Mulligan, Stephen P.

Abstract Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision‐making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

Abstract Background: Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients (pts) older than 65 y at diagnosis (US SEER). Historically, younger, more fit pts were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115) trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naïve (TN) CLL/SLL. This analysis examines safety and efficacy from these studies by age. Methods: RESONATE randomized 391 pts with R/R CLL/SLL to receive ibr (n=195; 420 mg once daily) until progressive disease (PD) or unacceptable toxicity or intravenous ofatumumab (n=196; 300 mg at week 1, 2000 mg weekly for 7 w and then every 4 w for 16 w). RESONATE-2 randomized TN pts aged ≥65 y to receive ibr (n=136; 420 mg once daily) until PD or chlorambucil (clb; n=133; 0.5 mg/kg to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pt data from both studies were grouped by age (ibr and comparators [comp]) and analyzed for effect of age on outcome. Results: Ibr group included 136 TN pts: 65 to <75 y (termed mid, n=90) and ≥75 y (termed old, n=46), and 195 R/R pts: <65 y (termed young, n=77), 65 to <75 y (mid, n=75), and ≥75 y (old, n=43). Table 1 lists key baseline pt characteristics. For ibr, median follow-up was 28.6 mo for TN and 36.1 mo for R/R pts. PFS is shown in Figure 1. For TN ibr pts, the 24-mo PFS rates were 88% (mid) and 89% (old), whereas clb pts aged ≥75 y did worse than those aged 65 to <75 y (23% vs 40%). For R/R pts, the 24-mo PFS was 75% (young), 77% (mid), and 62% (old). For ibr, median OS was not reached for any age subgroup (R/R or TN). The CR+CRi rates for TN ibr pts were 19% (mid) and 17% (old) and for R/R pts were 6% (young), 9% (mid), and 9% (old). Median treatment duration and the most common grade ≥3 AEs are listed in Table 2. The most frequent any-grade adverse events (AEs) were diarrhea, fatigue, cough, upper respiratory tract infection, nausea, pyrexia, and anemia for all pts and age subgroups. For ibr, grade ≥3 AEs occurred in 64% (mid) and 83% (old) of TN pts, and 70% (young), 84% (mid), and 84% (old) of R/R pts. The prevalence of common grade ≥3 AEs was typically highest in the first 12 mo of ibr therapy, and decreased thereafter for all age groups. Pts ≥75 y had a higher rate of grade ≥3 neutropenia and urinary tract infection in both TN and R/R populations. R/R ibr pts <65 y experienced a lower frequency of grade ≥3 pneumonia and atrial fibrillation (AF) than older subgroups. Any grade AF occurred in 11% (mid) and 9% (old) of TN ibr pts, and 1% (young), 20% (mid), and 14% (old) of R/R ibr pts. For ibr, dose reduction due to AE occurred in 9% (mid) and 22% (old) of TN pts and 6% (young), 20% (mid), and 12% (old) of R/R pts. 107 (79%) TN ibr pts remain on treatment: 81% (mid) and 74% (old); 99 (51%) R/R pts remain on treatment: 49% (young), 59% (mid), and 40% (old). For ibr, discontinuation due to AE occurred in 11% (mid) and 13% (old) of TN pts, and 6% (young), 11% (mid), and 19% (old) of R/R pts. The most common AE leading to discontinuation of ibr was infection(TN: n=4, RR: n=5). Conclusions: The PFS rate for TN ibr pts was similar regardless of age subgroup, whereas it was shorter for clb-treated pts ≥75 y compared with those 65 to <75 y. In the R/R population, ibr pts ≥75 y tended to have shorter PFS compared to those <75 y. There was no perceivable difference in CR rate by age within the TN and R/R ibr populations. The rates of grade ≥3 AEs tended to be higher in pts ≥75 y for both ibr and comp arms. Age did not impact discontinuation rates due to AE for TN pts treated with ibr, but increased with age for R/R pts. This study is limited by the number of pts ≤65 y who were only eligible for the R/R trial. This analysis supports single-agent ibrutinib as a treatment option regardless of pt age, but reinforces the need for close toxicity monitoring, especially in older pts. Disclosures Woyach: Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Brown:Pfizer: Consultancy, Honoraria, Other: travel, accommodations, expenses; Genentech: Consultancy, Honoraria; Roche: Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Sun Biopharma: Honoraria, Other: travel, accommodations, or other expenses. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Barr:AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Devereux:Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Reddy:KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ninomoto:AbbVie: Equity Ownership; Amgen: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Other: Travel, Accommodations, Expenses.

Abstract Introduction: Ibrutinib (Imbruvica®), an oral, first-in-class covalent BTK inhibitor, is a new treatment option approved by FDA for chronic lymphocytic leukemia (CLL) patients (pts) with ≥1 prior therapy. We previously reported results from the phase III trial, in which ibrutinib (ibr) significantly improved progression-free and overall survival vs ofatumumab (ofa) in pts with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) (Byrd et al. NEJM, 2014). Here, we report measures of patient well-being, including hematologic, immunologic, and quality of-life parameters, at interim analysis (IA). Methods: Pts with CLL/SLL after ≥1 prior therapy were randomized 1:1 to ibr 420 mg/day until progression or unacceptable toxicity, or to ofa for up to 24 weeks. At IA, secondary efficacy endpoints of hematologic improvement (sustained improvement ≥56 days without transfusions or growth factors) and FACiT-Fatigue (FACiT-F) outcomes were analyzed, along with exploratory endpoints assessing disease-related symptoms (DRS), serum immunoglobulin, patient-reported outcomes (PROs) by EORTC QLQ-C30, and medical resource utilization (MRU). Results: Of 391 enrolled pts (ibr n=195; ofa n=196), 63% had cytopenia(s) at baseline: 45% had anemia (hemoglobin ≤11 g/dL), 35% thrombocytopenia (platelets ≤100×109/L), and 20% neutropenia (absolute neutrophil counts [ANC] ≤1.5×109/L). On the ibr arm, 69% of pts with baseline cytopenias experienced sustained improvement in blood counts compared to 43% on ofa (P<0.0001, table). There was no decrement in serum immunoglobulins (IgA, IgG, IgM) during follow-up. IgA levels increased on the ibrutinib arm only (mean change from baseline: 41% at week 24). Immune cells CD4+ and CD8+ T-cell and NK-cell levels remained relatively stable during treatment. Mean change in FACiT-F score from baseline are shown in the figure for ibr and ofa arms. At week 24, clinically meaningful (≥3 points) improvement in FACiT-F occurred in more pts on ibr than ofa (59% vs 46%, P=0.06); clinically meaningful deterioration was reported by 14% vs 24% (P=0.08), respectively. A larger proportion of ibr vs ofa pts showed clinically meaningful improvement on EORTC-QLQ-C30 global health scores (46% vs 40%). Clinically meaningful improvement (≥10 points) from baseline to week 24 in ibr vs ofa pts was observed for fatigue (median 11 vs 0). A 50% reduction in lymph node based on IRC-assessed CT was observed in 93% (177/190 evaluable) of ibr pts compared with 17% (29/174 evaluable) of ofa pts (P< 0.0001). Splenic response based on IRC-assessed CT was reported for 85% (138/163 evaluable) of ibr pts compared with 54% (82/151 evaluable) of ofa pts. Baseline DRS were comparable between groups; however, improvement by at least 1 grade (G) post-baseline was observed in ibr relative to ofa pts for weight loss (100% vs 93%), fatigue (88% vs 72%), night sweats (95% vs 86%), and anorexia (100% vs 64%), respectively. Cumulative MRU was comparable for growth factors and transfusions, with ibr pts having longer median treatment duration: 8.6 months for ibr vs 5.3 for ofa. Hospitalizations in the first 30 days occurred in 2% ibr vs 15% ofa pts. After adjusting for treatment exposure duration, diarrhea, grade 1-2 bleeding events (e.g petechiae), and atrial fibrillation were among those noted to be more frequent on the ibrutinib arm while events such as fatigue, infusion reaction, and peripheral sensory neuropathy were seen more commonly with ofa. Major hemorrhage events were uncommon, observed in 2 patients on the ibr arm vs 3 on ofa arm without adjusting for exposure time. Exposure-adjusted analysis showed no difference in any-grade infection and a 43% relative reduction for grade 3 or higher infections for ibr. Conclusions: Ibr compared to ofa when administered to previously treated CLL/SLL pts led to improvements in hematologic function and disease burden. A survival benefit with ibr, together with sustained improvements in hematologic endpoints and PRO suggest that ibr enhances quality of life while prolonging survival. Table. Sustained hematologic improvement Parameter, n (%) ITT population Pts with cytopenias at baseline Ibr n=195 Ofa n=196 P value Ibr n=195 Ofa n=196 P value Platelets 60 (31) 19 (10) <0.0001 53/74 (72) 14/64 (22) <0.0001 ANC 52 (27) 19 (10) <0.0001 26/41 (63) 12/38 (32) 0.0047 Hemoglobin 42 (22) 32 (16) 0.1883 42/89 (47) 32/86 (37) 0.1815 Figure. Improvement in FACiT-F by treatment arm. Figure. Improvement in FACiT-F by treatment arm. Disclosures Barrientos: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulligan:Roche, Abbvie: Consultancy, Honoraria. Jaeger:Janssen Cilag: Honoraria. Devereux:Pharmacyclics, Janssen: Consultancy, Honoraria. Robak:Janssen: Consultancy, Research Funding. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Bloor:GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dearden:Roche, GSK, Gilead, Janssen, Napp: Honoraria. Jones:Pharmacyclics: Consultancy, Research Funding. Kierschniak:Pharmacyclics, GmbH: Employment. Eckert:Pharmacyclics: Employment. Suzuki:Pharmacyclics: Employment. Hsu:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding.

Abstract BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments. AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%. The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with <0.01% by both methods, 1 sample with 0.03% CLL by HTS and <0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log). CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to >95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with <0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. Disclosures Rawstron: Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

LBA7008 Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%), and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease. Clinical trial information: NCT01578707.