Search

Background Genomic abnormalities such as del(17p)/TP53 mutation, del(11q), and unmutated IGHV are risk factors that predict inferior outcomes with chemoimmunotherapy (CIT) in patients (pts) with CLL/SLL (Byrd J Clin Oncol 2006). Mutations in BIRC3, NOTCH1, SF3B1, and XPO1 have also been associated with poor outcomes with CIT in pts with CLL (Foa Haematologica 2013; Jain Am J Hematol 2016). Ibrutinib (ibr) is the only once-daily Bruton's tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival (OS) benefit shown in multiple randomized phase 3 studies versus established therapies in pts with previously untreated or relapsed/refractory CLL/SLL. Superior outcomes were demonstrated with ibr-based therapy versus comparators in the overall population, and in pts with high-risk disease features, such as TP53 aberrations, del(11q), and/or unmutated IGHV in the RESONATE-2 study of first-line single-agent ibr (Burger Leukemia 2020) and in the iLLUMINATE study of first-line ibr-obinutuzumab (Moreno Lancet Oncol 2019). In pts with relapsed/refractory CLL/SLL who were treated with ibr, mutations in BIRC3, NOTCH1, SF3B1, or XPO1 had no significant impact on the PFS benefit conferred by ibr (Byrd Blood 2019). To better understand outcomes in pts with previously untreated CLL with various high-risk genomic features, including integrated FISH cytogenetics and single gene mutations, we performed a pooled analysis of two phase 3 studies of ibr-based therapy in the first-line treatment of CLL/SLL (RESONATE-2 and iLLUMINATE). Methods In RESONATE-2 (NCT01722487), pts aged ≥65 years without del(17p) were randomized to single-agent ibr or chlorambucil (clb). In iLLUMINATE (NCT02264574), pts aged ≥65 years, or Results The pooled analysis included 498 pts treated with first-line ibr-based or clb-based therapy (n=249 each) with median follow-up of 49.1 mos (range, 0.1-78.7). Ibr-based therapy significantly improved ORR and PFS vs comparator (clb-based) therapy. At 42 mo, PFS rates were significantly higher across high-risk genomic subgroups in ibr-treated pts (63-82%) compared with clb-treated pts (6-34%), and consistent PFS benefit with ibr was observed across all high-risk genomic subgroups (Figure). When comparing ibr-treated pts with specified high-risk genomic features vs those without, PFS and ORR were comparable in the different subgroups, including pts with unmutated vs mutated IGHV (PFS HR, 1.79, 95% CI 0.99-3.24) or mutated vs not mutated NOTCH1 (PFS HR, 1.05, 95% CI 0.65-1.69) (Table). Improved outcome was also noted for pts with del(17p)/TP53 mutated/BIRC3 mutated, the highest risk category per Rossi 2013 (HR 1.05, 95% CI 0.54-2.04). At a median duration of ibr treatment of 35.7-43.8 mo across these high-risk subgroups, there were no meaningful differences in the rates of treatment-emergent adverse events (AEs) of any grade or grade ≥3 AEs compared to those of the overall population. Conclusions This integrated analysis of pts undergoing first-line ibr-based treatment, with up to 79 mo follow up, demonstrated similar PFS and ORR for ibr-treated pts with or without high-risk genomic features, and confirmed significant PFS and ORR benefits with ibr-based therapy versus clb (± obinutuzumab). This analysis across two phase 3 studies demonstrated the efficacy of first-line ibr-based treatment irrespective of cytogenetic and mutational risk features, including those with unmutated IGHV, NOTCH1 mutation, and those with the highest risk classification of del(17p)/TP53 mutation/BIRC3 mutation. Disclosures Burger: Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Other: Travel/accomodations/expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; BeiGene, Gilead, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Robak:BioGene: Honoraria, Research Funding; UCB: Honoraria, Research Funding; UTX-TGR: Research Funding; Bristol Meyers Squibb: Research Funding; Momenta: Consultancy; Medical University of Lodz: Current Employment; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; Pfizer: Research Funding; GSK: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Demirkan:AbbVie, Amgen, AstraZeneca, and Roche: Consultancy; AbbVie, AstraZeneca, Janssen, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Amgen, and Janssen: Speakers Bureau; AbbVie, Amgen, Janssen, and Pfizer: Other: Travel/accommodations/expenses. Bairey:AbbVie: Consultancy; Janssen: Consultancy, Research Funding. Moreno:Janssen: Speakers Bureau; AbbVie and Janssen: Research Funding; Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy. Simpson:BeiGene: Current Employment, Current equity holder in publicly-traded company; AbbVie and Janssen: Honoraria, Other: Travel/accommodations/expenses; AbbVie, Acerta, Amgen, BeiGene, Celgene, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Roche, Sanofi, and Pharmacyclics LLC, an AbbVie Company: Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Dai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie, Bristol-Myers Squibb, Exelixis, Gilead, GlaxoSmithKline, and Revance: Current equity holder in publicly-traded company. Cheung:Pharmacyclics LLC, an AbbVie Company: Current Employment, Patents & Royalties: and other intellectual property; AbbVie and Eli Lilly: Current equity holder in publicly-traded company. Kwei:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Gilead: Current equity holder in publicly-traded company. Lal:Pharmacyclics LLC, an AbbVie Company: Current Employment; The Permanente Medical Group (spouse): Current Employment; AbbVie, Clovis, Gilead Sciences, Infinity, Reviva Pharmaceuticals, and The Permanente Medical Group: Current equity holder in publicly-traded company. Hsu:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Kipps:AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company: Consultancy. Tedeschi:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

7524 Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by FDA for treatment (Tx) of patients (pts) with CLL. Following the outcome of the RESONATE-2 trial, ibr was approved as the first chemotherapy-free Tx option for treatment-naïve (TN) pts. In this study, ibr reduced the risk of progression or death by 84% compared with chlorambucil (chl). To assess the impact of ibrutinib vs this traditional chemotherapeutic agent on the immune system, quantitative changes in circulating cells were studied throughout the first year of Tx. Methods: Immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of TN CLL pts who received 420 mg ibr once daily (n=50) or 0.5-0.8 mg/kg chl twice a month (n=30). Medians of statistically significant changes (p+ and CD8+ T cells, except stem cell memory T cells (TSCM), decreased by 51%-90%. Regulatory T cells (Treg) and PD1+ T cells also decreased similarly; however, long-term activated T cells (TLA) were not impacted. On the other hand, ibr mainly reduced B cells (90%), MDSC (61%) and some T cells, specifically TLA, PD1+ T cells, Treg and effector T cells (27-52%). Naïve T cells, TSCM, central memory T cells and NK cells were spared throughout the full year of Tx. Classical monocytes were increased (+187%), while non-classical monocytes and intermediate monocytes remained relatively steady. Conclusions: Chl, a traditional chemotherapy, affected non-specifically most immune cell subsets in circulation, although surprisingly it did not affect TLA which have been reported as dysfunctional in CLL. Ibr represents a more targeted Tx approach than cytotoxic chemotherapy; essentially B cells, abnormal T subsets (TLA, PD1+T, Treg) and pro-tumor MDSCs were reduced. However, ibr preserved naïve T cells, NK cells and monocytes, which are important for mounting anti-tumor responses. Clinical trial information: NCT01722487.

Background: Chronic GVHD (cGVHD) is a serious complication of allogeneic stem cell transplantation. Effective therapy for patients (pts) with cGVHD who fail corticosteroids remains an unmet medical need. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through its inhibition of Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) (Dubovsky, J Clin Invest 2014). Ibr has recently been granted a breakthrough therapy designation (BTD) for cGVHD after failure of 1 or more lines of systemic therapy. The request for a BTD was supported by early data from a phase 2 study that evaluated the efficacy and safety of ibr in pts with cGVHD who are in need of additional therapy. The final results of this same study are presented here. Methods: Pts who had received ≤3 prior regimens for cGVHD and had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4 were treated with daily ibr (420 mg) until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on the 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety end points. The effects of ibr on lymphoid and myeloid cell signaling pathways, and phenotype along with plasma cytokines and chemokines were evaluated. Results: A recommended phase-2 dose of 420 mg was identified in phase 1b (n=6) with no dose-limiting toxicities reported. Of 42 pts treated with ibr, median age was 56 y (range, 19-74). Median duration of cGVHD before study entry was 13.7 mo (range, 1.1-63.2). Median number of prior regimens was 2 (range, 1-3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (28/42 pts; 9 [21%] CR, 19 [45%] PR), with 20/28 (71%) and 12/25 (48%) responders showing a sustained response of ≥20 and ≥32 weeks, respectively (Figure 1). Overall, 21 responders (75%) had corticosteroid doses 3 pts were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). Serious AEs (SAEs) occurred in 22 pts (52%); grade ≥3 SAEs reported in 17 pts (40%) included pneumonia (n=5), septic shock (n=2), and pyrexia (n=2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Five pts discontinued therapy for progressive cGVHD and 14 for AEs including fatigue (n=3) and pneumonia (n=2). Twelve pts (29%) continued ibr; their treatment duration ranges from 5.6-24.9 mo. Conclusions: With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose to an acceptable minimal level. Biomarker changes support an effect of ibr on immune cell subsets in pts with cGVHD. Reported AEs are consistent with those for ibr in B-cell malignancies and pts with cGVHD. Observed response rates in this pretreated, high-risk population support further study of ibr for frontline treatment of cGVHD. Disclosures Miklos: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, and Expenses, Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Sanofi Oncology: Other: Travel, Accommodations, and Expenses. Cutler:Insys: Consultancy; Seattle Genetics: Consultancy; Regimmunie: Consultancy; Incyte: Consultancy. Arora:Takeda Oncology: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Waller:Cerus: Equity Ownership; Chimerix: Equity Ownership; Cambium Medical Technologies: Equity Ownership, Other: Other relationship indicated, Patents & Royalties; Novartis: Consultancy, Honoraria, Research Funding; Helocyte: Consultancy. Jagasia:Theracos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Flowers:Pharmacyclics, LLC, an AbbVie Company: Research Funding. Logan:Amgen: Consultancy; Jazz: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Research Funding. Nakamura:Seattle Genetics: Consultancy; Amgen: Consultancy. Blazar:Tobira Therapeutics: Consultancy; Vulcan CApital: Consultancy; Idera Pharma: Consultancy; Sidley Austin LLP: Consultancy; Merck Serono: Consultancy; Fate Therapeutics: Consultancy; Merck, Sharpe & Dohme Corp: Consultancy; Bristol-Myers Squibb: Consultancy; Kadmon Pharmaceuticals Inc: Consultancy, Research Funding; Kymab: Consultancy; Five Prime Therapeutics: Consultancy; Vitae Pharmaceuticals, Inc.: Consultancy; Flx Bio: Consultancy; No Company: Patents & Royalties: no company. Li:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Lal:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Infinity: Equity Ownership; Clovis: Equity Ownership; Reviva Pharmaceuticals: Equity Ownership; The Permanente Medical Group: Employment, Equity Ownership; Gilead Sciences: Employment, Equity Ownership. Dubovsky:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Jaglowski:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding.