No abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet clinical need. Though BTK and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL treated with ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital PCR (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32/49 relapsing cases (65%) carried at least 1 hotspot BTK mutation and/or PLCG2 mutation(s); in 6/32, BTK mutations were only detected by ddPCR [variant allele frequency (VAF) 0.1-1.2%]. BTK/PLCG2 mutations were also identified in 6/49 responding patients (12%; 5/6 VAF &lt;10%), of whom 2 progressed at later time points. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, while BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n=11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut versus BTKwt relapsing cases, and ibrutinib treatment did not appear to favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.

Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr and chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As the addition of obinutuzumab (G) to clb provides superior efficacy over clb alone or rituximab-G, we investigated the potential for improved efficacy with addition of G to single-agent ibr vs clb-G in an international, open-label, randomized phase 3 study (PCYC-1130; iLLUMINATE) in first-line CLL/SLL. Methods : Eligible pts had previously untreated CLL/SLL requiring treatment per iwCLL criteria and were ≥65 years of age or were <65 years old with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation). Pts were randomized 1:1 to receive ibr (420 mg once daily continuously) combined with G (1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles, for a total of 6 cycles), or clb (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles) combined with G (as above). Primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included PFS in high-risk population (del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV), rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Pts with IRC-confirmed progression on clb-G could cross over to next-line therapy with single-agent ibr. Results : A total of 229 pts were randomized to ibr-G (n=113) or clb-G (n=116). Median age was 71 years (range, 40-87) and 65% of pts had high-risk genomic features. At a median follow-up of 31.3 mo, ibr-G significantly prolonged IRC-assessed PFS compared with clb-G (median not reached [NR] vs 19.0 mo; HR 0.231; 95% CI, 0.145-0.367; P<0.0001), with a 77% reduction in risk of progression or death (Figure 1). PFS rates at 30 mo were 79% and 31% with ibr-G and clb-G, respectively. Investigator (INV)-assessed PFS was also significantly improved with ibr-G vs clb-G (median NR vs 21.9 mo; HR 0.260; 95% CI, 0.163 to 0.415; P<0.0001). PFS benefit with ibr-G was consistent across subgroups examined. Superior PFS with ibr-G vs clb-G was also seen in the high-risk population (median NR vs 14.7 mo; HR 0.154; 95% CI, 0.087-0.270; P<0.0001), with an 85% reduction in risk of progression or death in this population (Figure 2). IRC-assessed ORR was 88% with ibr-G vs 73% with clb-G; complete response (CR/CRi) rate was also higher with ibr-G (19% vs 8%). INV-assessed ORR was 91% with ibr-G vs 81% with clb-G; CR/CRi rates were 41% and 16%, respectively. MRD was undetectable in blood and/or bone marrow (<10-4 by flow cytometry) for 35% of pts with ibr-G and 25% with clb-G. 30-mo OS rates were 86% and 85% in the ibr-G and clb-G arms, respectively, with 40% of pts randomized to clb-G receiving single-agent ibr as second-line therapy. Over a median follow-up of 31.3 mo, 4% in the ibr-G arm and 44% in the clb-G arm initiated subsequent therapy. Median treatment duration was 29.3 mo with ibr-G and 5.1 mo with clb-G. Most common (≥3%) serious adverse events (AEs) were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibr-G, and infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with clb-G. IRRs were less frequent with ibr-G vs clb-G for both any grade (25% vs 58%) or grade ≥3 or serious IRRs (3% vs 9%). No pt discontinued G due to IRRs with ibr-G vs 7 pts (6%) with clb-G. AEs leading to discontinuation of ibr or clb occurred in 18 (16%) and 11 pts (9%), respectively; AEs leading to discontinuation of G occurred in 10 pts (9%) in ibr-G arm and 15 (13%) in clb-G arm. With ~3 yrs of follow-up, 70% of pts in the ibr-G arm remain on single-agent ibr. Conclusions : Ibr-G resulted in superior PFS regardless of high-risk genomic features, compared with clb-G, a standard CIT regimen. Response rates and depth of remission (CR and undetectable MRD) were also higher with ibr-G. Combination therapy with ibr-G was tolerable with no new safety signals identified and represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population. Disclosures Moreno: Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Greil:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Demirkan:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Simkovic:Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Novak:Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Strugov:Beigene Ltd: Equity Ownership; Kite Pharma: Equity Ownership; Portola Pharmaceuticals Inc: Equity Ownership; Juno Therapeutics: Equity Ownership; TG Therapeutics Inc: Equity Ownership; Loxo Oncology Inc: Equity Ownership; Crispr Therapeutics AG: Equity Ownership; Intellia Therapeutics Inc: Equity Ownership; Editas Medicine Inc.: Equity Ownership; Ignyta Inc.: Equity Ownership; Astellas: Honoraria; AbbVie: Equity Ownership, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Janssen: Honoraria; ECO-SAFETY Medical Center: Employment; Aptose Biosciences Inc: Equity Ownership; Esperion Therapeutics Inc: Equity Ownership; Merck & Company: Other: TRAVEL, ACCOMODATIONS, EXPENSES. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Gribben:Roche: Honoraria; Abbvie: Honoraria; Kite: Honoraria; NIH: Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; Acerta Pharma: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding. Hsu:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Clow:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: LEADERSHIP; TRAVEL, ACCOMODATIONS, EXPENSES. James:AbbVie: Equity Ownership, Other: Spouse's employment and stocks, Patents & Royalties: AbbVie Patent Applications; Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Flinn:Genentech: Research Funding; Pharmacyclics: Research Funding; Trillium: Research Funding; Curis: Research Funding; Agios: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Gilead: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Merck: Research Funding; Portola: Research Funding.