No abstract

TO THE EDITOR Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9]. We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0-91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4), treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2). Sixty-

Background: Acalabrutinib is a highly selective, covalent irreversible Bruton tyrosine kinase inhibitor with minimal activity against other kinases. Acalabrutinib has demonstrated durable responses as a single agent or combined with O in treatment-naïve (TN) CLL. Here, interim results are presented for the multicenter, open-label Phase 3 ELEVATE-TN study (NCT02475681), which evaluated the efficacy and safety of acalabrutinib + O vs acalabrutinib alone vs O + Clb in pts with TN CLL. Methods: Eligible pts had TN CLL requiring treatment per iwCLL criteria and were aged ≥65 y or <65 y with coexisting conditions (CIRS score >6, creatinine clearance <70 mL/min). Pts were randomized 1:1:1 to receive oral acalabrutinib (100 mg twice daily continuously) alone or combined with intravenous O (1000 mg on Days 1, 2 [split 100/900], 8, and 15 of Cycle 2, and Day 1 of subsequent 28-day cycles for a total of 6 cycles), or O plus oral Clb (0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles). Pts were stratified by del(17p) status, ECOG status (≤1 vs 2), and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) with acalabrutinib + O vs O + Clb. Key secondary endpoints included IRC-assessed PFS with acalabrutinib vs O + Clb, IRC-assessed overall response rate (ORR), overall survival (OS), and safety. Minimal residual disease (MRD) in peripheral blood or bone marrow was assessed in pts with investigator-assessed complete response (CR)/CR with incomplete marrow recovery (CRi). Crossover to acalabrutinib monotherapy was allowed for pts in the O + Clb arm with IRC-confirmed progression. Results: From 9/14/2015-2/8/2017, 535 pts were randomized to the acalabrutinib + O (n=179), acalabrutinib (n= 179), or O + Clb (n=177) arms. The median age was 70 y (range, 41-91); 69% had high- and 12% had very high-risk CLL IPI scores. At a median follow-up of 28 mo, acalabrutinib + O significantly prolonged PFS vs O + Clb (median not reached [NR] vs 22.6 mo; HR 0.10, 95% CI 0.06-0.18, P<0.0001), reducing the risk of progression or death by 90% (Figure). Acalabrutinib (median NR) also prolonged PFS vs O + Clb (HR 0.20, 95% CI 0.13-0.31, P<0.0001). Estimated 30-mo PFS rates with acalabrutinib + O, acalabrutinib, and O + Clb were 90%, 82%, and 34%, respectively. PFS improvement with acalabrutinib + O or acalabrutinib vs O + Clb was consistent across subgroups examined including del(17p) (HR [95% CI]; 0.13 [0.04-0.46]; 0.20 [0.06-0.64]). Median OS was not reached in any arm; (HR [95% CI]; acalabrutinib + O vs O + Clb, 0.47 [0.21-1.06], P=0.0577; acalabrutinib vs O + Clb, 0.60 [0.28-1.27], P=0.1556). In the acalabrutinib + O, acalabrutinib, and O + Clb arms, the estimated 30-mo OS rates were 95%, 94%, and 90%, respectively. Five pts (3%) in the acalabrutinib + O arm, 11 pts (6%) in the acalabrutinib arm, and 55 pts (31%) in the O + Clb arm had received a next therapy; 45 pts (25%) in the O + Clb arm crossed over to the acalabrutinib monotherapy arm. IRC-assessed ORR was higher with acalabrutinib + O (94%; 95% CI, 89.3%-96.5%) vs O + Clb (79%; 95% CI, 71.9%-83.9%; P<0.0001); the ORR with acalabrutinib monotherapy was 85%. CR rates were higher with acalabrutinib + O (13%) vs O + Clb (5%); there was 1 CR in the acalabrutinib monotherapy arm. MRD data will be presented. The median treatment duration was 27.7 mo for acalabrutinib + O (range, 2.3-40.3) and acalabrutinib (range, 0.3-40.2) and 5.6 mo (range, 0.9-7.4) for O + Clb. Common adverse events (AEs) are shown in the Table. AEs were similar between the acalabrutinib-containing arms. Infusion reactions were less frequent with acalabrutinib + O (13%) than with O + Clb (40%). AEs led to treatment discontinuation in 20 pts (11%) on acalabrutinib + O, 16 pts (9%) on acalabrutinib, and 25 pts (14%) on O + Clb. With >2 y of follow-up, 79.3% of pts in both the acalabrutinib-containing arms remain on single-agent acalabrutinib. AEs of interest (acalabrutinib + O or acalabrutinib vs O + Clb) were atrial fibrillation (any grade: 3% or 4% vs 1%), bleeding (any grade/Grade ≥3: 43%/2% or 39%/2% vs 12%/0%), and hypertension (Grade ≥3: 3% or 2% vs 3%). Conclusions: Acalabrutinib + O and acalabrutinib monotherapy significantly improved PFS vs O + Clb, with tolerable safety in pts with TN CLL. Despite cross over for disease progression in the O + Clb arm, a trend toward improved OS was observed in both acalabrutinib arms, though longer follow-up is needed. Disclosures Sharman: AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Banerji:CIHR: Research Funding; LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Licensing fee, Research Funding; Abbvie: Consultancy, Honoraria. Herishanu:Janssen: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Munir:Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; AbbVie: Honoraria. Walewska:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Speakers Bureau; Takeda: Other: Travel grant; Novartis: Other: travel grant. Follows:Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Karlsson:Skane University Hospital: Employment. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Corbett:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Tauranga Hospital: Employment; Pathlab Waikato: Equity Ownership. Walker:Peninsula Health (public hospital): Employment; Alfred health (public hospital): Employment; Roche: Other: Travel grant. Jurczak:Incyte: Research Funding; Takeda: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Roche: Research Funding; Gilead: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events. Janssens:Novartis: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; idem consultancy: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Cymbalista:AstraZeneca: Honoraria; Janssen: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Gilead: Honoraria; Abbvie: Honoraria. Wierda:Juno Therapeutics: Research Funding; Janssen: Research Funding; Cyclcel: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding. Coutre:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Skarbnik:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Kamdar:AstraZeneca: Consultancy; University of Colorado: Employment; Celgene: Consultancy; Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Izumi:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib patents. Munugalavadla:Acerta Pharma: Employment; Gilead Sciences: Equity Ownership; AstraZeneca: Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Wang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Wong:Acerta Pharma: Employment. Byrd:Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau.

There is a significant difference between serum infliximab levels in patients with IBD in remission, compared with those who relapse. A trough threshold during maintenance > 2 µg/ml is associated with a greater probability of clinical remission and mucosal healing.

Histone deacytelase inhibitiors (HDACi) represent a new class of anti-lymphoma therapeutics. Data in the clinical setting regarding on- and off-target effects of these agents are limited. Epstein-Barr virus (EBV)-positive lymphomas represent a highly defined system in which to make these observations. We present a case of a patient with multiple relapsed EBV-positive Diffuse Large B-cell Lymphoma that was chemo-refractory to anthracylcines, alkylating agents and rituximab. Treatment was commenced with the HDACi sodium valproate (VPA) in combination with the anti-viral nucleoside analogue ganciclovir (GCV). Therapy resulted in detectable cell-free unencapsulated circulating EBV-DNA providing supportive evidence for the first-time that lysis of virus infected lymphoma cells is induced using this therapeutic combination. EBV-specific CD8+ effector T-cell immunity was not impaired by VPA/GCV. Although GCV/VPA was insufficient to induce clinical remission, our data furthers the rationale that more potent HDAC inhibitors such as butyrate or gemcitabine together with GCV, perhaps in combination with chemotherapy, should be further investigated as therapy in relapsed/refractory EBV-positive lymphomas.