ALBERT

Description: Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p

Description: Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: 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; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Overexpression of the oncomiR, miR-155, is known to be predictive of poor outcome in chronic lymphocytic leukemia (CLL) patients. Using NanoString Technologies’ nCounter platform, we interrogated the miR-155 expression levels in 109 previously untreated CLL patients receiving chemoimmunotherapy on CALGB 9712 or CALGB 10101. The data, dichotomized around median expression, showed that high expressers of miR-155 had shorter progression-free survival (p=0.005) and a higher risk of death after 4 years on study (p=0.004). The expression of miR-155 was not significantly associated with the majority of baseline demographic, clinical and cytogenetic characteristics, including age, Rai stage and high-risk cytogenetics [del(17p)/del(11q)] (p〉0.15). Association of high miR-155 expression with IGHV un-mutated disease(p=0.03) and ZAP70 methylation

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: Restoring nuclear localization of tumor suppressors by blocking exportin 1 (XPO1) holds promise as a new therapeutic paradigm in many cancers, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Oral selective inhibitor of nuclear export (SINE) compounds that covalently modify XPO1 were recently discovered and are exciting new compounds to implement this strategy. Selinexor, the clinical lead SINE, has made progress in Phase I/II clinical trials and is generally well tolerated, but limited to twice weekly dosing, with supportive care. The discovery of novel SINE compounds with improved tolerability is therefore of considerable clinical interest and represents a significant contribution beyond the targeted therapies currently available for hematologic malignancies and a variety of other cancers where upregulation of XPO1 is observed. Presented herein is the discovery of KPT-8602, the next generation SINE compound that shows lower brain penetration, improved tolerability allowing continuous dosing, and improved efficacy beyond any current XPO1 inhibitor. Results: Our crystallography data revealed that KPT-8602 binds covalently to XPO1 through a Michael acceptor that is activated by an electron withdrawing pyrimidyl moiety, allowing a 2-fold increased reversible interaction with XPO1 compared to earlier SINE compounds. The crystal structure of the KPT-8602-XPO1 complex showed interactions between XPO1 and the activating pyrimidyl group. In vitro pull-downs using immobilized GST-nuclear export sequences and purified recombinant XPO1 demonstrated greater reversible binding of KPT-8602 compared to KPT-330 (selinexor). In vivo toxicology studies demonstrated that KPT-8602 possesses lower brain penetration compared to KPT-330 allowing for continuous dosing and improved tolerability. Our results also showed that KPT-8602 induced a comparable level of cytotoxicity as well as inhibition of cell proliferation compared to KPT-330 in primary CLL tumors and in a representative panel of DLBCL cell lines. Furthermore, KPT-8602 inhibited proliferation and induced apoptosis in AML cell lines and primary AML blasts while inducing nuclear accumulation of p53 and NPM1. We hypothesized that these improved pharmacological parameters would allow daily KPT-8602 to abrogate disease progression in CLL and AML animal models. The Eµ-TCL1-C57BL/6 transplant model of CLL was used to evaluate the therapeutic benefit of continuous dosing of KPT-8602. Eµ-TCL1-engrafted mice were treated with KPT-8602 given daily or 2x/week. The KPT-8602 daily cohort had significantly improved survival with a median overall survival of 70 vs 50 days (vs vehicle 33 days), compared to those treated only 2x/week with KPT-8602 (p=0.001). Mice treated with KPT-330 2x/week showed a similar survival to mice treated with KPT-8602 2x/week. Mice given daily KPT-8602 had significantly smaller spleens and reduced circulating leukemic cells compared to all the other groups (p

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: Key PointsAEB071 demonstrates preclinical in vitro and in vivo activity against CLL independent of survival signaling and stromal cell protection. AEB071 can either inhibit or activate the WNT pathway emphasizing the importance of pharmacodynamic monitoring in its development.