ALBERT

Description: Introduction The oral BTK inhibitor ibrutinib was recently approved for frontline CLL therapy based on RESONATE-2, which included only patients (pts) age ≥65 (Burger et al., 2016). In the absence of comparative data, FCR remains a standard initial therapy for younger CLL pts, particularly in light of recent data suggesting that mutated IGHV predicts long disease free survival after FCR (Thompson et al., 2016, Fischer et al., 2016). However, pts with higher risk CLL such as del(17p) and unmutated IGHVhave less durable responses. Moreover, only about 20% of CLL pts will achieve complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) with frontline FCR (Boettcher et al., 2012). Given the favorable toxicity profile and substantial efficacy of ibrutinib across CLL risk types, we developed an investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548). Methods The primary objective is to determine the rate of CR with BM MRD-neg in younger CLL pts treated upfront with iFCR. Secondary endpoints include response rate, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is started 7 days prior to FCR, which is given at standard doses together with ibrutinib for up to 6 cycles. Responders continue on ibrutinib maintenance until progression or unacceptable toxicity. Growth factor support and antimicrobial prophylaxis are mandatory. Eligibility criteria include: age ≤ 65, requiring initial treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. CTCAE v4 and IW-CLL criteria are used to evaluate toxicity and efficacy, with response evaluations after 3 cycles, 2 mos. after final FCR (primary endpoint evaluation), and q6 mos. thereafter. MRD is assessed by 4-color flow cytometry (10-4sensitivity). Results As of August 1, 2016, the study reached full accrual at 35 pts. The median age at enrollment was 55 yrs (range 38-65). 9/33 tested (27%) had del(11q) and 4/33 tested (12%) had del(17p). Unmutated IGHV was present in 20/31 tested (65%), ZAP-70 was positive in 21/32 tested (66%), TP53 mutation was present in 2/31 tested (6%), and NOTCH1 mutation was present in 2/21 tested (10%). We initially enrolled 10 pts in a safety lead-in cohort and did not see any unexpected toxicities. In the entire cohort of 35 pts, hematologic toxicity included grade (gr) 4 neutropenia in 1 pt (3%), as well as gr 3 neutropenia (15%), thrombocytopenia (18%), and anemia (6%). All grade non-hematologic toxicities occurring in 〉15% of pts included nausea (68%), bruising (35%), fatigue (29%), and rash (21%) (all gr 1/2) and diarrhea (21%) (all gr 1). The only bleeding events were gr 1 epistaxis in 2 pts. SAEs included gr 4 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumonia, and gr 3 appendicitis in 1 pt each. 9% of pts experienced ≥gr 3 infection. A median of 6 cycles of FCR were given (range 3-6). One pt had ibrutinib dose reduction (pt with febrile neutropenia), and 18% of pts had at least 1 dose reduction of chemotherapy. Twenty-eight pts have undergone primary endpoint re-staging after completing the iFCR combination and 26 pts have been tested for BM MRD. In these 26 pts, the rate of CR with BM MRD-neg is 39% (10/26). In the 28 pts with re-staging, the ORR is 100%, including 39% (11/28) with CR or CRi. 17/28 (61%) pts had a PR, and all 17 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. BM was MRD-neg in 23/26 tested (89%), including 13/17 (76%) of pts in PR. With a median follow-up of 12.1 months (range 0.1-21.1), all pts are alive, and 33 of the 35 pts remain on treatment. One pt who completed 6 cycles of iFCR and achieved CR with BM MRD-neg declined ibrutinib maintenance and remains in MRD-neg CR at 10 months off therapy, and one pt with del(17p) achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant. Conclusions iFCR induces deep responses in previously untreated young CLL pts, with 39% of evaluable pts achieving CR with BM-MRD-neg and 89% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities were observed, possibly due to mandatory use of growth factor support and antimicrobial prophylaxis. 76% of PR pts have achieved BM MRD-neg, and all of these pts have small residual lymph nodes. Pts continue on ibrutinib maintenance and will be monitored for conversion to CR with BM MRD-neg. over time. Disclosures Davids: Genentech: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Abramson:Gilead: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Consultancy. Fisher:Pharmacyclics: Consultancy. Brown:Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy.

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

Description: Background: Venetoclax (Ven), an orally bioavailable BCL2 inhibitor, is approved as monotherapy (Ven-mono) and in combination with rituximab (R; VenR) for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and combined with obinutuzumab in 1L CLL. Herein, we present the long-term efficacy data, including durability of response of continuous and fixed-duration therapy, from the initial phase 1b study (Seymour, et al. Lancet Oncol. 2017) of VenR in R/R CLL with median follow-up on study of 4.9 yrs. Methods: Pts with relapsed CLL received Ven daily (200 - 600 mg) and 6 - 9 doses of R over 6 mo, then Ven-mono (NCT01682616). Minimal residual disease (MRD) was assessed in bone marrow (BM) using multicolor flow cytometry (1 pt were pneumonia (n=2) and osteoarthritis (n=2). Thirty-three pts (67%) achieved CR or BM uMRD by 12 mo and opted to remain on Ven-mono (n=15) or stopped therapy with Ven due to good response (n=18) and stayed on study; DOR and PFS estimates using Kaplan-Meier methodology are presented in the Table. Of the 16 pts not achieving CR or uMRD by 12 mo and continuing therapy, all subsequently discontinued the trial (withdrew consent [n = 2], AEs [n = 2], progressive disease [PD] with CLL [n = 7], or Richter transformation [n = 5]). One pt (1/16) had PD at 36.9 mo (best response on therapy was partial response [PR]) and received an additional round of R treatment starting at 51.9 mo, but the disease did not respond to intensified treatment and the pt came off Ven at 58.4 mo. Of the 15 pts (CR or BM uMRD by 12 mo) who remained on Ven-mono long-term, PD occurred in 5 pts and 1 pt died in ongoing response due to myocardial ischemia (unrelated) (Figure). Two pts received an additional round of R treatment after PD, one at 55.3 mo (achieved uMRD CR [DOR post-R, 11.3+ mo]) and the other at 70.5 mo (recently restarted R). At data cut-off, 10 pts were in remission: 6 in CR (including 1 pt retreated with R and 1 pt who recently stopped Ven after 4.3 yr due to being disease-free) and 4 in uMRD PR. Response for the last pt post-R retreatment is pending. Of the 18 pts who stopped Ven in deep response (14 uMRD CR, 2 MRD-positive CR, 2 uMRD PR [Figure]), the median time on Ven prior to cessation was 16 mo (5 - 40) and median time off Ven is 40.3 mo (1.1 - 70.0) to date. Four have discontinued study without progression (withdrew consent [n = 2], elected for stem cell transplant [n = 1], lost to follow-up [n = 1]). Four pts (2 MRD-positive CR and 2 uMRD CR) had PD after stopping Ven (all asymptomatic) at 25.5, 29.0, 33.3 and 42.0 mo off Ven and have been re-treated with VenR or Ven-mono, and 3 have been re-evaluated for response. All achieved at least PR (2 without BM assessment so unevaluable for CR), with 2 having ongoing response. One pt with PR but residual BM infiltrate had subsequent PD 18 mo later. The fourth pt was recently re-treated with Ven-mono; response is pending. Two additional pts had PD off Ven and had not been re-treated as of the data cutoff; both remain on study. Conclusions: In relapsed CLL, VenR induces deep responses within 12 mo in 67% of pts. These responses are highly durable whether on continuous or limited duration therapy, with treatment-free remissions of 〉4 yr now being observed. Re-treatment of pts with Ven or VenR re-exposure has resulted in response in some pts. In addition to long PFS, which represents time to first PD or death, pts who cease Ven in deep response have the opportunity for further disease control through reintroduction of Ven. Disclosures Brander: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding. Seymour:Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Kipps:Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, 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; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Ma:Abbvie: Research Funding; Beigene: Research Funding; Janssen: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Kite: Consultancy; Bioverativ: Consultancy; Incyte: Research Funding; Juno: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Xeme: Research Funding. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Masud:AbbVie: Employment, Other: Stock/stock options. Nandam:AbbVie: Employment, Other: Stock/stock options. Jacobson:AbbVie: Employment, Other: Stock or options. Roberts:Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; BeiGene: Research Funding.

Description: Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p

Description: Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date. Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive. Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p

Description: Background Studies from the chemoimmunotherapy (CIT) era and more recently with venetoclax have demonstrated the correlation between minimal residual disease (MRD) response measured by at least four-color flow cytometry (FC), and progression free (PFS) and overall survival (OS) in CLL. Despite high overall (ORR) and complete (CR) response rates observed with fludarabine-based combination CIT, the ability to achieve sustained undetectable MRD (uMRD) remission is lacking for the majority of patients treated with these regimens. We have previously reported on the promising combination of ibrutinib plus FCR (iFCR), which demonstrated a 98.8% ORR, 32.9% CR/CRi with bone marrow (BM) uMRD at EOT, and 77.7% BM-uMRD by flow at EOT (83.5% at best response) [Davids et al, Lancet Haematology, 2019]. Adaptive's next generation sequencing (NGS)-MRD assay targets immunoglobulin receptor sequencing with up to 10E-6 sensitivity for detection of B-cell malignancies. Here we present expanded MRD analysis by standard flow cytometry and the first results assessed using NGS-MRD, focusing on mid-FCR (C3) and 2 month post-FCR (EOT) timepoints. Methods iFCR is a multicenter single-arm phase 2 trial at seven sites in the USA. 85 patients aged 65 years or younger with previously untreated CLL were enrolled and treated with iFCR as previously published [Davids, Lancet Haematology, 2019]. Per protocol analyses of MRD in both peripheral blood (PB) and BM by standard four-color FC were performed at local laboratories at C3. Both PB and BM samples were submitted to Adaptive for NGS-MRD evaluation at EOT. Forty-eight patients had paired BM and PB samples with 16 additional PB only samples. NGS-MRD status was evaluated at 10E-5 and 10E-6 levels, and defined as positive if ≥ 1 rearrangement was detected per 100,000 or per million cells, respectively. An indeterminate finding was reported if insufficient cells were assayed, as NGS-MRD testing is limited by the number of cells evaluated, which can often be lower than needed for 10E-6 sensitivity, particularly in PB. Results At the C3 restage, the BM-uMRD rate by flow was 47%, with 100% concordance to flow PB-uMRD status in all patients with BM-uMRD. However, 33% (12/36 evaluable) with detectable cells in marrow had PB-uMRD, demonstrating enhanced sensitivity of BM-MRD testing as shown in Table 1. At EOT, BM-uMRD rates rose to 78%, compared with 86% in PB, including 14/24 patients converted from BM-pos/PB-pos to BM-neg/PB-neg and 7/12 BM-pos/PB-neg to BM-neg/PB-neg. In NGS-MRD analysis from 48 patients with evaluable BM and PB samples at EOT, a larger number of patients were MRD positive in BM (n=21; 43.8%) vs. PB (n=13; 27.1%) (McNemar test: p=0.04). Figure 1 illustrates the improving detection of residual disease in both BM and PB with increasing sensitivity, with greater detection in BM; 54% positive at 10E-6 sensitivity in this cohort, compared with 36% in PB. Evaluation for true negative samples at 10E-6 sensitivity was limited by samples with inadequate cells for evaluation (indeterminate), hence definite uMRD was seen in only 23% BM and 9% PB. Fifty-two patients with PB-uMRD by FC at EOT had associated PB NGS-MRD results: 10 PB-uMRD by FC were positive at 10E-5 with 8 additional positive at 10E-6 (35% greater than FC). Similar results were observed in BM: of forty-four patients with BM-uMRD by FC at EOT, 13 were positive at 10E-5 with 9 additional positive at 10E-6 by NGS-MRD (50% greater than FC), summarized in Table 2. When this higher sensitivity BM-uMRD data is used to define overall clinical response at EOT, the CR/CRi with BM-uMRD rate at 10E-5 is 32.6% (14/43), and at 10E-6 is 16.2% (6/37), compared to 43.8% (21/48) using four-color FC. The rate of BM-uMRD would be 60.5% (26/43) at 10E-5 sensitivity and 29.7% (11/37) at 10E-6, with NGS-MRD. Discussion This first report of NGS-MRD testing after iFCR demonstrates that 50% of patients with BM-uMRD by flow cytometry have detectable CLL cells at the level of detection of ≥ 1 per million cells. While iFCR has improved upon historical uMRD results by four-color flow cytometry, these findings suggest that CLL cells are still frequently present. Longer follow-up will be required to correlate these minimal levels of residual disease with PFS in this setting. Future studies should incorporate NGS-MRD assessment with larger volume cell sampling to ensure adequate sensitivity and evaluate venetoclax-based regimens. Disclosures Brander: Novartis: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Research to Practice: Honoraria. Brown:Novartis: Consultancy; Sunesis: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; AbbVie: Consultancy; Morphosys: Other: Data safety monitoring board; Pharmacyclics: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria.

Description: Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in 〉25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in 〉10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: 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, Other: Travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Description: Background : Prior to the approvals of ibrutinib (ibr), idelalisib, and venetoclax, data from the Connect CLL registry showed that across 199 US centers only 65% of patients (pts) had FISH testing and 6% had IGHV testing performed prior to the first chronic lymphocytic leukemia (CLL)-directed treatment (tx), and 40% had repeat FISH testing prior to a subsequent therapy (Mato, Br J Haematol 2016). In today's era, molecular-genetic testing should be universally performed to guide tx decisions for pts with CLL, particularly for pts with 17p deletion (del[17p]), TP53 mutation, and/or unmutated IGHV (U-CLL), as recommended by several guidelines. Whether the widespread availability of novel agents has improved prognostic testing patterns and if those results are appropriately utilized in selecting therapies remain important unanswered questions. InformCLL (NCT02582879) is a US, multicenter, prospective, observational real-world registry of pts with CLL receiving various lines of tx across 150 centers (96% community, 4% academic). This analysis describes rates of prognostic testing in pts with CLL stratified by line of therapy, proportions of pts with specific abnormalities, and current tx patterns in clinical practice in this registry. Methods : Enrollment began in Oct 2015. Eligible pts had to be ≥18 years (y), start approved anti-CLL tx within 30 days of enrollment, and provide consent. First tx at enrollment was classified into 5 groups: chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), ibr, and other novel agents. For this interim analysis (data cut: Feb 2018), the number of pts with CLL who had testing performed for FISH, TP53 mutational status, and IGHV mutational status, as well as CLL tx for subgroups of pts stratified by abnormality, was summarized as frequency counts and percentages. Results : At the time of this analysis, the registry had enrolled 840 pts (459 previously untreated; 381 relapsed or refractory [R/R]). The majority of pts were male (64%) and Caucasian (92%); median (range) age was 70y (34-95), and median (range) Charlson Comorbidity Index was 2 (0-9). Overall, prognostic biomarker testing was performed infrequently. Among all pts (N=840), 262 (31%) had FISH testing, 89 (11%) had testing performed for TP53 mutation, and 94 (11%) had testing for IGHV mutational status (Table 1). Among 459 pts tested prior to first-line tx, 164 (36%) had testing for FISH, 54 (12%) for TP53, and 55 (12%) for IGHV; among 381 R/R pts, 98 (26%) had testing for FISH, 35 (9%) for TP53, and 39 (10%) for IGHV. For tested pts, 70/262 (27%) pts had del(17p), 23/89 (26%) had mutated TP53, and 69/94 (73%) had U-CLL. For previously untreated tested pts, 47/164 (29%) had del(17p), 14/54 (26%) had mutated TP53, and 35/55 (64%) had U-CLL; for tested R/R pts, 23/98 (23%) had del(17p), 9/35 (26%) had mutated TP53, and 34/39 (87%) had U-CLL. Among 70 pts with del(17p), the most common tx was ibr (n=38; 54%); however, a considerable proportion of pts received CT/CIT (n=24; 34%) (Table 2). In 47 previously untreated pts with del(17p), 27 (57%) received ibr and 16 (34%) received CT/CIT; in 23 R/R pts with del(17p), 11 (48%) received ibr and 8 (35%) CT/CIT. Among 23 pts with mutated TP53, 15 (65%) were treated with ibr, while 7 (30%) with CT/CIT. Of 14 previously untreated pts with mutated TP53, 9 (64%) received ibr and 5 (36%) CT/CIT; of 9 R/R pts with mutated TP53, 6 (67%) received ibr and 2 (22%) CT/CIT. Among 69 pts with U-CLL, 30 (43%) were treated with ibr and 32 (46%) with CT/CIT. In 35 previously untreated pts with U-CLL, CT/CIT was more common (n=20; 57%) than ibr (n=13; 37%), while in 34 R/R pts with U-CLL, ibr was more common (n=17; 50%) than CT/CIT (n=12; 35%). Conclusions : There remains a considerable lack of prognostic marker testing among pts with CLL in the modern era. These findings, as compared to prior registry results, suggest that the advent of novel agents and specific testing guidelines (eg, iwCLL) have not improved prognostic testing patterns in the real-world setting. Moreover, of pts tested who had abnormalities such as del(17p), TP53 mutation, or U-CLL, approximately one-third still received CIT. These results underscore a need to educate on how to utilize these markers to guide CLL tx decisions for optimal clinical outcomes. Additional evaluations (eg, regression analyses) to identify factors associated with failure to perform FISH, TP53, and IGHV testing are planned. Disclosures Mato: Portola: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Johnson & Johnson: Consultancy; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Barrientos:Janssen: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Brander:BeiGene: 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; Novartis: Consultancy, Other: DSMB; DTRM: 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; TG Therapeutics: 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. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Kadish:Pharmacyclics, an AbbVie Company: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Ghosh:Celgene: Consultancy; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; Forty seven Inc: Research Funding; TG Therapeutics: Honoraria, Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Genentech: Research Funding; Spectrum: Consultancy; Abbvie: Consultancy, Speakers Bureau; Juno: Consultancy, Research Funding. Giafis:Pharmacyclics, an AbbVie Company: Employment, Other: Travel; AbbVie: Equity Ownership. Ipe:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie Company: Employment, Other: Travel. Upasani:Pharmacyclics, an AbbVie Company (self and immediate family member): Employment; AbbVie (self and immediate family member): Equity Ownership. Sundaram:AbbVie: Employment, Equity Ownership, Other: Travel; Johnson & Johnson: Employment, Equity Ownership, Other: Travel. Ferrante:Janssen: Employment, Equity Ownership. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Iyengar:Pharmacyclics, an AbbVie company: Employment; AbbVie: Equity Ownership; Express Scripts: Patents & Royalties. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding.

Description: Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor which exhibits a differentiated safety profile from other PI3Kδ inhibitors, both approved and in development, and has demonstrated activity in patients (pts) with advanced heme malignancies (ASH 2014). Herein we present updated safety and efficacy results from a Ph I study of TGR-1202 in pts with rel/ref CLL and lymphoma. Methods: TGR-1202 is administered orally once-daily (QD) following a 3+3 dose escalation design. Eligible pts have rel/ref non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other B-cell malignancy and an ECOG PS ≤ 2. Endpoints include safety, PK/PD, and efficacy. Results: As of August 2015, 75 pts are evaluable for safety including pts with CLL, FL, Hodgkin's (HL), DLBCL, MCL, and MZL. Patients had a median age of 65 yo (range: 22-85), 67% male, ECOG 0/1/2: 26/47/2, median prior Tx: 3 (range: 1-14), and 49% refractory to prior Tx. No Gr≥3 AEs were observed in ≥10% of pts. AEs (all grades, all causality) in 〉20% of pts were limited to nausea (44%, Gr3/4 0%), diarrhea (36%, Gr3/4 1%), and fatigue (31%, Gr3/4 3%). Notably, general tolerability and the incidence of hepatotoxicity and colitis appear significantly less than that reported with other agents in this class. Expansion cohorts are open at 800 mg, 1000 mg, and 1200 mg QD. Of 16 evaluable CLL pts, 15 (94%) achieved a nodal PR (median nodal ↓ of 76%), of which 10 (63%) achieved a PR per Hallek 2008 criteria. Among the 32 evaluable NHL patients, 10 achieved an objective response, including 3/11 evaluable patients with DLBCL, while responses have been limited in pts with MCL (1/5) and HL (1/9). Of the 16 evaluable indolent NHL (FL & MZL) pts, 14 (88%) have achieved reductions in tumor burden with 6 pts on study for over 12 cycles (and durations upwards of 29+ cycles), with 5/12 FL and 1/4 MZL pts achieving an objective response to date. Notably, a strong exposure-response relationship has been observed. Of the 24 patients starting TGR-1202 at 800 mg or 1200 mg of the micronized formulation, 19 (79%) remain on therapy, with 9/18 (50%) evaluable pts (6 too early to evaluate) achieving an objective response to date (range on study 3 - 49+ weeks). Conclusions: TGR-1202 is well tolerated in pts with rel/ref heme malignancies with a distinct safety and tolerability profile from other PI3K-delta inhibitors (with 43% of pts on study 6+ Cyc) and promising activity in CLL and NHL. Enrollment continues in expansion cohorts and registration directed Phase 3 studies are planned. Disclosures Flinn: Celgene Corporation: Research Funding. Fenske:Millennium/Takeda: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy; Otsuka American Pharmaceutical: Consultancy; Azaya Therapeutics: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership.

Description: Introduction: Lenalidomide is an immunomodulatory small molecule with efficacy in CLL, though monotherapy responses are typically partial and delayed. Plerixafor, a small molecule inhibitor of the CXCR4 receptor responsible for homing CLL to the microenvironment, has been safely utilized in CLL. The combination of plerixafor with lenalidomide offered a novel non-cytotoxic alternative to improve anti-tumor activity through targeting of the essential pro-survival microenvironment. Figure 1 Figure 1. Methods: The primary objective of this single institution, open label, phase I clinical trial (NCT01373229) was to evaluate safety of daily lenalidomide in combination with escalating dose levels of plerixafor. Secondary objectives examined objective response rates, disease symptom improvement, and laboratory correlatives of the drugs’ synergy or resistance. The 3 stage study design is outlined in Figure 1. All adverse events (AEs) on combined therapy were recorded according to CTCAEv4, with dose limiting toxicity (DLT) assessment period defined as the first 28 days of combination therapy. Blood was collected throughout study conduct for analyses including an extended CLL phenotyping by flow cytometry with analysis of CLL subpopulations by CXCR4 expression levels. Phospho-protein analysis was performed by phospho-flow cytometry (phosflow). Figure 2 Figure 2. Results: Fifteen subjects (4 female) with a median age of 62 years were enrolled, and all have completed treatment on the trial. Subjects received a median 4 (range 1-8) prior chemotherapy regimens (100% with previous alkylator and rituximab, 93% with prior fludarabine) and had poor prognostic features (73% with del 17p, 93% with unmutated IGHV). Ten subjects initiated plerixafor, and 7 completed at least 1 combination cycle. Two dose limiting toxicities (neutropenia, thrombocytopenia) occurred in plerixafor dose 2 (0.32 mg/kg), thus MTD was exceeded at this level. A total of 6 subjects completed dose cohort 1 confirming 0.24 mg/kg as the MTD. Most common grade 3/4 toxicities (〉20%) on combination therapy included neutropenia (60%), thrombocytopenia (60%), and anemia (40%). Six patients reached interval response assessment and each had stable disease (SD). All response-evaluable patients derived improvement in nodal/splenic mass and disease symptoms. Of 4 subjects who completed the planned combination therapy, 2 continued on amended lenalidomide monotherapy with 1 subject obtaining a PR. Phenotyping demonstrated CD40, CD95, CD80 and CD86 significantly increased within the CXCR4 high population 4 hours post first plerixafor dose. For the five subjects completing greater than 4 months of combination treatment with end on study (EOS) samples, CD52 declined significantly; and although total WBC decreased over treatment course, the proportion of the high CXCR4 population increased with time (Figure 2). Phosflow demonstrated a significant increase of p-Erk (T202/Y204) by EOS. Conclusions: The MTD was oral lenalidomide 10mg daily with plerixafor SQ 0.24mg/kg thrice weekly for 3 weeks of a 28 day cycle. The majority of grade 3/4 toxicities (and DLTs) were cytopenias (anemia, neutropenia, thrombocytopenia). These toxicities may have been augmented from the combination treatment, or may be a reflection of study subjects with preexisting disease or therapy related marrow suppression. Other emerging lenalidomide clinical results suggest that lower doses may produce less myelosuppression while maintaining or improving clinical benefits by decreasing treatment disruptions that precipitate disease symptoms or tumor flare. Overall, the SD and single PR among heavily pretreated subjects with very high risk features are encouraging given the duration these subjects remained on trial without progression. Correlates demonstrated a decrease in CD52, a marker that has been previously associated to poorer CLL outcomes, and suggests a possible therapeutic effect given these subjects did not have disease progression while on treatment. Increases of CD40, CD95, CD80 and CD86 on lenalidomide monotherapy within 4 hours of plerixafor addition suggest immunomodulatory actions in circulating CLL cells (CXCR4 high expressing). Increased p-Erk by the end of trial may be an emerging resistance marker, and exploration of this effect in select patients could translate into other combination strategies that target this mechanism. Disclosures Brander: Celgene: Mentor received research funding Other. Off Label Use: This is a phase I clinical investigational study of lenalidomide and plerixafor combination in previously treated CLL/SLL.. Rizzieri:Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy. Lanasa:MedImmune, LLC: Employment; Genentech/Roche: Consultancy; Celgene: Research Funding.