolent B-cell malignancies (8.1%, 46/565), and aggressive lymphomas (8.3%, 47/565). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/565) of patients were treatment naïve. Prior to ibrutinib, 144 of 565 patients (25.5%) had a history of thrombosis. Sixty-four (11.3%, 64/565) patients had only venous thromboses, 66 (11.7% 66/565) had only arterial thromboses, and 14 patients had both. Concurrently with ibrutinib, 193 (34.2%) patients received antiplatelet agents, 16 (2.8%) patients received AC, and 31 (5.5%) patients received both. Total ibrutinib exposure for the cohort was 1,429 person-years with a median exposure of 2.39 (range 0-7.36) years per patient. A second antineoplastic agent was given with ibrutinib in 30.8% (174/565) of cases, including an immunomodulatory drug in 24 (4.2%, 24/565) patients. During ibrutinib treatment, 22 of 565 (3.9%) patients experienced 24 acute thrombotic events, mostly arterial (Table 1). The incidence of thrombosis was 1.7 (95% CI 1.1-2.5) per 100 person-years of ibrutinib exposure. Of the venous thromboses, 87.5% (7/8) were deep vein thromboses and developed at a median of 7.5 (range 0.5-75.3) months after starting ibrutinib. Of the arterial thromboses, the majority were acute cerebrovascular accidents (37.5%, 6/16) and developed at a median of 27.4 (range 0.4 - 56.6) months after starting ibrutinib. Thrombosis treatment is summarized in Table 1. After thrombosis, ibrutinib was discontinued or held in the majority of cases (75%, 18/24). One patient developed a recurrent thrombosis while on ibrutinib and AC. There were six bleeding events, 3 major (based on ISTH criteria) and 3 minor: all were taking ibrutinib and most were on AC (2 patients on antiplatelet, 1 on AC, 2 on both, 1 on neither). On univariable analysis, the only factors associated with significant (p2) increased risk of venous thrombosis were prior venous (HR 4.73, CI: 1.06-21.11) and arterial (HR 15.66, CI: 3.07-79.87) thromboses. Antiplatelet use was not significantly associated with either thrombus type. CONCLUSIONS: The cumulative incidence of thrombosis during ibrutinib treatment was low (1.7 per 100 person-years), with the majority being arterial. Prior thrombosis was associated with increased venous thrombosis risk. There are more bleeding than thrombotic complications after patients develop thromboses on ibrutinib, and optimal treatment strategies for this population requires further investigation. Disclosures Kander: AstraZeneca: Consultancy. Wang:Daiichi Sankyo: Consultancy, Other: Travel.

Description: Key Points Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome. This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.

Description: BACKGROUND Development of targeted therapies for CLL including the anti-CD20 monoclonal antibody obinutuzumab (OBIN), Bruton's tyrosine kinase inhibitor ibrutinib (IBR), and Bcl-2 inhibitor venetoclax (VEN) have demonstrated significant clinical activity in CLL. As they have high response rates as single agents, largely non-overlapping toxicities, and distinct and potentially synergistic mechanisms of action, we designed and initiated a triplet regimen with OBIN, IBR, and VEN for a fixed duration of treatment. The goal of the regimen is to achieve deep remissions and facilitate treatment discontinuation. The previously reported phase 1b cohort on this study established VEN 400 mg daily as the recommended dose for use with the label doses of OBIN and IRB in this combination. To determine response rates, eradication of minimal residual disease (MRD), and progression-free survival (PFS) in relapsed/refractory (RR) and treatment-naïve (TN) CLL with this regimen, two separate cohorts were accrued to a phase 2 trial. METHODS Patients with RR or TN CLL requiring therapy were eligible. Patients were required to have ECOG PS ≤1 and preserved end-organ function, including normal serum creatinine or creatinine clearance ≥50 mL/min/m2. RR patients had to have ≥1 prior CLL therapy. Treatment was given at the doses and schedule established in the preceding phase 1b study (Jones ASH 2016) for 14 cycles (C) of 28 days with OBIN, IBR, and VEN started sequentially over the first 3 cycles. Risk for tumor lysis syndrome (TLS) with VEN was assessed according to US prescribing information with monitoring instituted according to risk. Adverse events (AEs) were assessed and graded using the NCI CTCAE v4.03 except hematologic AEs which were graded according to the IWCLL 2008 guidelines. Response was determined according to IWCLL 2008 criteria after C8 (mid-therapy) and 2 months after completing C14 (EOT). MRD was measured in the bone marrow and peripheral blood by standard 10-color flow cytometry at these time points. The primary endpoint was MRD negative complete response at EOT. For each cohort, 25 patients provided at least 90% power to detect an increase in MRD negative complete response rate from 10% to 30% using a single stage design and constraining type I error rate to 10%. Herein, toxicity and mid-therapy responses are presented. RESULTS The study enrolled a total of 50 patients with 25 RR and 25 TN in separate cohorts. Baseline characteristics are in Table 1. The adverse event (AE) profile was similar to the phase 1b study and consistent with the known toxicities of the included individual agents. Frequent treatment-related AEs are found in Table 2. Hematologic toxicity was most frequent with the majority of patients experiencing thrombocytopenia (80%) and/or neutropenia (76%). The most frequent non-hematologic toxicities were hypertension (70%), infusion related reactions (66%), bruising (52%), myalgia (50%), and nausea (50%). Grade 3-4 toxicities were largely hematologic with 56% experiencing grade 3-4 neutropenia and 34% grade 3-4 thrombocytopenia. The only frequently occurring non-hematologic grade 3-4 toxicity was hypertension (32%). The median follow-up for the study was 18.0 months (range 0-24.8) for the RR cohort and 20.6 months (range 7.4-23.9) for the TN cohort. At mid-therapy assessment 23/25 of the RR patients remained on study and all had achieved a response. Three patients achieved CR, 3 a CR with incomplete marrow recovery, and 17 a partial remission. The ORR in RR patients at mid-therapy was 92% (95% CI: 74-99%). Twenty-three (92%) RR patients tested for mid-therapy MRD, with 16 (70%) MRD negative in both the blood and marrow. Two patients had MRD in the blood only, 2 in the marrow only, and 3 in both the blood and the marrow. Mid-therapy responses for the TN cohort have previously been reported (Rogers ASH 2017). To date in 21 (84%) TN patients completed treatment through C14 and 23 (92%) RR remain on study with 21 completing treatment. No patients in either cohort had progressive disease. There was one death from neutropenia and colitis in a TN patient. CONCLUSIONS OBIN, IBR, and VEN in combination have a tolerable safety profile in both RR and TN CLL patients with the majority of toxicities being hematologic. This regimen has a high mid-therapy response rate (92%) in RR patients with early MRD negative responses. EOT responses in TN and RR patients will be presented at the meeting. Disclosures Maddocks: Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Jones:Celgene: Employment, Equity Ownership.

Description: Introduction: Hairy Cell Leukemia (HCL) is a rare, chronic hematological malignancy that makes up approximately 2% of all leukemias. HCL patients are at a markedly increased risk for infection related to a combination of disease-related and treatment-related immunosuppression which has been well described in the literature. However, the significance of infection prior to initiation of HCL therapy and its impact on the subsequent selection of HCL treatment, or outcomes, is not well described. Using the HCL patient data registry, we report here the impact of antecedent infection on the treatment patterns and outcomes of HCL patients. Methods: We evaluated adult (≥18 years) patients with HCL who had information regarding antecedent infections and subsequent HCL treatment during 1984-2018. The primary endpoint was progression-free survival (PFS-1). Secondary endpoint included time to next treatment (TTNT). PFS-1 was measured from the date of first HCL treatment to date of progression/death or last follow-up. TTNT was defined as the time from first HCL treatment to initiation of second HCL treatment. The study population was stratified into 3 groups based on the presence or absence of antecedent infections: no infection prior to first HCL treatment (no infection group), infection within 30 days prior to first HCL treatment (infection1 group) and infection 〉30 days prior to first HCL treatment (infection2 group). Fisher's exact test or Kruskal-Wallis test was used to compare the characteristics among the no infection and infection groups and the Cox proportional hazard model was used to evaluate the association with PFS-1 and TTNT. Results: A total of 205 HCL patients who had information regarding antecedent infections and subsequent HCL treatment were eligible for the study. Among these, 144 (70%) belonged to the no infection group, while 26 patients (13%) belonged to infection1 group and 35 (17%) to infection2 group. Patient characteristics are shown in Table 1 with a breakdown between the three groups. The majority of the patients were Caucasian with a male preponderance and had classic HCL. The patients in the infection1 group had a lower median WBC (K/uL) (1.9 vs 3.1 vs 2.9), particularly the absolute neutrophil count (K/uL) (0.4 vs 0.7 vs 0.8) and significantly lower median hemoglobin (gm%) (10.1 vs 12.2 vs 12.4) relative to the no infection and infection2 groups, respectively (p=0.01). Similarly, a greater proportion of patients in the infection1 group had significant comorbidities (including pulmonary, gastrointestinal and hepatic disease) relative to no infection and infection2 groups as shown in Table 1. The majority of patients received purine nucleoside analogs as their first HCL treatment (no infection group=92%, infection1 group=85%, infection2 group=94%). The median PFS-1 (in years) was better in the no infection group compared to the infection1 group but was not statistically significant (17.0 [95% CI=7.9-not reached (NR)] vs 8.8 [95% CI=4.2-NR], respectively, p=0.98, Figure 1). However, the median TTNT (in years) was significantly longer for HCL patients with no infection versus the infection1 group (6.3 [95% CI=5.4-7.8] vs 3.6 [95% CI=0.7-NR], respectively, p=0.001, Figure 1). On subgroup analysis, relative to the no infection group, median PFS-1 (in years) was not significantly different in infection1 group treated with Pentostatin (10.7 [95% CI=3.53-NR] vs NR [95% CI=1.38-NR], respectively, p=0.43), however, the median PFS-1 (in years) was shorter in the infection1 group treated with Cladribine (17.0 [95% CI=7.67-NR] vs 4.0 [95% CI=2.00-NR], respectively), although not reaching statistical significance (p=0.09) probably due to small sample size. Conclusion: In this large series of HCL patients who received treatment, we show that the patients who had infections at the time of HCL treatment have a significantly shorter TTNT. The reasons for this are unclear but may indicate that patients were unable to receive treatment in a timely manner because of the infection, or were unable to complete treatment because of complications. The significant difference in hemoglobin between the infection1 and other groups indicates the possibility that these patients had more advanced HCL at the time of diagnosis. These findings indicate the potential long term negative impact of infections in patients who need treatment for HCL and reinforce the need for careful management in this setting. Disclosures Lozanski: Beckman: Research Funding; Coulter: Research Funding; Stem Line: Research Funding; Genentech: Research Funding; Novartis: Research Funding; BI: Research Funding. Andritsos:HCLF: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.

Description: Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Description: 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)

Description: Background: Aberrant activation of B-cell receptor (BCR) signaling is considered to be a major oncogenic mechanism that leads to the development and progression of multiple B-cell malignancies. ARQ 531 is a reversible ATP competitive inhibitor of BTK that inhibits ibrutinib-resistant BTK-C481S mutant CLL cells and has demonstrated antitumor activity in CLL, Richter's transformation, and DLBCL mouse models. Objectives: The primary objectives of the clinical study are to assess the safety and tolerability, and to determine the recommended Phase 2 dose and schedule of ARQ 531. The secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity of ARQ 531. Methods: This is a first in human, Phase 1 dose escalation study in patients with relapsed or refractory CLL/SLL, Waldenstrom's macroglobulinemia, or B-cell NHL who received at least 2 prior lines of systemic therapy. Prior therapy must have included a BTK inhibitor, if FDA approved for their disease. 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: A total of 16 patients enrolled (median age 65.5 years, male 93.8%, 2 DLBCL, 2 follicular lymphoma, 12 CLL/SLL, 5 median prior systemic regimens) and were treated at dose levels of 5, 10, 15, 20 and 30mg QD. No dose limiting toxicities have been reported with ARQ 531. Drug related TEAEs included diarrhea, nausea, vomiting, fatigue, pneumonia, amylase increased, lipase increased, neutrophil count decreased, platelet count decreased, decreased appetite, hypernatraemia, arthralgia, groin pain, dizziness, facial paralysis, headache, tremor and restlessness in one patient (6.3%) each. Drug related grade 3 or worse TEAEs included lipase increased and platelet count decreased in one patient (6.3%) each. No drug related serious TEAEs were reported. Among the 12 patients who have received at least 1 dose of study drug and have at least 1 post-treatment tumor measurement data, 5 achieved stable disease (SD) (1 follicular lymphoma, 1 DLBCL, 3 CLL) and 7 had progressive disease (6 CLL, 1 follicular lymphoma). Three of 5 SD patients (1 follicular lymphoma, 1 DLBCL, 1 CLL) had 35%, 34% and 29% tumor reduction and 2 of them are ongoing on study treatment at 53 and 18 weeks. The CLL patient with 29% tumor reduction had BTK C481S mutation. Preliminary PK data showed ARQ 531 exposure was close to dose proportional and the estimated plasma half-life generally ranged from 20-24 hours. Consistent with increases in exposure, pBTK knockdown was observed. In Cohort 4 (20mg QD), all three patients showed 100% pBTK knockdown at a mean plasma Cmax exposure of 300nM (~4h post dose). Levels of CCL3 protein, a plasma biomarker for BCR pathway activation, was significantly suppressed in CLL patients. Conclusions: ARQ 531 has demonstrated a manageable safety profile to date. Diminished pBTK signaling and CCL3 protein levels have been observed in CLL patients. Additionally, preliminary anti-tumor activity has been observed at doses of ARQ 531 that were not predicted to completely inhibit BTK. Updated safety, PK, biomarker and anti-tumor activity data will be presented at the meeting. Disclosures Flinn: Gilead: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Verastem: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Curis: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Calithera: Research Funding; Genentech: Research Funding; Forma: Research Funding; Agios: Research Funding; Constellation: Research Funding; Trillium: Research Funding; Verastem: Research Funding; Portola: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding. Savage:ArQule, Inc.: Employment. Eathiraj:ArQule, Inc.: Employment. Tith:ArQule, Inc.: Employment.