Mato, Anthony R.

Abstract Introduction: Rituximab (R) improves survival in CLL when added to intensive chemotherapy (such as fludarabine and cyclophosphamide [FCR]), and has been shown to improve progression-free survival when given as maintenance therapy following first- or second-line chemoimmunotherapy. However, early phase 2 studies demonstrated only modest activity of R monotherapy (R mono), particularly at standard dose, and its use as a single agent for pts with CLL has remained controversial. Here we describe the characteristics and outcomes of pts with CLL receiving R mono in a real-world setting. Methods: The Connect CLL registry (NCT01081015), a multicenter, prospective observational cohort study, enrolled 1,494 pts with CLL between 2010-2014 from 179 community, 17 academic, and 3 government sites throughout the USA. Pts were ≥ 18 years and were enrolled ≤ 2 months after initiating any line of therapy (LOT). Pts were treated according to individual physician/patient decision making, and adherence to IWCLL standards cannot be determined. Bone marrow biopsy and CT scans were at the physician's discretion; responses were physician assessed and not centrally reviewed. For this analysis, pts were stratified by first (LOT1) or subsequent LOT (LOT≥2), and by treatment with R mono or other treatments (Tx). Kaplan-Meier methods were used to estimate event-free survival (EFS; event defined as death, progression/relapse, or transformation). A log-rank test was used to evaluate differences in EFS. A multivariate analysis of EFS in LOT1 pts was performed using the Cox regression model. Results: Of the pts enrolled, 105 (11.8%) pts in LOT1 and 81 (13.4%) pts in LOT≥2 received R mono. Of the pts receiving other Tx, 620/784 pts (79%) in LOT1 and 333/524 pts (64%) in LOT≥2 received R in combination. In LOT1, pts receiving R mono were older than pts receiving other Tx (74 vs 67 years; P < 0.0001); in LOT≥2 median ages were comparable (71 vs 70 years). Pts receiving R mono were more likely to have Rai stage 0-1 CLL than pts receiving other Tx, both in LOT1 (63.9% vs 51.8%; P = 0.05) and LOT≥2 (70.4% vs 49.9%; P = 0.005). The proportion of pts receiving R mono vs other Tx with a CCI score of ≥ 4 was similar in LOT1 (25.7% vs 22.8%) and LOT≥2 (32.1% vs 28.4%). Median absolute lymphocyte count at enrollment was lower in pts on R mono vs other Tx in LOT1 (27.7 vs 46.1 x 109/L) but similar in LOT≥2 (35.6 vs 30.2 x 109/L). A lower proportion of pts receiving R mono had FISH/cytogenetics performed at enrollment than pts receiving other Tx in LOT1 (48.6% vs 67.0%; P = 0.0002) and LOT≥2 (30.9% vs 49.6%; P = 0.002). The most common Tx regimens in LOT1 were FCR (25.9%), bendamustine plus R ([BR] 21.0%), R mono (11.8%), fludarabine plus R ([FR] 6.3%), and chlorambucil (4.6%); and in LOT≥2, BR (27.6%), R mono (13.4%), FCR (8.6%), bendamustine (7.4%), FR (4.1%), and ofatumumab (4.0%). The most common reason to initiate treatment in any LOT was bone marrow failure (LOT1, 44.8% vs 39.3%; LOT≥2, 37.0% vs 31.5%; R mono vs other Tx). Duration of therapy was shorter for pts receiving R mono vs other Tx in LOT1 (1.4 vs 4.1 months) and LOT≥2 (1.6 vs 3.3 months). In LOT1, responses were lower in pts on R mono vs other Tx: overall response rate (ORR) was 38.1% vs 64.2% (complete response [CR], 16.2% vs 41.2%; P < 0.0001). In LOT≥2, ORR was 25.9% vs 24.6% for pts on R mono vs other Tx (CR, 9.9% vs 11.5%; P = 0.68). Partial response did not differ significantly between pts receiving R mono vs other Tx in LOT1 and LOT≥2. Pts receiving R mono in LOT1 had inferior median EFS vs other Tx (34 vs 50 months; log-rank P = 0.04); however, after adjusting for factors such as ECOG status and del(17p) status, there was no difference in EFS (HR 0.932; P = 0.79). In pts in LOT≥2, median EFS was similar for R mono and other Tx (15 months for both groups; P = 0.93). Conclusions: Pts receiving R mono as frontline CLL therapy were older than pts receiving other Tx. They also had lower stage disease and lower lymphocyte counts, a shorter duration of treatment, and inferior response rates. Pts receiving R mono in relapsed CLL, more closely approximated pts receiving other Tx in terms of age. Despite the shorter duration of therapy for pts receiving R mono in LOT1 and LOT≥2, both groups had similar ORR and EFS in LOT≥2. These data reinforce the idea that R mono is inadequate as frontline therapy in progressive CLL, and demonstrate the opportunity for improvement in relapsed/refractory disease with novel agents relative to traditional chemoimmunotherapy approaches. Disclosures Sharman: Celgene: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Research Funding. Davids:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: 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; AbbVie, Janssen, Gilead: Consultancy; Celgene Corporation: Consultancy. Farber:Seattle Genetics: Research Funding. Grinblatt:Celgene Corporation: Consultancy, Speakers Bureau. Lamanna:Gilead: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pronai: Research Funding; Celgene Corporation: Research Funding. Mato:TG Therapeutics: Consultancy; Abbvie: Research Funding; Acerta Pharma: Research Funding; Gilead Sciences: Research Funding; ProNAi: Research Funding; TG Therapeutics: Research Funding; Theradex: Research Funding; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Nabhan:Astellas: Research Funding; Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Employment, Equity Ownership. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Flowers:Seattle Genetics: Research Funding; Optum Rx, Seattle Genetics, Genentech/Roche: Consultancy; Celgene Corporation: Consultancy, Honoraria; Spectrum, Janssen, Infinity, AbbVie, Acerta, Pharmacyclics, TG Therapeutics: Research Funding; Millennium: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.

Abstract Introduction: Given the availability of several active treatment (tx) options for CLL, providers frequently make tx recommendations based on their interpretation of objective data from consensus criteria and clinical trials. There are limited data describing patient (pt) experience, values, and insights when encountering multiple tx choices. The CLL Society, a pt-driven, physician-curated nonprofit organization focused on the unmet needs of the CLL community, sought to explore how CLL pts make tx decisions. Methods: A 64 question survey was distributed online and in paper to CLL pts from Oct-Dec 2017. The survey was developed by CLL experts. The research was IRB-approved. Chi square was used for statistical comparison; all other analyses are descriptive in nature. Results: 1147 pts from 48 states completed the survey. Median age was 65 (range 28-86), 46% male, 96% Caucasian. Who Influences Tx: Of the 79% of pts who have seen a CLL expert, defined as a provider focused on CLL at an academic/research center, 95% rated their provider as very/extremely influential. 83% of pts rated their own opinions as influential, and 59% rated the opinion of a general hematologist/oncologist (gen heme/onc), a provider who sees a variety of cancer types, as influential. Only 27% let their provider unilaterally decide on tx. Of these pts, 19% trusted their provider to select the best tx and 5% didn't have enough understanding to be involved in the decision. 64% were influenced by outside sources of information, such as family members, live CLL support groups, or online sources including pt experts and forums. Factors in Deciding Tx: Of the 67% pts surveyed who have been treated, 73% were offered > 1 tx choice by their provider. In deciding on a specific tx, 94% of respondents stated that it was very/extremely important to know there were tx options beyond their current regimen. The most important factors in selecting tx were response rate (91%), overall survival (88%), progression-free survival (86%), long-term side effects (82%), ability to achieve undetectable MRD (80%), cost/insurance coverage (66%), and location of tx (50%) with significant differences between subgroups (Table 1). Tx was impacted by cost or insurance issues for 16% (n=104). Of these 104 pts, cost/insurance issues resulted in tx delay for 34 and change in tx plan for 24 pts. 16 pts reported that an appeal led to coverage and 16 pts received financial assistance. Pts' willingness to accept potentially curable but high-risk tx was heavily influenced by availability of alternate options. For example, 18% of pts would be willing to consider cytotoxic chemotherapy if alternate options were available vs. 72% if no options were available. Similar patterns were seen with CAR-T tx (28% vs. 79%) and bone marrow transplantation (BMT) (15% vs. 66%) with significant differences between subgroups (Table 2). 82% were willing to take a life-long tx for long-term control without potential for cure. Willingness to accept long-term tx was significantly higher in treated vs. untreated pts (84% vs. 77%, p=.006) and men vs. women (84% vs. 78%, p=.008). Clinical Trial Education: Of those treated by a gen heme/onc, 31% received no education on clinical trials. Only 15% reported good understanding of trial opportunities vs. 52% treated by a CLL expert (p<.001). 9% of pts treated by gen heme/onc were offered clinical trial participation vs. 47% treated by a CLL expert (p<0.001). Pts who declined or would have declined participation cited reasons including preference for "proven" tx (38%), distance from trial site (29%), fear (20%), frequent imaging (20%), overall lack of understanding about trials (15%), and lack of information (14%). Summary: Most respondents want to be and are involved in tx decisions. While providers are influential in decision making, CLL pts also rely on outside sources. Gender, age, and tx status influence which factors drive decision making. Pts select tx based on response rate, survival, side effects, and ability to achieve deep response and want a plan in place for sequencing tx. The majority are willing to consider long-term tx without cure. Few want chemotherapy, CAR-T, or BMT unless they have no other options. A significant opportunity for improvement in education on clinical trial opportunities was identified. This description of pt experience, values, and preferences enriches the informed consent process and may lead to more tailored and patient-centered care. Disclosures Kennard: AbbVie, Gilead, Verastem: Consultancy. Furman:TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Sunesis: Consultancy; Verastem: Consultancy; Incyte: Consultancy, Other: DSMB; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Gilead: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Merck: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy, 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; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: 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; Pharmacyclics: 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; Verastem: Consultancy, Research Funding; Surface Oncology: 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; Pharmacyclics: 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; Celgene: Consultancy; Roche: Consultancy; Pharmacyclics: 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; BMS: Research Funding; Verastem: Consultancy, Research Funding; BMS: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: 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; Sunesis: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Roche: Consultancy. Nabhan:Cardinal Health: Employment, Equity Ownership. Kay:Acerta: Research Funding; Tolero Pharmaceuticals: 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; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees. Siddiqi:Juno Therapeutics: Other: Steering committee. Brander:Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other: DSMB; TG Therapeutics: 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; Acerta: 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. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Hill:Abbvie: 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; Novartis: 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; 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; 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; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Abbvie: 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. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Choi:Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Rigel: Consultancy; Genentech: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau. Mato:AstraZeneca: Consultancy; Prime Oncology: Honoraria; Portola: Research Funding; Johnson & Johnson: Consultancy; Medscape: Honoraria; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Regeneron: Research Funding.

Abstract 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.

Abstract Background: Synthetic lethality (SL) is characterized by the chemical inhibition of multiple aberrant genes to differentially kill malignant cells. We investigated small-molecule combinations for SL through in vitro and in vivo screening and optimization studies (as in the granted patents in USA and China) and demonstrated the synergistic potential of best-in-class combinations of targeted agents, drug repositioning, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition coupled with an IMID will target multiple key signaling pathways, improve differential apoptosis and target acquired drug resistance. DTRM-555, an optimized mechanism-based combination, consists of the clinically differentiated BTK inhibitor DTRMWXHS-12 (or DTRM-12), everolimus (EV) and pomalidomide (POM). In xenograft tumor models, DTRM-555 administered orally has demonstrated superior efficacy over monotherapy at very low dose combinations of the three agents (1/18 of DTRM-12, 1/6 of EV, and 1/6 of POM). DTRM-12 monotherapy has been safe and well tolerated in simultaneous phase Ia trials (US and China) with preliminary efficacy across 50 mg through 400 mg once daily (QD). Here we report the US clinical results of the oral combination therapies DTRM-505 (DTRM-12 plus EV) and DTRM-555 (DTRM-12 plus EV plus POM) for the first time (NCT02900716). Methods: The safety and anti-tumor activity of the oral doublet therapy DTRM-505 and the oral triplet therapy DTRM-555 are evaluated using a "3+3" study design. Enrollment was conducted concurrently with a phase Ia study of DTRM-12 monotherapy; with DTRM-505 opened for accrual when monotherapy DTRM-12 cleared the 200-mg dose level. Eligible patients are at least 18 years old, having ECOG performance status less than 2 with relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or classical Hodgkin lymphoma (cHL). Study treatment is administered daily for 21 consecutive days over a 28-day cycle. The dose-limiting toxicity (DLT) period was defined during the first cycle of therapy, and treatment was continued until disease progression or unacceptable toxicity. Patients underwent tumor evaluations every 2 months and response was recorded using revised response criteria (IWCLL and Cheson 2014). Results: Between 9/2016 and 7/2018, 19 patients have been treated with DTRM-12 monotherapy in the USA (6 pts, 50-300 mg) and China (13 pts, 50-400 mg). Patients have tolerated up to 23+ cycles of DTRM-12 monotherapy. Seven patients, including DLBCL, CLL, MCL, FL and cHL, have been treated with oral doublet therapy DTRM-505 for 2 to 12 cycles. Three patients (2 DLBCL, 1 FL) have been treated with oral triplet therapy DTRM-555, including one patient transitioned from the doublet DTRM-505 under an exploratory arm. No patient has discontinued due to an adverse event (AE) and no DLT has occurred. Recurring AEs are mostly grade 1 or 2 and responses have been seen with DTRM-505 and DTRM-555 across diverse lymphoma histologies (See Tables). All patients evaluable for response demonstrated partial response to DTRM-505 and DTRM-555, with 2/7 (doublet) and 3/3 (triplet) patients remaining on therapy. Conclusion: The maximum tolerated dose has not been reached for DTRM-12 monotherapy and for the current fixed dose doublet and triplet combinations. Toxicities have been mild and repeated cycles of study treatment have been well tolerated without delays of subsequent treatment cycles. Enrollment continues for refractory lymphoma patients to demonstrate the safety and efficacy for the first-in-class oral triplet therapy DTRM-555. Disclosures Huntington: Janssen: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Schuster:Merck: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Dava Oncology: Consultancy, Honoraria; Physician's Education Source, LLC: Honoraria; 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; Novartis Pharmaceuticals Corporation: Honoraria, 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. He:Zhejiang DTRM Biopharma Co. Ltd.: Other: Founder and CEO; Zhejiang DTRM Biopharma LLC: Other: Founder and CEO. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Kennard:AbbVie, Gilead, Verastem: Consultancy. Dwivedy Nasta:Incyte: Research Funding; Takeda/Millenium: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Merck: Other: DSMC; Celgene: Membership on an entity's Board of Directors or advisory committees. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Acerta: 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; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Ding:Merck: Research Funding. Mato:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Research Funding; Celgene: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Portola: Research Funding; Johnson & Johnson: Consultancy; Prime Oncology: Honoraria; Medscape: Honoraria.

Abstract Introduction The natural history of patients (pts) with CLL varies considerably. Some pts may have asymptomatic, indolent disease, while others may require therapy soon after diagnosis. Clinical staging systems cannot identify early-stage pts at risk for inferior survival. Genetic and molecular markers can provide additional information regarding prognosis and response prediction, however their utilization is limited in routine practice (Mato, ASCO 2015) and results can be conflicting. There is a need to identify characteristics of early-stage CLL pts at highest risk of early progression and/or death. Such characteristics, if readily available and reproducible, may identify such pts as candidates for early-intervention studies; particularly in the era of kinase inhibitor therapy. The Connect CLL registry is the largest prospective study describing real-world management of a diverse cohort of 1494 CLL pts. In this analysis, we evaluate key factors that are associated with early CLL-associated mortality in clinical practice. Methods Connect CLL is a multicenter, observational cohort study aimed at understanding patterns of CLL management without a study-specific intervention. Eligible pts were adults with a clinical diagnosis of CLL, enrolled between 2010-2014 at 179 community (n=1311), 17 academic (n=155), and 3 government (n=28) sites within ≤ 2 months of initiating either a first line of therapy (LOT1), or a second-line or subsequent LOT (LOT≥2). The goal of this analysis was to assess potential predictors of death occurring within 18 months following initiation of frontline therapy (LOT1). Because CLL usually presents as an indolent disease associated with a prolonged clinical course, we chose to define early mortality as any death occurring ≤ 18 months following enrollment. Univariate logistic regression was performed against potential predictor variables including several clinical characteristics and comorbid conditions, race, treatment (Tx) site, insurance type, geographic region, presence of prior malignancies, genetic prognostic factors (FISH and cytogenetics) at enrollment, cell surface markers (Zap70, CD38), reasons for Tx initiation and Tx choice for LOT1 (BR or FCR). IgVH mutation status and genetic mutations (P53, Notch1, etc.) were not included as these tests were not readily performed in community practice. Predictors that were found to be significant at the 0.15 significance level were included in the multivariable logistic regression using a stepwise variable selection process, to identify factors associated with early mortality. Results 1344 pts completed 18 months of follow-up (n=1111) or died (n=233) within the first 18 months of study enrollment. Of these, 801 pts were enrolled in LOT1 (median time from diagnosis to LOT1 was 1.3 yrs; IQR, 0.1-3.7 yrs). 82 of 801 pts (10.2%) died within 18 months of LOT1 initiation; 41% of pts with available clinical information who died, were defined as early-stage (Rai stage 0-1). Of 26 potential predictors evaluated, 12 were associated with early mortality among LOT1 pts at the 0.15 significance level in univariate analyses including site, race, age>75, CD-38, del(17p), ECOG PS, CCI group, RAI stage, creatinine clearance, insurance status, reasons for Tx initiation, anemia and lymphocytosis. In multivariable logistic regression analyses we identified 4 independent predictors of mortality within 18 months of LOT1 initiation (Table): pt age, CD38 expression, baseline decreased hemoglobin (as a reason for Tx initiation), and race. Conclusions In CLL pts with Rai stage 0-1, we have identified 4 factors which are associated with increased risk of death within 18 months of initiation of frontline therapy. Interestingly, neither choice of FCR vs BR chemoimmunotherapy nor the presence of del(17p)/del(11q) were predictors of early mortality. Using these results, we are currently designing a model to predict early mortality in early-stage pts. Once validated, these results may provide a framework for trials targeting the "early stage, symptomatic" CLL pts for novel interventions. Table. Multivariable Analysis: Predictors of Early Mortality Odds ratio estimate 95% CI P -value LOT1, n=781 Age ≥75 years, yes vs no 2.2 1.4-3.5 0.0012 CD38 expression, positive vs negative/not specified 1.8 1.1-2.9 0.0182 Anemia as reason for treatment, yes vs no 2.1 1.3-3.4 0.0040 Race, other vs Caucasian 1.9 1.0-3.8 0.0501 Disclosures Farber: Gilead: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Mato:TG Therapeutics: Research Funding; Genentech: Consultancy; AbbVie: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Janssen: Consultancy. Nabhan:Celgene Corporation: Honoraria, Research Funding. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Flowers:Spectrum: Research Funding; Pharmacyclics: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; Spectrum: Research Funding; Genentech: Research Funding; Onyx Pharmaceuticals: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy; Onyx Pharmaceuticals: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Celegene: Other: Unpaid consultant, Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding. Kay:Pharmacyclics: Research Funding; Hospira: Research Funding; Genentech: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Kozloff:Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Calistoga: Honoraria; Roche: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

Abstract Introduction: Results of several large clinical trials have demonstrated inferior outcomes when CLL patients (pts) with del(17p), or to a lesser extent del(11q), are treated with chemoimmunotherapy. Despite recent advances in targeted therapies, management of unfavorable-risk CLL pts remains challenging. The Connect CLL registry is the largest prospective study describing real-world management of a diverse cohort of CLL pts. Here we describe the management of genetically unfavorable-risk CLL pts enrolled in the Connect CLL Registry, and test associations between del(17p)/del(11q) mutations and treatment choice, timing of therapy, and outcomes. Methods: Connect CLL is a longitudinal, multicenter, observational cohort study of 1,494 CLL pts enrolled between 2010-2014 at 179 community (n=1,311), 17 academic (n=155), and 3 government (n=28) sites within ≤ 2 months of initiating any line of therapy (LOT). For this study, pts were categorized into 3 risk-groups based on FISH or cytogenetic results at enrollment: unfavorable risk [either del(17p)/del(11q) positive]; favorable risk [absence of del(17p)/del(11q)]; and unknown risk (testing not performed). Analyses were stratified by LOT at enrollment (LOT1 vs LOT≥2). The risk of an EFS defining event was compared across risk-groups stratified by LOT, including only pts who had been followed for ≥ 2 years (yr) or those who had an EFS defining event (death, progression/relapse, transformation) within 2 yr, using multivariable (MV) logistic regression. Logistic regression analyses of 18 potential predictors were performed, and significant predictors (0.10 significance level) were then included in a MV logistic regression model to identify factors associated with inferior 2 yr EFS. Results: Of 1,494 pts enrolled, 225 had unfavorable risk [del(17p), n = 94; del(11q), n = 131], 621 favorable risk, and 648 unknown risk. For pts enrolled at LOT1 (n = 889), 141 had unfavorable risk, 425 favorable risk, and 323 unknown risk. Baseline characteristics for unfavorable-risk pts in LOT1 included: median age 69 yr (62% age ≥ 65 yr); 91% White; 53% Rai stage ≥ 2; 86% community sites; 0.9 yr median time from dx to LOT1; 8% family history CLL. With the exception of age, unfavorable-risk pts treated at LOT1 with FCR (median age 63) and BR (median age 74) had similar demographic characteristics. Median time from dx to LOT1 was 1.0, 1.3, and 2.0 yr for unfavorable risk, favorable, and unknown-risk pts, respectively (P < 0.001 for comparison of the 3 risk-subgroups). Reasons for initiating treatment in unfavorable-risk pts were lymphadenopathy (42%), bone marrow failure (36%), and lymphocytosis (33%) (similar across the 3 risk-subgroups). The three most common therapies for unfavorable-risk pts in LOT1 were FCR (36%), BR (21%), and FR (6%). Favorable-risk (FCR 26%, BR 24%, and R 10%) and unknown-risk pts (FCR 22%, BR 18%, and R 17%) were treated similarly in LOT1. Median time from dx to LOT≥2 was 3.5 yr in unfavorable-risk pts (vs 4.1 yr in favorable and 4.6 yr in unknown risk pts; P = 0.04 for comparison of the 3 risk-groups). For unfavorable-risk pts in LOT≥2, BR (26%), R (11%), and FCR (10%) were most commonly prescribed. At any LOT, only 10% of unfavorable-risk pts participated in a clinical trial and 4% underwent allogeneic SCT. Overall, 33% (LOT1) and 68% (LOT≥2) of pts experienced an EFS defining event within 2 yrs. Pts with unfavorable risk (vs favorable risk) had significantly worse outcomes, with a higher-risk of death/progression/relapse/transformation within 2 yr (LOT1: 42% vs 29%, respectively, P = 0.008; and LOT≥2: 80% vs 61%, P = 0.004). Unfavorable-risk pts treated with either FCR or BR at LOT1 had similar risk of an EFS defining event (odds ratio [OR] 0.9, CI 0.6-1.5). Results from MV analyses of LOT1 pts identified unfavorable risk (OR 1.9; 95% CI 1.1-3.1; P = 0.0168) and age ≥ 75 years (OR 2.6; 95% CI 1.5-4.3; P = 0.007) as independent predictors of inferior EFS at 2 yr. Conclusions: Although similar treatment approaches were used among the 3 risk-subgroups, pts with unfavorable-risk CLL had inferior outcomes at LOT1 and LOT≥2. These results, from a real-world setting, validate the findings for unfavorable risk pts from large clinical trials. These data underscore the importance of performing genetic risk stratification on all CLL pts, and support consideration of clinical trials and/or B cell receptor targeted agents for unfavorable risk CLL pts when treatment is considered. Disclosures Mato: Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Nabhan:Celgene Corporation: Honoraria, Research Funding. Flowers:Celegene: Other: Unpaid consultant, Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Onyx Pharmaceuticals: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Spectrum: Research Funding; Millennium/Takeda: Research Funding; Pharmacyclics: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Acerta: Research Funding. Kay:Pharmacyclics: Research Funding; Genentech: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: 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, Research Funding; Hospira: Research Funding. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Calistoga: Honoraria; Roche: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding.

Key Points Early progression of disease within 2 years of initial therapy independently predicts inferior survival in CLL. Early progression of disease is a robust clinical end point and a useful posttreatment risk stratification tool.

Abstract The majority of pts with newly diagnosed CLL are classified with Rai stage 0 or 1 disease and typically experience an indolent clinical course. However, little is known regarding the reasons for initiating therapy in this population or patterns of initial treatment in the contemporary era of our practicing community. We utilized data from the Connect CLL registry, a US-based multi-center, prospective observational cohort study that is aimed at understanding patterns of CLL management without a study-specific intervention. Eligible pts were adults with a clinical diagnosis of CLL who initiated therapy ≤2 months prior to enrollment, and were enrolled from academic (n=155), community (n=1311), or government (n=28) sites between 2010-2014. Descriptive statistics were applied to examine data on demographics, baseline characteristics, treatment selection, early treatment outcomes, and reasons for initiating therapy that were reported for pts with Rai 0/1 CLL receiving first-line therapy. Multivariable logistic regression models were constructed to evaluate predictors of complete response (CR) and event-free survival (EFS) defined as the occurrence of the first of disease progression, relapse or death within 24 months of enrollment. Among 684 pts who received first-line therapy at enrollment and for whom Rai stage was available, 363 had Rai 0/1 CLL. This group had a median age of 68 years (range 41-90); 94% were white, 60% male, 98% insured, and 93% were treated in community practices; 47% had Rai stage 0 disease (54% Binet A); 33% had ≥1 constitutional symptoms; 96% had ECOG performance status of 0 or 1; 35% had conventional cytogenetics and 53% had FISH analysis performed. Among pts for whom cytogenetic or FISH analysis were performed, 159 (72%) were abnormal, of them 37 pts (23%) had del(11q), 104 pts (65%) had del(13q), 33 pts (21%) had trisomy 12, and 20 pts (13%) had del(17p) by conventional cytogenetics and/or FISH, including 8% with del(17p) by FISH. The median time from diagnosis to initiation of therapy was 2.5 years (range 0-20 years) for Rai 0/1 pts compared with 0.5 years for pts enrolled with Rai stage ≥2 (range 0-32). The most common reasons for initiating therapy (with >1 reason possible) in Rai 0/1 CLL were: bulky or progressive or lymphadenopathy (40%), progressive lymphocytosis (39%), any disease-related symptom (weight loss, fatigue, fever, night sweats; 28%), anemia (20%), and thrombocytopenia (15%); 42% of pts had >1 reason for initiation. The most common first-line regimens used in this cohort were: fludarabine/cyclophosphamide/rituximab (FCR; 29%), bendamustine/rituximab (BR; 20%), and rituximab alone (12%). Of the 317 pts who either responded to treatment during the first 24 months of enrollment or were followed ≥24 months, 143 pts (45%) achieved CR (investigator assessed as per protocol) and 264 (83%) achieved CR or partial response. Female gender (odds ratio [OR] = 2.22), treatment with BR or FCR (OR = 3.41), and time from diagnosis to therapy (OR = 0.92; with each year increase in time from diagnosis to initiation of therapy, relative odds of CR decreases by 8%), were independent predictors of CR. Of the 311 evaluable pts, 82 pts (26%) experienced an EFS event during the 24 months on study, of which 19 (23%) were deaths and 48 (59%) were progressions. Age ≥75 years (OR = 4.46), lymphocytosis as a reason for therapy initiation (OR = 1.89), and male gender (OR = 1.73) were independent predictors of an EFS event within 24 months. The Connect CLL registry represents the largest comprehensive prospective cohort of CLL pts collected from multiple practices across the US. In concordance with other studies, pts with Rai 0/1 initiated therapy approximately 2.5 years following CLL diagnosis and included a cohort of pts with poor prognostic FISH characteristics. Although chemoimmunotherapy was associated with a significantly higher likelihood of CR, progressive lymphocytosis as a reason for initiating therapy (and not any form of treatment) was more likely to predict an early EFS event. Approaches using novel agents or combination therapies aimed towards addressing pts with progressive lymphocytosis should be considered in future studies. Disclosures Flowers: Seattle Genetics: Consultancy; OptumRx: Consultancy; AbbVie: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding. Nabhan:Celgene Corporation: Honoraria, Research Funding. Kay:Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharma: Research Funding. Mato:AbbVie: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Kozloff:Roche: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Calistoga: Honoraria; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding.