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e18559 Background: Real-world data on practice patterns in Black pts with CLL are limited. We evaluated treatment (tx) patterns and prognostic biomarker testing in Black pts enrolled in the informCLL registry. Methods: Pts who initiated FDA-approved tx for CLL/SLL (index tx) were enrolled from October 2015 to June 2019. Baseline (BL) characteristics, FISH testing rates, BL factors associated with FISH testing, and patterns of index tx are summarized by line of therapy (LOT; previously untreated [1L] and relapsed/refractory [R/R]). Results: Of 1462 enrolled pts (overall registry population), 106 (7%) were Black (Table). Community-based practices enrolled 87% of Black pts, similar to the overall population (93%). Black pts were predominantly enrolled in the South (69%). Among Black pts, median age was 66 y, 65% had ECOG status ≥1, 64% had Rai stage III-IV, and median time from diagnosis to tx on registry was 40 mo (7 mo for 1L). In the overall population, median age was 71 y, 53% had ECOG status ≥1, 51% had Rai stage III-IV, and median time from diagnosis to tx was 41 mo (19 mo for 1L). FISH testing was performed in 25% of Black pts, similar to the testing rate in the overall population (28%). In a multivariate analysis, BL factors significantly associated with FISH testing were shorter time from initial diagnosis to tx, better ECOG status, earlier LOT (1L), community practice setting, and prior malignancy (p

7044 Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine (Aza) or decitabine (Dec) is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients (pts) who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated Ven + HMA in an inpatient setting due to concerns of tumor lysis syndrome (TLS). This Phase 3b, single-arm, multicenter, open-label study (NCT03941964) evaluated the efficacy and safety of Ven + HMA in a US community-based outpatient setting. Methods: Pts with ND AML who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Pts received Ven (400 mg) in combination with Aza (75 mg/m2) or Dec (20 mg/m2) for up to 6 cycles during the study period. Pts could continue receiving commercially acquired Ven after the study period. All pts received TLS prophylaxis. The primary endpoint was the composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) per modified International Working Group criteria. Secondary endpoints included CR or CRi rates and transfusion independence (TI). TLS was assessed per Howard criteria (Howard. N Engl J Med. 2011;364:1844). Results: At the 19 Oct 2021 cutoff date, 60 pts were enrolled and treated (Ven + Aza, n=30; Ven + Dec, n=30). Efficacy outcomes are shown in the Table. The composite CR rate was 58%. CR and CRi rates were 13% and 45%, respectively. Most pts (>50%) maintained TI, and 41% and 57% of pts dependent on red blood cells or platelets, respectively, converted to TI. Bone marrow blast clearance was achieved in 42 pts (70%) at a median 26 days after treatment initiation. The most common (≥50%) AEs were anemia (75%), neutrophil count decrease (55%), white blood cell count decrease (52%), and nausea (50%). Serious AEs occurred in 67% of pts, most commonly (≥15%) febrile neutropenia (28%) and sepsis (15%). Two pts (3%) had TLS; neither event led to treatment discontinuation. Of pts who achieved blast clearance, 12/42 (29%) had a new event of myelosuppression post-blast clearance and prior to the next cycle. Conclusions: The results of this US community-based study indicate that Ven + HMA is an effective treatment option for pts with ND AML and, with appropriate TLS prophylaxis and monitoring, can safely be initiated in an outpatient setting. Clinical trial information: NCT03941964. [Table: see text]

7558 Background: In the pivotal Phase III POLARIX trial, Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP, with a similar safety profile in patients with previously untreated DLBCL (Tilly et al. 2022). An Asia subpopulation analysis was included as part of the trial design; patients enrolled in Asia were analyzed for the purpose of registration in China of POLARIX (NCT03274492). Methods: Patients from mainland China, Hong Kong, Japan, South Korea, and Taiwan (enrolled during the global phase), and from the China extension cohort were included in the Asia subpopulation. POLARIX methods were previously described (Tilly et al. 2022). Briefly, patients with untreated DLBCL were randomized 1:1 using the same stratification factors to receive six cycles of Pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The purpose of this analysis was to evaluate consistency of PFS (defined as ≥50% risk reduction in PFS) in the Asia subpopulation with the global population. Results: Overall, 281 patients (intent-to-treat population; 150, 85, 31 and 15 patients in mainland China, Japan, South Korea and Taiwan, respectively) were analyzed (141 received Pola-R-CHP and 140 received R-CHOP); 160 patients from the global population and 121 from the China extension cohort. Median age was 63 (range 19–79) years, and most patients had an International Prognostic Index of 3–5 (61.9%). At the data cut-off of June 28, 2021, (median follow-up of 24.2 months) PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.40–1.03) and met the consistency definition with the global population. The 2-year PFS rate was 74.2% (95% CI: 65.7–82.7) with Pola-R-CHP vs 66.5% (95% CI: 57.3–75.6) with R-CHOP. Other key efficacy results were similar to the global study results (Table). The safety profile was generally comparable for Pola-R-CHP vs R-CHOP, including rates of grade 3–4 adverse events (AEs; 72.9% vs 66.2%), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to discontinuation of any study treatment (5.0% vs 7.2%), and incidence of peripheral neuropathy (all grades, 44.3% vs 50.4%), respectively. Key efficacy results. CR, complete response. Conclusions: The results from the Asia subpopulation of POLARIX were consistent with the global study, with a clinically meaningful improvement in PFS (risk of disease progression, relapse or death reduced by 36%) following treatment with Pola-R-CHP vs R-CHOP, and a comparable safety profile in Asian patients with previously untreated DLBCL. Clinical trial information: NCT03274492. [Table: see text]

7539 Background: For ELEVATE-TN (NCT02475681), we previously reported superior efficacy of acalabrutinib (A) ± obinutuzumab (O) vs O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months (mo) median follow-up. Now, we report results from a 5-y update. Methods: Pts were randomized to A+O, A, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: A total of 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) had a median age of 70 y. At a median follow-up of 58.2 mo (range, 0.0–72.0; data cutoff Oct 1, 2021), median PFS was not reached (NR) (hazard ratio [HR]: 0.11) for A+O and A (HR: 0.21) vs 27.8 mo for O+Clb (both P

e19513 Background: Concerns about adverse events (AEs) related to CAR T cell therapy have resulted in administration of this therapy largely in an inpatient setting. OUTREACH (NCT03744676) evaluates safety and efficacy of liso-cel in patients (pts) with R/R large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers (NMCs). Methods: NMCs, including centers naïve to CAR T cell therapy, enrolled adults with R/R LBCL in this open-label, multicenter study. Eligible pts had R/R PET-positive disease after ≥2 lines of prior systemic therapy, ECOG PS ≤1, and adequate organ function. Prior autologous HSCT was allowed. Pts received sequential infusions of equal target doses of CD8+ and CD4+ cells at a total target dose of 100 × 106 CAR+ T cells. Primary endpoint was incidence of grade (G) ≥3 cytokine release syndrome (CRS) graded per 2014 Lee criteria, neurological events (NEs), prolonged cytopenias (Day 29 G ≥3 lab values), and infections. Secondary endpoints were safety and overall response rate (ORR). Outpatient AE monitoring/management was managed by a multidisciplinary CAR T cell therapy team following standard operating procedures (SOPs). Results: At data cutoff, 46 pts (inpatients n = 16, outpatients n = 30) were treated with liso-cel. Inpatients and outpatients had similar demographics and baseline disease characteristics; median age was 63 y (range, 34–83), 63% had diffuse LBCL not otherwise specified, and 91% were refractory to last therapy. Safety data were similar across inpatients and outpatients (Table). Early (study Day ≤4) and overall hospitalization in outpatients was reported in 27% and 63%, respectively; median time to hospitalization was 5 (2–61) days and median length of stay was 6 (1–28) days. For efficacy-evaluable pts (n = 44), ORR was 75% for inpatients and 79% for outpatients; CR rates were 50% and 61%, respectively. Conclusions: Liso-cel was successfully administered to pts with R/R LBCL in the outpatient setting and pts were monitored for CAR T cell therapy–related toxicities by multidisciplinary teams using SOPs. The incidences of severe CRS and NEs and use of tocilizumab and/or corticosteroids were similar in inpatients and outpatients, and consistent with the pivotal study observations (Abramson, The Lancet 2020). Updated data with longer follow-up will be presented. Clinical trial information: NCT03744676. [Table: see text]

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]

7509 Background: Early results from ELEVATE-TN (NCT02475681) at a median follow-up of 28.3 mo demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) (Sharman et al. Lancet 2020;395:1278-91). Results from a 4-year update are reported here. Methods: Pts received A±O or O+Clb. Crossover to A monotherapy was permitted in pts who progressed on O+Clb. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) were randomized with a median age of 70 y; 63% had unmutated IGHV and 9% del(17p). At a median follow-up of 46.9 mo (range, 0.0–59.4; data cutoff: Sept 11, 2020), the median PFS was not reached (NR) for A+O and A pts vs 27.8 mo for O+Clb pts (both P

e24044 Background: First-line (1L) ibrutinib monotherapy (IM) is commonly prescribed for CLL but is associated with cardiovascular adverse events (CVAEs) that may lead to discontinuation. Existing data are largely from clinical trials (both 1L and relapsed/refractory), and real-world evidence is limited. The aim of this study was to compare baseline cardiac risk factors and CVAEs in patients (pts) receiving 1L IM vs intensive therapy (IT; aggressive, less tolerable, majority were bendamustine plus anti-CD20 antibody) or non-intensive therapy (NIT; less aggressive, more tolerable, majority were anti-CD20 antibody alone). Methods: We compared 3 treatment groups (IM, IT, and NIT) in terms of clinical characteristics, baseline CV risk factors, and subsequent CVAEs. Pts were selected from the Flatiron Health database based on the following criteria: aged ≥18 years, CLL/SLL diagnosis, had ≥2 clinic encounters, and initiated 1L treatment between 1/1/2016 and 12/31/2019. Baseline characteristics and subsequent CVAEs were descriptively compared between IM and IT/NIT groups; significance was assumed if p < 0.05. Results: Data on 515 pts were included (IM, 191; IT, 195; NIT, 129). Age at baseline differed significantly between the IM group (mean 71.2 years) and the other 2 groups (IT, 66.2 years; NIT, 74.5 years). The proportion of del(17p) was significantly higher in the IM group vs IT/NIT groups (IM, 26.7%; IT, 3.6%; NIT, 3.1%). Significant differences between IM and IT groups were seen in baseline ECOG (ECOG 0: IM, 28.8%; IT, 43.1%), diabetes mellitus (IM, 56.0%; IT, 44.1%), and hypercholesterolemia (IM, 68.6%; IT, 58.0%). Significant differences between IM and NIT groups were seen in baseline angina/coronary revascularization (2.6% vs 8.5%), atrial fibrillation/atrial flutter (AF; 14.1% vs 26.4%), and cerebrovascular disease (8.9% vs 20.2%). The rate of any CVAE was significantly higher in IM (35.6%) vs IT and NIT groups (IT, 20.0%; NIT, 24.8%) (Table). For IM vs IT treated pts, significant differences were observed in new or worsening (N/W) AF (11.5% vs 5.1%), other arrhythmias (9.4% vs 3.1), and hypertension (HTN; 20.4% vs 8.2%). Conclusions: This is one of the first real-world studies focused specifically on 1L CLL to describe baseline CV risk factors and compare CVAE events in CLL pts treated with IM as compared to IT or NIT. Results show higher CVAE rates of AF, other arrhythmias, and HTN for IM vs IT. [Table: see text]

7513 Background: Standard treatment is lacking for patients with relapsed indolent NHL (iNHL). PI3K inhibitors reported a median PFS of < 1 y in R/R iNHL. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported a 39.4-mo median PFS in R/R iNHL patients (AUGMENT; Leonard. ASH 2018:445). Methods: MAGNIFY is a multicenter, non-registrational phase IIIb trial in patients with R/R FL grade 1-3a and MZL designed to determine the optimal duration of lenalidomide. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in patients with stable disease or better to continued R2 vs rituximab maintenance. These analyses evaluate the primary endpoint of ORR by 1999 IWG criteria for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment with baseline/post-baseline assessments. Results: At a median 16.7 mo follow-up, 370 patients (80% FL grade 1-3a; 20% MZL) were enrolled with a median age of 66 y, 83% stage III/IV disease, and a median of 2 prior therapies (95% prior rituximab-containing). Efficacy-evaluable patients showed a 73% ORR and 45% CR (Table). Median TTR was 2.7 mo, median DOR was 36.8 mo, and median PFS was 36.0 mo. 142 of 370 patients have been randomized and entered maintenance. The most common all-grade AEs were 48% fatigue, 40% neutropenia, 35% diarrhea, 30% nausea, and 29% constipation. Grade 3/4 AE neutropenia was 34%; all other grade 3/4 AEs were < 6%. Conclusions: R2 therapy is active with a tolerable safety profile in patients with R/R FL and MZL, and in patients refractory to rituximab. Clinical trial information: NCT01996865. [Table: see text]

7519 Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor, has a 24% overall response rate (ORR) as a single agent in R/R DLBCL. Pem targets PD-1, an immune checkpoint that limits anticancer responses. Pem showed responses in patients (pts) with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib + Pem in R/R DLBCL. Methods: Pts with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received acalabrutinib 100 mg PO BID until progressive disease (PD) + Pem 200 mg/kg IV Q3W up to 2 y. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one pts (30 GCB; 31 non-GCB) were accrued, with a median age (range) of 67 y (30-85) and a median of 3 (1-8) prior therapies; 1 pt had prior autologous transplant. The most common Gr 3/4 adverse events (AEs) were neutropenia (15%) and anemia (11%). Gr 5 AEs were respiratory failure (n=3), sepsis, septic shock and abdominal abscess (n=1 each). All Gr atrial fibrillation was 5% (n=3), and major hemorrhage (≥ Gr 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Gr 3/4 immune-mediated events were elevated alanine aminotransferase (n=4), pneumonitis (n=2) and colitis (n=1). The ORR was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 mo (0.4-30.4+). Acalabrutinib/Pem discontinuations were due to PD (62%/56%) and AEs (15%/26%). As of June 2018, 10 pts remain on study; 6 on active therapy and 7 without PD. Conclusions: Acalabrutinib + Pem was well tolerated, with meaningful activity and some exceptional responders (>24 mo) in these R/R DLBCL pts. Randomized trials of the combination vs single agent are needed. Clinical trial information: NCT02362035. [Table: see text]

7530 Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range

7504 Background: Patients (pts) with high-risk chronic lymphocytic leukemia (CLL) defined by interruptions in TP53 (either by mutation or deletion) or loss of chromosome 11q experience inferior outcomes with ibrutinib (IB) monotherapy (O’Brien ASH 2016). Ublituximab (UTX) is a novel glycoengineered mAb with enhanced ADCC targeting a unique epitope on the CD20 antigen. GENUINE is the first randomized Ph 3 trial conducted assessing the addition of a novel agent to ibrutinib in high-risk rel/ref CLL, and evaluates IB monotherapy vs. UTX + IB. Methods: Eligible pts with rel/ref CLL and centrally confirmed del17p, del11q, and/or a TP53 mutation were randomized 1:1 to receive IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cycle 1, D1 of Cycle 2-6, and Q3 Cycles thereafter). There was no limit on number of prior therapies. Prior IB exposure was excluded. The primary endpoint was overall response rate (ORR) per iwCLL 2008 criteria, with secondary endpoints including CR rate, MRD negativity, PFS, time to response (TTR) and safety. Results: 126 pts were randomized at sites in the US and Israel, with 117 pts treated (59 on UTX + IB, 58 on IB alone). Median age 67, median 3 prior therapies (range 1-8), > 70% of were male. High-risk cytogenetics were relatively balanced with ~ 50% of pts having del17p. UTX+IB was well tolerated, with infusion reactions the most prevalent AE (44%, GR3/4 5%). Neutropenia was comparable with the combination (17%, Gr3/4 7% vs. 10%, Gr3/4 9%), and other AE’s were similar or lower with UTX+IB vs. IB alone (all grades), including fatigue (17% vs. 31%), dizziness (12% vs. 21%), contusion (12% vs. 26%), anemia (10% vs. 16%), and myalgia (9% vs. 14%). At median follow-up of 12 mo, best ORR per independent central review was 80% for UTX + IB vs. 47% for IB alone (p < 0.001). While not powered for secondary endpoints, observed advantages were seen in PFS and radiographic CR rate in the UTX + IB arm. CR and MRD confirmation is ongoing. Median TTR for the combo was 1.97 mo vs. 3.8 mo for IB alone. Both arms have responses pending confirmatory assessments. Conclusions: The addition of UTX to IB demonstrated a superior response rate compared to IB alone without additional clinically significant toxicity. Clinical trial information: NCT02301156.

7518Background: Acalabrutinib, a selective, covalent inhibitor of Bruton tyrosine kinase (BTK), was evaluated in combination with the PI3Kδ inhibitor ACP-319 in pts with R/R B-cell malignancies. Me...

7516Background: In the relapsed/refractory (R/R) setting for indolent non-Hodgkin lymphoma (iNHL), duration of response (DOR) to and types of prior therapy are important factors in predicting outco...

TPS7589Background: R-CHOP remains the standard of care in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL). However, pts with high-risk disease have poorer outcomes wi...

7542Background: Elderly patients (pts) with Hodgkin lymphoma (HL) have few treatment (tx) options and poor outcomes compared to younger pts. This phase 2, frontline, open-label trial studied brentu...

7502 Background: Chemoresistant patients with FL and those who progress within 2 y after initial diagnosis have poor outcomes (Casulo. JCO. 2015) and highlight an unmet need. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of relapsed/refractory (R/R) NHL patients, including grades 1-3b or transformed FL (tFL). Patients receive 12 cycles of lenalidomide plus rituximab (R2); those with stable disease or better are randomized 1:1 to maintenance R2 or rituximab alone. The primary endpoint is progression-free survival (PFS). This analysis focuses on FL: double-refractory (DR) patients are refractory to both rituximab (as monotherapy or combination) and an alkylating agent, and early relapse (ER) patients progressed or relapsed within 2 y of initial diagnosis. Results: As of July 19, 2016, the R/R FL population (N = 117) included 32 (27%) DR and 43 (37%) ER patients, median ages of 64 and 65 y, respectively, mostly grade 1-3a FL (94%; 91%) and 2 tFL (1 DR; 1 ER); 72% and 49% were stage IV at study entry. Patients had a median of 2 prior regimens (DR 3; ER 2). Of ER patients, 31 had first-line R-chemo vs 12 with R-mono/other. Response rates are in Table 1. Median time to response was 2.8 mo for DR and 2.7 mo for ER patients, with median duration not reached. 1-y PFS for FL patients was 66% (DR 66%; ER 45%); 1-y PFS for ER patients with first-line R-chemo was 50% vs 27% in others. Common grade ≥3 treatment-emergent AEs for DR and ER patients were neutropenia (53%; 33%), leukopenia (9%; 12%), and lymphopenia (9%; 5%). Conclusions: R2 followed by maintenance showed favorable activity and tolerable safety profiles in FL patients who are double-refractory or had early relapse ( < 2 years) after initial diagnosis. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865. [Table: see text]

7565 Background: ENTO is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk, a mediator of B-cell receptor [BCR] signaling). Targeting the BCR-signaling pathway has been a focus in B-cell related hematological malignancies including LPL/WM. Methods: This reports the LPL cohort in a phase 2 trial that more broadly evaluated efficacy and safety of ENTO (800 mg BID) in patients with relapsed and refractory (R/R) B-cell malignancies. Tumor response was assessed at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 24. Results: 17 LPL patients (median age 72 years [range: 47–89], 65% male, and median of 3 prior regimens [range: 1–8]) were enrolled. Prior therapies included anti-CD20 antibodies (100%), alkylating agents (71%; bendamustine 24%), purine analogues (24%), and vinca alkaloid (41%). No patient had prior ibrutinib. Median treatment duration was 16 weeks (range: 1-84), with 3 patients continuing on treatment. The most common treatment-emergent AEs (any grade/≥grade 3, independent of causality) were fatigue (53%, 6%), constipation (47%, 0%), nausea (47%, 6%), diarrhea (29%, 6%), insomnia (29%, 0%) and lab abnormalities including neutropenia (53%, 12%), increased creatinine (53%, 0%), increased ALT (41%, 6%) and decreased WBC (41%, 6%). One death due to progressive disease (PD) was reported within 30 days from last dose. 12 (71%) patients were evaluable for tumor response. 5 patients (29%) discontinued prior to initial tumor assessment: PD (n = 2), withdrawal consent (n = 2) and AE (n = 1). ORR was 24% (90% CI: 9%, 46%), with 1 (6%) patient achieving PR, 3 with minor response (18%) and 7 (41%) maintaining stable disease. Reductions of IgM from baseline were greatest in the patient with PR. PFS rate at week 24 was 82% (95% CI: 44%, 95%). Median time to treatment failure and median time to response were 3.7m and 1.9 m respectively. Median duration of response has not been reached. Conclusions: ENTO was well tolerated and demonstrated limited activity in patients with R/R LPL. Further development of ENTO in LPL will focus on its role in combination therapies. Clinical trial information: NCT01799889.

7523 Background: Bendamustine (B) + rituximab (R; BR) is a commonly used 1L treatment for CLL. The CLL10 study reported an ORR of 96% and CR of 31% with BR. Obinutuzumab (GA101; G) is a glycoengineered, type II anti-CD20 monoclonal antibody. A randomized Phase III trial in 1L CLL pts showed that G significantly improved PFS and CR rate compared with R, when used in combination with chlorambucil (Goede 2014). B + G (BG) was evaluated in a subgroup of CLL pts in the GREEN study (Stilgenbauer 2015). We present results of a Phase II study (NCT02320487) evaluating the efficacy and safety of BG as 1L treatment for CLL pts. Methods: 102 pts with previously untreated CLL received BG, consisting of 6 cycles of G (cycle [C] 1: 100mg day (D) 1, 900mg D2, 1000mg D8 and D15; C2–6: 1000mg D1) and B (90mg/m2: C1, D2 and D3; C2–6, D1 and D2). Each cycle was 28 days. Primary endpoint was CR assessed using iwCLL criteria. Secondary endpoints included ORR, PFS, OS, and MRD. Median follow-up at the time of analysis was 11.0 months. Results: Median pt age was 61 yrs (range 35–90); 68.6% were male; 44.1% had Rai stage 3–4. For evaluated pts, IgVH status was 32.9% mutated and 67.1% unmutated. The incidences of trisomy 12, normal cytogenetics, and deletions of 13q, 11q, and 17p were 23.4%, 37.5%, 17.2%, 15.6%, and 6.3%, respectively. Investigator-assessed CR rate was 49.0% (95% CI 39.0–59.1) and ORR was 89.2% (95% CI 81.5–94.5) after 6 cycles. MRD negativity (MRD-) in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of pts at the end of induction response assessment and in 75.5% of pts at any time following treatment. MRD- in bone marrow (BM) was 60.8% in pts with BM samples. The most common AEs (all grades [Gr]) were infusion reactions (72.5%), nausea (52.0%), pyrexia (36.3%), neutropenia (34.3%), fatigue (34.3%), constipation (26.5%), and rash (26.5%). The most common Gr 3–4 AE was neutropenia (26.5%). Incidence of Gr 3–4 infections was 11.8%. Incidence of TLS was 4.9% (all Gr 3). Three pts died; none were deemed related to study treatment or CLL by investigators. Conclusions: BG is an effective regimen for 1L treatment of CLL pts, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed. Clinical trial information: NCT02320487.

7531Background: Idelalisib (IDELA) is effective in the treatment of patients (pts) with relapsed/refractory (R/R) CLL. Nonetheless, pts may discontinue (D/C) IDELA due to progressive disease (PD) o...

8503 Background: Based on early evidence of cumulative toxicity of PoV at a dose of 2.4 mg/kg (Morschhauser ASH 2014 NCT01691898), a dose of 1.8 mg/kg was explored. We report updated results of the...

7013 Background: Genetic aberrations detected by fluorescence in situ hybridization (FISH) and cytogenetic (CG) testing provide prognostic information for CLL pts. The identification of genetic abn...

7011 Background: IDELA is a first-in-class PI3Kδ inhibitor approved in combination with rituximab for pts with relapsed CLL. Methods: Pts with R/R CLL were treated continuously with 150 mg BID oral...

e13584 Background: Entospletinib (ENTO/GS-9973) is an orally bioavailable, selective, reversible, small molecule spleen tyrosine kinase (Syk) inhibitor. ENTO is currently in a Phase 2 clinical tria...

TPS8606 Background: Combination of the immunomodulatory agent lenalidomide (Revlimid) with rituximab (R2) is a promising therapeutic option for patients with R/R NHL. As frontline therapy, R2 provi...

7012 Background: Idelalisib (IDELA), an oral inhibitor of PI3Kδ, is highly active in heavily pretreated patients with CLL as single agent or combined with rituximab (R) as demonstrated in Phase 1 t...

7014 Background: CLL/SLL is generally very responsive to chemoimmunotherapy. However, relapses occur and resistance develops. In particular, del(17p) is associated with poor outcomes using all curr...

7083 Background: Early phase 1/2 trials with GA101 in CLL demonstrated single-agent activity with suggestion of a dose response. GAGE (NCT01414205) is a multicenter, randomized study that evaluated...

11109 Background: Next generation sequencing (NGS) of routinely fixed tissue from pts with advanced solid tumors may inform treatment planning. Foundation Medicine has developed a CLIA-certified, C...

7011^ Background: Idelalisib (IDELA) is a potent and selective inhibitor of PI3Kδ, which is critical for activation, proliferation and survival of B cells and their homing and retention in lymphoid...

7007 Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, selective inhibitor of Syk (Kd 7.6 nM,...

8519 Background: PoV and PiV, antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in Phase I. The current study aims to compare PoV and PiV + RTX in R/R DLBCL and R/R follicular lymphoma (FL). Methods: Pts were randomized to receive PoV or PiV + RTX (ADC 2.4 mg/kg + RTX 375 mg/m2) every 21 days. Tumor assessments were performed every 3 months. Results: As of 8 November 2013, 58 received PoV + RTX (38 DLBCL; 20 FL), 63 PiV + RTX (42 DLBCL; 21 FL). Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced between treatment arms; 46% were RTX refractory. Median treatment (tx) cycles in DLBCL: 5 for both ADC (1-15); FL: 8.5 PoV (3-15) and 6 PiV (1-13). Overall safety profiles of both regimens were similar. Tx-emergent adverse events (AE) >25%: fatigue (52%), diarrhea (42%), nausea (37%), peripheral neuropathy (PN) (32%), constipation (26%). Grade ≥ 3 AE >3%: neutropenia (21%), diarrhea (6%), dyspnea (4%), febrile neutropenia ...

7099 Background: Pt-reported outcomes (PROs) evaluated HRQL among CLL pts randomized to IDELA + rituximab (R) (n=110) vs double-blind placebo + R (n=110). Methods: The 44-item Functional Assessment...

TPS8617 Background: Immunomodulation with lenalidomide (L) + rituximab (R) is a promising treatment approach for patients (pts) with indolent NHL. In indolent NHL, frontline L+R provided a 90% over...

8501 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown monotherapy activity in recurrent MCL (Kahl, ICML 2011). Methods: This phase 1 study is evaluating the activity of continuous idelalisib (Id), 150 mg BID, in combination with everolimus (E) (10 mg PO qD) (Id+E regimen), with bortezomib (V) (1.3 mg/m2 SC day 1, 8, 15 per 28 day cycle) (Id+V regimen), or with rituximab (R) (375 mg/m2, on Day 1) and bendamustine (B) (90 mg/m2x 2), for 6 cycles (Id+BR regimen). Investigators assessed response according to standard criteria (Cheson 2007). Results: Study enrolled 22 patients with relapsed/refractory MCL. Results are from 14 Jan 2013 data cutoff. The 3 cohorts included Id+E (N=12), Id+V (N=6), and Id+BR (N=4). Patients were 73% male, median age [range] of 68 [47E79] years, 32% with refractory disease and 73% stage III/IV. The median [range] number of prior therapies was 3 [1E7]. The median [range] duration of treatment was 2.5 [0.5-8.3+] months. Overall response rate (ORR) was 10/22 (46%), with 2 CR (9%). The ORR/CR for Id+E, was 25%/0%, Id+V was 50%/0%, and Id+BR was 100%/50%. The median duration of response (mDOR) and median PFS (mPFS) were not reached. Most common adverse events included (total%/≥G3%) diarrhea (41/9), fatigue (41/0), rash (27/14), cough (27/0), decreased appetite (23/0), and epistaxis (23/0). Lab abnormalities included (total%/≥G3%) thrombocytopenia (82/27), neutropenia (32/14), and ALT/AST elevations (50/5). Conclusions: Preliminary data indicates idelalisib-based combination therapy is active in patients with relapsed/refractory MCL. All combinations were tolerable. These data support further clinical development in larger trials to further characterize safety and response duration. Clinical trial information: NCT01088048.

8500 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.

7086 Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACT-Leu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group

TPS7133 Background: PI3K-delta is critical for the activation, proliferation and survival of B cells and plays a role in homing and retention of B cells in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and alters trafficking of malignant B cells in lymphoid tissues (Lannutti, 2011). Phase 1 trials demonstrated that idelalisib is highly active in heavily pretreated pts with CLL as a single agent or in combination with rituximab (R), bendamustine (B), or BR: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Coutre et al, 2012; Sharman et al, 2011). Methods: Study will enroll 390 pts with previously treated CLL who have measurable lymphadenopathy, have received prior therapy containing a purine analog or B and an anti-CD20 monoclonal antibody, are not refractory to B, have experienced CLL progression within 36 months from the completion of the last prior therapy, and are currently sufficiently fit to receive cytotoxic therapy. Pts are randomized in a 1:1 ratio to Arm A or B. On Arm A, subjects receive idelalisib continuously at 150 mg BID + R at 375 mg/m2 (1st dose) and then 500 mg/m2 every 4 weeks for 6 cycles + B at 70 mg/m2 on Days 1 and 2 of each 4-week cycle for 6 cycles. On Arm B, subjects receive placebo instead of idelalisib. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set. The study was initiated in June 2012 and a data monitoring committee has begun regular review of data. Clinical trial information: NCT01569295.

7017 Background: PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in pts with heavily pretreated CLL. Methods: This phase I study evaluated idelalisib continuously given at 150 mg BID in combination with rituximab (R, 375 mg/m2 every wk x 8), bendamustine (B, 70 or 90 mg/m2 x 2, every 4 wks x 6) or BR (every 4 wks x 6) for relapsed/refractory CLL. Pts still on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 52 pts (23F/29M) with a median (range) age of 64 (41-87) years were enrolled. Adverse disease characteristics included bulky lymphadenopathy (62%), refractory disease (50%), multiple prior therapies (median 3, range: 1-14) with 96% receiving prior R and 44% receiving prior B. As of 14 Jan 2013, the median (range) treatment duration was 18 (1-33) months. 31/52 (60%) pts enrolled into the extension study; of those, 24/52 (46%) pts are continuing idelalisib treatment on the extension study. The ORR was 81%, with 1 CR, and a median (range) time to response of 1.9 (1.5-8.3) months. The 2-year PFS and OS were 62% and 85%, respectively. At 2 years follow up, 71% of responses were still enduring. There was no difference in outcomes for pts with

6122 Background: Clinicians and investigators commonly use ECOG PS and clinician-reported patient (pt) fatigue as surrogates for HRQOL, a multi-faceted construct that comprehensively looks at the pt perspective on disease and well-being. Because limited data exist on the relationships between PS, fatigue, and HRQOL for CLL pts, we examined the associations between these measures, and 3 validated HRQOL instruments: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), EQ-5D, and Brief Fatigue Inventory (BFI). Methods: Data were collected in CONNECT CLL, a prospective US observational registry initiated in 2010. Patient demographics and clinical characteristics were provided by clinicians. Patient HRQOL was self-reported at enrollment using the FACT-Leu, EQ-5D, and BFI. Scores were analyzed by ECOG PS (0, 1, 2-4) and clinician-reported fatigue (yes, no). Differences in HRQOL scores were assessed by ANOVA. Results: HRQOL data were reported by 899 pts from 148 community, 10 academic, and 3 government centers. ECOG PS was available on 711 pts. Overall HRQOL, measured by mean FACT-Leu, FACT-G and EQ-5D Visual Analogue Scale (VAS), worsened with ECOG PS severity and was worse in pts with fatigue (all p CLL results confirm that HRQOL worsens with worsening ECOG PS and was worse among pts with fatigue, especially in physical/functioning domains, pain/discomfort, and mobility. These results indicate that baseline ECOG PS and physician-rated fatigue are rapid assessments that predict robust measures of HRQOL. Future analyses are planned to examine how HRQOL, ECOG PS and fatigue change over time with changes in treatment and CLL disease status.

6518^ Background: PI3Kδ is expressed in cells of hematopoietic origin where it regulates the survival and proliferation of malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor that selectively targets PI3Kδ and is highly active in patients with hematologic malignancies. Methods: This Phase 1/2 study evaluated repeated 28-day cycles of GS‑1101 in combination with ofatumumab. GS-1101 (150mg BID) was co-administered with a total of 12 infusions of ofatumumab over 24 weeks (300mg initial dose either on Day 1 or Day 2 (relative to the first dose of GS-1101), followed 1 week later by 1,000mg weekly for 7 doses, followed 4 weeks later by 1,000mg every 4 weeks for 4 doses). Thereafter, each subjects received single-agent GS‑1101 as long as the subject was benefitting. Results: Accrual is complete with 21 subjects enrolled and 11 evaluable. Six subjects started ofatumumab treatment on Day 1 and 5 on Day 2. Median [range] age was 63 [54‑76] years. The majority (9/11; 82%) of patients had bulky adenopathy. The median [range] number of prior therapies was 3 [1‑6], including prior exposure to alkylating agents (10/11; 90%), rituximab (9/11; 82%), purine analogs (8/11; 72%), alemtuzumab (3/11; 28%) and/or ofatumumab (2/11;18%). At the data cutoff, the median [range] treatment duration was 5 [0‑7] cycles. Almost all subjects (9/11;82%) experienced marked and rapid reductions in lymphadenopathy within the first 2 cycles. The lymphocyte mobilization that is expected with PI3Kδ inhibition was significantly reduced in magnitude and duration and persisted past Cycle 1 in only 1 patient. Early follow up data support a favorable safety profile and confirm a lack of clinically significant myelosuppression. Elevated baseline levels of CCL3, CCL4, CXCL13, and TNFa were significantly reduced after 28 days of treatment. Conclusions: GS-1101/ofatumumab offers a well-tolerated noncytotoxic combination regimen with substantial activity in previously treated patient with bulky adenopathy. Data on the complete cohort of 21 subjects will be presented.

3069 Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. Expression of CD30 in other solid tumors and non-lymphomatous malignancies has been reported but not investigated systematically. CD30 is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate (ADC) that is approved for the treatment of patients with relapsed HL and systemic ALCL after failure of other therapies. A study was initiated to determine the incidence of CD30 expression in non-lymphomatous malignancies and to identify patients who may be candidates for treatment with brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies were eligible for screening if they were relapsed or refractory to previous therapy or had no effective treatment options available. Archived tissue from solid tumors was tested for CD30 expression by immunohistochemistry (IHC); fresh bone marrow or blood samples from multiple myeloma or leukemia patients were tested by flow cytometry. Patients were considered CD30 positive and eligible for a companion treatment protocol with brentuximab vedotin if ≥10% of malignant cells stained positive by IHC or ≥20% by flow cytometry. Results: At this interim analysis, a total of 875 patients have been tested for CD30 expression: 95% had solid tumors, 3% had leukemia, and 2% had multiple myeloma. Twenty-two patients (2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer (7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid carcinoma (33%). One patient was identified with CD30-positive mast cell leukemia. In positive patients, the percent of CD30-positive malignant cells varied between 10 and 80%. Conclusions: CD30 expression was observed in multiple types of non-lymphomatous malignancies, thereby identifying additional populations who may be candidates for treatment with a CD30-targeted ADC, such as brentuximab vedotin. A companion clinical trial with brentuximab vedotin is currently ongoing.

6507 Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline cytopenias (Hgb < 11g/dl or plts 3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.

8032 Background: Btk supports activation, survival, and proliferation of malignant B cells in CLL and B-NHL. AVL-292 is an oral, potent (IC50 < 0.5nM), selective small molecule covalent inhibitor of Btk. Methods: Patients (pts) with previously treated CLL or B-NHL were administered AVL-292 in escalating cohorts of 125, 250, or 400 mg po QD using a 3+3 design in continuous 28 day cycles until progressive disease (PD) or toxicity. Key objectives were safety, DLT, MTD, PK, and Btk occupancy. Plasma AVL-292 levels were assessed by LC-MS-MS. Btk occupancy by AVL-292 was assessed by covalent probe assay in peripheral blood mononuclear cells. Results: 12 pts have enrolled (3 each at 125 and 250 mg and 6 at 400 mg: 5M/7F; median age 68 years, range 45-79; median 2.5 prior therapies, range 1-10) including 8 CLL (2 with 17p-, 2 with 11q22-, 2 with both 17p-/11q22-; 2 mutated IGHV, 5 unmutated IGHV, 1 missing) and 4 B-NHL (1 diffuse large B cell lymphoma (DLBCL); 1 follicular (FL); 2 marginal zone (MZL)). Median time on treatment is 65 days, range 28-158. Ten of 12 pts continue on treatment: 1 pt (DLBCL) discontinued for PD after 1 cycle and 1 pt (FL) for DLT (Gr 4 plts; 400 mg QD). No other DLTs or grade 4 adverse events (AEs) have occurred and MTD has not been reached. Most frequent AEs reported include transient diarrhea, rash/skin infection, URI, nausea, and fatigue. Gr 3 AEs include 1 atrial fibrillation (not drug related) and 1 ANC low (probably drug related). To date, 8 of 8 CLL patients have stable disease (SD) with median 28% decrease from baseline lymph node measurement (range 3-40% decrease). Six of 8 pts with CLL experienced increased ALC in cycle 1: median increase 89.5% (range 50-212%). Two of 4 NHL pts have SD (both MZL), 1 PD (DLBCL), and 1 not evaluable due to DLT (FL). Full Btk occupancy was achieved with dose levels ≥ 250 mg. Multiple dose PK exposure (AUClast) was linear with no accumulation from Day 1 to 15. Conclusions: AVL-292 was well tolerated from 125-400 mg po QD and early efficacy analysis in CLL and B-NHL shows 10/11 efficacy evaluable pts with SD. Full Btk occupancy was achieved with ≥ 250 mg QD and PK was predictable with no accumulation. Dose escalation is ongoing and MTD cohort expansion is planned.

8563 Background: IDELA, a selective oral PI3Kδ inhibitor, is approved for use in relapsed CLL (in combination with rituximab [R]) and iNHL (as monotherapy). Both diseases occur mainly in the elderl...

7506 Background: Rituximab (RTX) alone or with chemo has substantially improved outcomes for patients (pts) with marginal zone lymphoma (MZL), but relapse is common and not all pts are candidates for or respond to current salvage therapies. Umbralisib is a novel, next-gen PI3Kδ inhibitor with unique inhibition of casein kinase-1ε (CK1ε) and a differentiated tolerability profile compared to earlier PI3Kδ inhibitors (Burris et al, 2018). This registration-directed study evaluates the efficacy and safety of umbralisib in pts with rel/ref (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS ≤2, and ≥1 prior therapy including ≥1 anti-CD20 mAb-containing regimen. Pts received umbralisib 800 mg orally once daily until PD or unacceptable toxicity. The primary endpoint was overall response (ORR) as assessed by independent review (IRC) per 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), PFS, and safety. Results: 69 pts were enrolled; we report on the first 38 who are eligible for at least 6 months (mos) of follow-up as of the data cutoff. Among the 38 pts: extranodal (n = 23), nodal (n = 8), and splenic (n = 7). Median age was 67 years (range, 34-81). Median # of prior systemic therapies was 2 (range, 1-5). Seven pts (18%) had monotherapy RTX only, and 26 (68%) had at least one anti-CD20 mAb-containing chemoimmunotherapy. Median follow-up was 9.6 mos. ORR was 55% (4 CRs and 17 PRs). Eleven pts (29%) had stable disease (SD) of which 6 of these SD pts remain on study ranging from 7-12+ mos. The clinical benefit rate (CR+PR+SD) was 84%, and 91% of pts with at least 1 post-baseline assessment experienced tumor reductions. Median time to initial response was 2.7 mos, while median DOR was not reached (95% CI: 8.4-NR). The 12-month PFS was 71%. The most common all causality (≥20%) adverse events (AE) of any grade included: diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). The most common Grade 3/4 events were neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). As of the cutoff date 58% continue treatment. Conclusions: PI3Kδ inhibition with single-agent umbralisib is active and well tolerated in pts with R/R MZL, achieving durable responses with chemotherapy-free therapy. Clinical trial information: NCT02793583.