Mato, Anthony R.

Abstract Background: Patients (pts) with deletion 17p (del17p) CLL follow an aggressive clinical course and experience poor outcomes with chemoimmunotherapy. Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), is approved for pts with CLL with ≥1 prior therapy and for pts with del17p CLL (including first-line). In the phase 2 RESONATE-17 study (PCYC-1117), ibrutinib demonstrated high efficacy with a favorable risk-benefit profile in del17p CLL/SLL (O'Brien, ASH 2014). We evaluate the baseline genetic features and prognostic factors of these pts to determine their impact on outcome. Methods: Pts with del17p CLL or SLL defined by peripheral blood FISH who failed ≥1 therapy received 420 mg oral ibrutinib once daily until progression or unacceptable toxicity. Using the primary analysis data cut, the overall response rate (ORR; iwCLL 2008 criteria by investigators), progression-free survival (PFS), and overall survival (OS) were assessed by subgroup. Results: Among 144 treated pts (137 CLL, 7 SLL), the median age was 64 (range 36-89). At baseline, 63% of pts had Rai stage III or IV disease, and 39% had received ≥3 prior therapies. Baseline cytogenetics included del11q (16%), del13q (74%), and trisomy 12 (17%), in addition to del17p in all pts. Of 116 pts with valid baseline genomic samples, IGHV status was unmutated in 84%; genomic variants that included mutations, rearrangements, insertions, deletions, and copy number variants affecting coding regions were identified as follows: ATM (14%), BIRC3 (3%), BTK (1%), MYC (2%), MYD88 (2%), NOTCH1 (16%), PLCG2 (3%), SF3B1 (27%), and TP53 (92%), which were consistent with previously identified mutations in pts with CLL (Wang, NEJM 2011; Winkelmann, Haematologica 2015). At a median follow-up of 11.5 months, the investigator-assessed ORR including partial response with lymphocytosis (PR-L) for all treated pts was 83% (17% PR-L). Median PFS and OS were not reached, with 12-month PFS and OS rates of 79% and 84%. Any-grade adverse events (≥15%) included diarrhea (36%), fatigue (31%), cough (24%), arthralgia (22%), nausea (19%), hypertension (19%), anemia (19%), pyrexia (17%), decreased appetite (17%), muscle spasms (17%), neutropenia (17%), and peripheral edema (15%). Serious AEs occurred in 40% of pts (38% ≥ grade 3). ORR, 12-month PFS, and 12-month OS are presented by subgroup for baseline characteristics, cytogenetics, and genomic variants (Table). There were no substantial differences in response rates and survival outcomes in the subgroups with and without baseline cytogenetic aberrations or genomic variants (Table). Response rates were similar for pts with and without NOTCH1 or SF3B1 variants. Of 11 pts with del17p CLL who developed Richter transformation, baseline aberrations included ATM (n=2), SF3B1 (n=3), and/or NOTCH1 (n=3); none had BIRC3 variants. Overall at baseline, there were 3 pts with a PLCG2 mutation (L163F, H193Q, P236L), and 1 with a BTK mutation (R236Q); all achieved a best overall response of PR-L or better. None had received prior therapy with a BTK or PI3K inhibitor. Two pts had a baseline MYD88 mutation (L265P, L142F) with a best overall response of PR in 1 pt. Two pts had baseline MYC amplifications with 5 of 5 exons amplified to 6 and 7 copies, respectively; 1 pt achieved a best overall response of PR. Conclusions: These results provide further evidence of ibrutinib's robust clinical activity and encouraging survival outcomes in this high-risk population regardless of baseline cytogenetic aberrations or genomic variants. The prognostic role of these clinical characteristics and genetic anomalies will continue to be elucidated with longer term follow-up of this population. Figure 1. Investigator-assessed efficacy outcomes by subgroups Figure 1. Investigator-assessed efficacy outcomes by subgroups Disclosures Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jones:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; TA Therapeutics: Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses. Hillmen:AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Osterborg:Gilead: Honoraria; Janssen: Honoraria, Research Funding; GSK: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Thirman:Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment. Hallek:Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract Introduction Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of BTK that has excellent single-agent activity in patients with previously treated CLL/SLL, based on results of published clinical studies. In the HELIOS trial, addition of ibrutinib to BR resulted in an 80% reduction in disease progression or death and confirmed for the first time, in a randomized setting, the benefit of ibrutinib-based therapy compared with standard chemoimmunotherapy (CIT) in previously treated patients (Chanan-Khan et al. ASCO 2015). In patients with CLL or SLL, deletion 17p (del17p) and 11q (del11q), complex karyotype, unmutated IgVH, and elevated ZAP70 are known high-risk prognostic factors. The current analysis reports on the efficacy of ibrutinib + BR vs placebo + BR in patients in the HELIOS trial with relevant high-risk biomarkers. Methods HELIOS is a randomized, double-blind, placebo-controlled, phase 3 study. Patients with active CLL/SLL following ≥ 1 prior therapy were randomized 1:1 to receive BR (≤ 6 cycles) with either ibrutinib (420 mg daily) (n = 289) or placebo (n = 289). Patients with del17p (> 20% of cells) were excluded. Ninety patients in the placebo arm with independent review committee (IRC)-confirmed progressive disease crossed over to ibrutinib, per protocol amendment. The primary end point was IRC-assessed progression-free survival (PFS), and overall survival (OS) was a secondary end point. A total of 287 patients in each arm had data available for at least 1 biomarker, and this population was used for the biomarker analyses. Correlation of biological risk factors at baseline with PFS and OS was analyzed using Kaplan-Meier analysis and curves compared using log-rank tests. Hazard ratios (HRs) were estimated using univariate Cox proportional hazards models. Results At a median follow-up of 17 months, IRC-assessed PFS was significantly longer with ibrutinib + BR vs placebo + BR in the overall study population (median not reached vs 13.3 months, respectively; HR: 0.203; 95% CI: 0.150-0.276; p < 0.0001). All subgroups of patients, including those with adverse prognostic parameters, e.g., del11q, complex karyotype, unmutated IgVH and elevated ZAP70 levels, had a significantly longer PFS with the addition of ibrutinib to BR as compared with placebo + BR (Table 1). As expected, each of these adverse prognostic parameters had a negative impact on PFS in the placebo + BR arm, e.g., the median PFS was shortest in patients with complex karyotype [8.5 months vs 13.8 months in patients without complex karyotype] and in patients with unmutated IgVH (11.3 months vs 22.1 months in patients with mutated IgVH). Interestingly, in the ibrutinib + BR arm, the adverse impact of these risk factors could not be detected (median PFS not reached irrespective of presence of risk factors). For example, in Figure 1 showing the PFS curves stratified by both del11q status and treatment, the outcome for patients in the ibrutinib + BR arm with del11q was similar to those without, with a trend toward better outcome in the del11q patients (e.g., longer PFS - not reached vs 24.9 months), unlike for patients in the placebo + BR arm (11.01 months vs 13.86 months). In patients with del11q, unmutated IgVH, or elevated ZAP70, there were also statistically significant benefits in OS for those receiving ibrutinib + BR vs placebo + BR (del11q: HR: 0.326, 95% confidence interval [CI], 0.122-0.870; p = 0.025; unmutated IgVH: HR: 0.515, 95% CI, 0.298-0.890: p = 0.017; elevated ZAP70, HR 0.536, 95% CI, 0.289-0.994: p = 0.048). Addition of ibrutinib also increased PFS in patient subgroups with other cytogenetic or clinical prognostic markers (such as del13q or bulky disease) compared with placebo. Conclusions All subgroups of patients, irrespective of adverse risk factors, such as del11q, complex karyotype, elevated ZAP70, and unmutated IgVH, benefit from the addition of ibrutinib to BR compared with placebo + BR. The negative impact of these known risk factors is apparent in patients in the placebo + BR arm, but is not seen in patients in the ibrutinib + BR arm. These results suggest that ibrutinib + BR is a suitable treatment regimen for all patients with previously treated CLL/SLL, including those with high-risk prognostic markers. Disclosures Cramer: Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Mundipharma: Other: Travel grant; Glaxo Smith Klein/Novartis: Research Funding; Astellas: Other: Travel grant; Gilead: Other: Travel grant, Research Funding. Fraser:Janssen: Honoraria, Research Funding, Speakers Bureau; Hoffman LaRoche: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Santucci Silva:Janssen: Other: Travel reimbursement, Research Funding; GSK: Research Funding; Celgene: Research Funding; Merck: Research Funding; Novartis: Other: Travel reimbursement; Hoffman LaRoche: Other: Travel reimbursement, Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses; TA Therapeutics: Research Funding. Damle:Janssen: Employment. Phelps:Janssen/J&J: Employment, Equity Ownership. Mahler:Janssen: Employment, Other: Travel reimbursement. Salman:Janssen/J&J: Employment, Equity Ownership. Schaffer:Janssen: Employment. Howes:Janssen/J&J: Employment, Equity Ownership. Balasubramanian:Pharmacyclics LLC, an AbbVie Company: Equity Ownership; Janssen: Employment, Equity Ownership.

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.