Abstract: In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment. METHODS Undetectable MRD (uMRD) was assessed by next-generation sequencing at 〈 1 CLL cell per 10,000 ( 〈 10 −4 ) and 〈 1 CLL cell per 100,000 ( 〈 10 −5 ) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3). RESULTS Ibrutinib + venetoclax achieved deeper uMRD ( 〈 10 −5 ) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD ( 〈 10 −5 ) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10 −4 ) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD ( 〈 10 −4 ) and dMRD (≥10 −4 ) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM. CONCLUSION Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD ( 〈 10 −4 ), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.

Abstract: TPS7131 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 reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Ofatumumab (O) is an anti-CD20 monoclonal antibody approved for the treatment of pts with CLL refractory to fludarabine and alemtuzumab. Phase 1 studies demonstrated that idelalisib, as monotherapy or combined with O, is highly active in pts with heavily pretreated CLL: pts experienced profound and rapid regression of lymphadenopathy, reductions in disease-associated chemokines, and durable clinical benefit with an acceptable safety profile (Furman et al, 2012). Methods: This study will enroll 210 pts with CLL previously treated with a purine analog and/or bendamustine, with measurable lymphadenopathy who require treatment for CLL and have disease that is not refractory to ofatumumab, and are expected to benefit from a change in therapy because of CLL progression 〈 24 months since completion of their last prior treatment. Pts are randomized in a 2:1 ratio (Arm A:Arm B). In Arm A, pts receive idelalisib at 150 mg BID continuously in combination with 12 infusions of O at 1000 mg over ~24 weeks (weekly x 8 then monthly x 4). In Arm B, pts receive 12 infusions of O at 2,000 mg over ~24 weeks. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary study endpoint is PFS. 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 using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012. Clinical trial information: NCT01659021.

Abstract: Background: MRD status is an established predictive marker for progression-free survival (PFS) in CLL following chemoimmunotherapy as well as for fixed-duration treatment with venetoclax and an anti-CD20 antibody. To date, this relationship has not been explored for the combination of Ibr+Ven, an all-oral, once-daily, fixed-duration treatment with complementary mechanisms of action that work synergistically to eliminate CLL subpopulations in distinct tumor compartments. In the primary analysis of the phase 3 international GLOW trial, independent review committee (IRC)-assessed PFS for Ibr+Ven was superior to Clb+O (hazard ratio, 0.216; p & lt; 0.0001). Herein we further investigate MRD outcomes at the time of the GLOW primary analysis. Methods: GLOW (NCT03462719) enrolled patients (pts) aged ≥65 years or 18-64 years with cumulative illness rating scale score & gt;6 or creatinine clearance & lt;70 mL/min. Pts with del(17p) or known TP53 mutations were excluded. Pts were randomized 1:1, stratified by IGHV mutational and del(11q) status, to Ibr+Ven (3 cycles of ibrutinib lead-in, followed by 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. The primary end point was PFS assessed by IRC and rate of undetectable MRD (uMRD; & lt;10 -4) was a secondary end point; additional MRD analyses reported here are exploratory. MRD samples were collected for responders every 3-4 months in peripheral blood (PB) and at Months 9 and 18 in bone marrow (BM). MRD was evaluated using next-generation sequencing (NGS; clonoSEQ) and 8-color flow cytometry. PB/BM concordance was calculated for pts with uMRD in PB at end of treatment plus 3 months (EOT+3) who had a paired BM sample. Analysis of PFS by MRD status includes pts with known MRD status at EOT+3 and no prior progression, death, or withdrawal. Results: 106 pts were randomized to Ibr+Ven and 105 to Clb+O. Median age was 71.0 years, 51.7% had confirmed unmutated (u)IGHV, 18.0% had del(11q), and 4.3% had a TP53 mutation. Median follow-up was 27.7 (range, 1.7-33.8) months. MRD results are all via NGS and reported for EOT+3 unless otherwise noted. MRD Results at 10 -4: Rate of uMRD was significantly higher for Ibr+Ven vs Clb+O in BM (51.9% vs 17.1%; p & lt; 0.0001) (Fig A) and in PB (54.7% vs 39.0%; p = 0.0259). PB/BM uMRD concordance with Ibr+Ven was 92.9%. In the Ibr+Ven arm, 65.9% (27/41) of pts with a complete response (CR) or CR with incomplete marrow recovery (CRi) and 54.9% (28/51) with a partial response achieved uMRD in BM; rates for Clb+O were 33.3% (4/12) and 16.9% (13/77), respectively. BM uMRD rates were higher for Ibr+Ven vs Clb+O across prespecified subgroups, including bulky disease (≥5 cm), del(11q), and uIGHV . In the Ibr+Ven arm, BM uMRD was higher for uIGHV (58.2%) vs mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of pts maintained PB uMRD from EOT+3 to EOT+12 vs 29.3% (12/41) with Clb+O. For pts with detectable MRD after Ibr+Ven (n = 30), MRD levels remained stable for most patients from EOT+3 to EOT+12 (Fig B). MRD Results at 10 -5: Rate of uMRD & lt;10 -5 was higher for Ibr+Ven vs Clb+O in BM (40.6% vs 7.6%) (Fig A), including pts with uIGHV (45.5% vs 5.6%). With Ibr+Ven, PB/BM uMRD concordance at & lt;10 -5 was 90.9% (40/44). Among pts with uMRD & lt;10 -4 in the Ibr+Ven arm, the majority achieved & lt;10 -5 in PB (79.3%) and BM (78.2%), including pts with uIGHV. uMRD & lt;10 -5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46] of pts) but not Clb+O (26.3% [5/19] of pts) (Fig B). PFS by MRD Status at 10 -4 : In the Ibr+Ven arm, PFS rate during the first 12 months after EOT was & gt;90% for pts with uMRD as well as pts with detectable MRD. In contrast, pts in the Clb+O arm with detectable MRD in PB relapsed more quickly than those with uMRD (Fig C). PFS trends were similar according to MRD status in BM (Fig D). Note that not all pts in the Ibr+Ven arm had 12 months' follow-up post-EOT. Conclusion: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment vs Clb+O in elderly or unfit pts with previously untreated CLL. Most pts with uMRD in the Ibr+Ven arm, including those with uIGHV, achieved clearance below 10 -5, and deeper clearance in PB was mirrored in BM. In the Ibr+Ven arm, clinical relapse was infrequent during the first year off treatment for pts with known MRD status at EOT+3 (whether uMRD or detectable MRD), supported by largely sustained uMRD/MRD levels over the same period. Additional follow-up will be important to confirm these early results. Figure 1 Figure 1. Disclosures Munir: Janssen, Abbvie, AstraZeneca, Morphosys, Alexion, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen, Abbvie, AstraZeneca, Alexion, Apellis, Gilead, Novartis: Honoraria. Moreno: Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Janssen, Abbvie: Research Funding. Owen: Abbvie, AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen, Roche, Merck, Gilead, Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows: Roche, Abbvie, Janssen, Takeda, Janpix: Consultancy. Benjamini: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Janssens: Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Robak: AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; Medical University of Lodz: Current Employment. Simkovic: Janssen-Claig, Gilead, Roche, AstraZeneca, Abbvie: Consultancy, Honoraria, Other: Travel Grants, advisiory boards. Voloshin: Janssen, Abbvie, Sanofi, AstraZeneca, Takeda: Other: Clinical Trials, Non-finanfial support, Speakers Bureau; Novartis, Pfizer, MSD, La ROche: Other: Clinical Trials, Non-finanfial support. Vorobyev: Janssen, Roche, Sanofi, Takeda, Biocad, Abbvie: Other: Advisory Boards, Speakers Bureau; Astellas, Novartis, AstraZeneca: Speakers Bureau. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Qi: Janssen: Current Employment. Steele: Janssen: Current Employment. Schuier: Janssen: Current Employment. Baeten: Janssen: Current Employment. Bennett Caces: Janssen: Current Employment. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding.

Abstract: Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response [CR] in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL. Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment. Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score 〉 6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached [NR] vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P 〈 0.0001); this was consistent within subgroups including age ≥70 years, del11q, and unmutated IGHV. As assessed by investigator, ibr reduced the risk of progression or death by 91% (HR 0.09; 95% CI, 0.04-0.17; P 〈 0.0001; Figure 1A), with an 18-mo PFS of 93.9% vs 44.8%. Ibr significantly prolonged OS vs clb (median NR for either arm; HR 0.16, 95% CI 0.05-0.56, P=0.0010; Figure 1B); 24-mo OS was 97.8% vs 85.3%, respectively. Three deaths occurred on the ibr arm vs 17 deaths on clb arm. The IRC-assessed ORR was 86.0% with ibr (4.4% CR/CRi) vs 35.3% with clb (1.5% CR/CRi). ORR with ibr was higher than clb at all evaluated time points; at 8 mos, ORR was 84% and 31%, respectively. Investigator-assessed ORR was 90.4% (9.6% CR/CRi) vs 35.3% (4.5% CR/CRi), respectively. Median EFS was also prolonged with ibr (NR vs 12 mos; HR 0.17, 95% CI 0.10-0.26; P 〈 0.0001). A ≥50% reduction in lymph node burden was observed in 91.2% vs 36.8% (P 〈 0.0001), and reduction in spleen enlargement in 75.7% vs 39.1% (P 〈 0.0001), for ibr and clb, respectively. Rates of sustained hematologic improvements were significantly higher with ibr vs clb, including in pts with baseline anemia (84% vs 45%; P 〈 0.0001) or thrombocytopenia (77% vs 43%; P=0.0054). Median duration of treatment was 17.4 mos with ibr and 7.1 mos with clb. Most frequent (≥20% of pts) adverse events (AEs) with ibr included diarrhea, fatigue, cough and nausea. Most frequent AEs with clb included nausea, fatigue, neutropenia, anemia and vomiting. AEs leading to treatment discontinuation were less frequent with ibr (9% vs 23%). Atrial fibrillation occurred in 6% (6 pts grade 2 and 2 pts grade 3) with ibr and 1% with clb. Hypertension was noted more frequently on ibr, but was limited to grade 1-3 and managed without ibr dose modification or discontinuation. Major hemorrhage occurred in 4% (1 pt grade 2, 4 pts grade 3, 1 pt grade 4) with ibr over median follow-up of approximately 1.5 years, and in 2% with clb. At the time of study closure, 87% of pts randomized to ibr continue to receive ibr. Conclusions: Treatment with single-agent ibr was superior to clb in terms of PFS, OS, ORR, EFS and hematologic improvement in treatment-naïve older CLL/SLL patients, with an 84% reduction in risk of death, and an acceptable safety profile. Disclosures Off Label Use: ibrutinib in first-line CLL (including non-del17p CLL). Barr:Gilead: Consultancy; Abbvie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria; Lundbeck: Honoraria; Gilead: Honoraria; Roche: Honoraria. Ghia:Adaptive: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Roche: Consultancy, Research Funding; Acerta Pharma BV: Research Funding. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bartlett:Novartis: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; MERC: Research Funding; Insight: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Coutre:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Quach:Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Janssens:Mundipharma: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy. O'Dwyer:Celgene: Honoraria, Research Funding. Hellmann:BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau; Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau. Schuh:Acerta Pharma BV: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Tam:AbbVie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Keating:Glaxo-Smith-Kline Inc.: Other: Advisory board; Celgene Corp.: Consultancy. Suri:Pharmacyclics LLC, an AbbVie Company: Employment. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding.