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What is this summary about? This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. What were the results? Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. What do the results of the study mean? In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT01724346 ( ClinicalTrials.gov )

Figure S2C displays probability of progression-free survival over time in subgroups of patients with and without bulky disease

Purpose:In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.Patients and Methods:Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.Results:As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).Conclusions:Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.

Supplemental Figure Legend

Figure S3 displays probability of overall survival over time in the study population

•Table S1 shows a summary of prior anticancer therapies received by all patients in the study •Table S2 shows best overall response, overall response rate, and duration of response by investigator in the study population of patients while receiving ofatumumab in the parent DUO study before crossover •Table S3 shows rates of all serious TEAEs and individual hematologic and non-hematologic serious TEAEs in {greater than or equal to} 2% of patients in the study population • Table S4 shows rates of all TEAEs leading to death in patients in the study population •Table S5 shows a summary of patient disposition information

Figure S1 displays probability of progression-free survival over time in the study population and in the subgroup of patients with del(17p) and/or TP53 mutations that received ofatumumab while participating in the parent DUO study before crossover

The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous, and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that affect only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the nonmalignant microenvironment. Using CXM, we defined genetic variants on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3IL2Rγ consomic model compared with the SSIL2Rγ parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3IL2Rγ background. Through comparative mapping and whole-genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment that underlie differences in breast cancer risk. Cancer Res; 74(22); 6419–29. ©2014 AACR.

Expanded Materials and Methods, Supplemental Figures, and Supplemental Tables Figure S1. Flow cytometric analysis of peripheral blood from SS, SS.BN3, SSIL2Rγ, and SS.BN3IL2Rγ rats. Figure S2.SH2B3 specifically marks CD31+ blood vessels, but not LYVE1+ lymphatic vessels. Table S1. Peripheral blood analysis of SS, SS.BN3, SSIL2Rγ and SS.BN3IL2Rγ rats. Table S2. Genes located in the overlapping portions of the rat chromosome 3 cancer QTLs. Table S3. Variants that cosegregate between tumor resistant (BN and Cop) and tumor susceptible (ACI, F344, and SS) rat strains.

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

Background: RIC-alloHSCT had been our standard of care for patients more than 50, with comorbidities or previously transplanted. Methods: 484 consecutive RIC-alloHSCT were included. GVHD prophylaxis consisted of CsA-MTX(147), CsA-MMF(124), tacro-siro(145) and PTCy-tacro(68). Results: The median time of overall follow-up in survivors was 8-years (with at least 3-years in all four GVHD prophylaxis groups).Neutrophil and platelet engraftment was longer for PTCy-tacro (p0.0001). CumInc of grade III-IV aGVHD was 17% at 200 days and of moderate-severe cGvHD was 36% at 8-years. GVHD prophylaxis was the only prognostic factor in the MVA(p0.0001). NRM and relapse were 29% and 30%; OS and PFS were 43% and 39% at 8-years. At 3-years, OS was highest in the PTCy-tacro (68%) than in the tacro-siro (61%) and CsA+MTX/MMF (49%) cohorts (PConclusion: This large single institution experience shows the improvement of RIC-alloHSCT over time, mainly due to a better prevention of acute and chronic GVHD. Based on our recent results we strongly support PTCy as the current standard of care since in our hands associates to the best 3-year survival.

Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune hemolytic anemia and immune thrombocytopenia and, less frequently, with pure red cell aplasia and immune neutropenia. The emergence of these complications is related to an intertwined and complex relationship between patient, disease, and treatment characteristics. The prognostic repercussion of autoimmune cytopenia (AIC) in patients with CLL mainly depends on its response to therapy. For patients with AIC and nonactive CLL, treatment is as in primary, uncomplicated AIC, keeping in mind that no response is an indication for CLL therapy. The success of treating active CLL-related AIC widely relies on a flexible strategy that should include initial therapy with corticosteroids and a rapid shift to effective CLL therapy in nonresponding patients. Targeted therapies (e.g., ibrutinib) that have already demonstrated to be effective in CLL-related AIC will likely offer a unique possibility of treating both AIC and CLL as a single target.

Background Hyperkalemia is common among hemodialysis (HD) patients and has been associated with adverse clinical outcomes. Previous studies considered a single serum potassium (K) measurement or time-averaged values, but serum K excursions out of the target range may be more reflective of true hyperkalemia events. We assessed whether hyperkalemia excursions lead to an elevated risk of adverse clinical outcomes. Methods Using data from 21 countries in Phases 4–6 (2009–18) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), we investigated the associations between peak serum K level, measured monthly predialysis, over a 4-month period (‘peak K’) and clinical outcomes over the subsequent 4 months using Cox regression, adjusted for potential confounders. Results The analysis included 62 070 patients contributing a median of 3 (interquartile range 2–6) 4-month periods. The prevalence of hyperkalemia based on peak K was 58% for >5.0, 30% for >5.5 and 12% for >6.0 mEq/L. The all-cause mortality hazard ratio for peak K (reference ≤5.0 mEq/L) was 1.15 [95% confidence interval (CI) 1.09, 1.21] for 5.1–5.5 mEq/L, 1.19 (1.12, 1.26) for 5.6–6.0 mEq/L and 1.33 (1.23, 1.43) for >6.0 mEq/L. Results were qualitatively consistent when analyzing hospitalizations and a cardiovascular composite outcome. Conclusions Among HD patients, we identified a lower K threshold (peak K 5.1–5.5 mEq/L) than previously reported for increased risk of hospitalization and mortality, with the implication that a greater proportion (>50%) of the HD population may be at risk. A reassessment of hyperkalemia severity ranges is needed, as well as an exploration of new strategies for effective management of chronic hyperkalemia.

BACKGROUND AND AIMS As part of the renal filtration barrier, podocytes are critical to the function of kidney glomeruli. Their loss is one of the hallmarks of chronic kidney disease, including diabetic kidney disease (DKD). Indeed, many drug discovery efforts focus on preventing podocyte apoptosis triggered by diabetic stressors to delay kidney disease progression. In order to discover and characterize new therapeutic agents, phenotypic screens are a powerful tool to directly screen for the desired cellular outcome. These need to be complemented by target-centric assays to support the chemical optimization of compounds. Generally, the deconvolution and confirmation of molecular targets are considered challenging, but necessary in the follow-up of phenotype-based drug discovery programmes to allow progression towards the clinic. We have combined novel technologies like high-throughput next-generation sequencing (NGS) and Cell Painting [1] to develop an unbiased approach for deconvolution of targets from phenotypic screens. As an outcome, we identified a small molecule compound that can protect conditionally immortalized human podocytes (CIHP) from apoptosis in vitro. In a second step, we were able to identify the target responsible for this effect. METHOD Phenotypic screen: CIHP [2] were treated with high glucose and palmitate, a common DKD injury model, as the main driver for apoptosis as evaluated by caspase 3/7 activation [3]. Potentially protective agents were screened against apoptosis from a library of 50 000 small molecules. We selected a hit compound (CpdX) for subsequent target deconvolution to identify the target causing the protective effect. Target deconvolution and compound profiling: We compared the molecular signatures triggered by CpdX treatment to those of a reference panel of known, bio-annotated compounds (#L3500; Selleckchem). Dimensional reduction based on UMAP and PCA applied to transcriptomic data (NGS) as well as Cell Painting fingerprints were used to identify known compounds exhibiting a similar transcriptomic and morphological profile as the CpdX. We hypothesized that the molecular targets of these compounds also constitute likely targets for the new CpdX. RESULTS We developed a screening cascade (Figure 1A) to identify novel targets for kidney disease. A first-pass phenotypic podocyte apoptosis screen delivered a potent compound, able to rescue CIHP from a diabetic challenge in vitro (Figure 1B, C). Integrated analysis and alignment of cellular changes in transcriptomic profile and morphology following CpdX or reference compound treatment enabled us to identify the serine/threonine-protein kinase Ataxia Telangiectasia Mutated (ATM) as one of the putative targets of the orphan compound. Both KU-60019, a known inhibitor of ATM [4] (Figure 1D) and CpdX showed remarkably similar effects in NGS and Cell Painting (Figure 2A, B) and were also equally protecting the cells from apoptosis in vitro (Figure 1B). From this data, we inferred that ATM is a likely effector of CpdX treatment. CONCLUSION The initial lack of specific target candidates following primary phenotypic screens is a widespread problem in drug discovery. In the absence of a target deconvolution strategy, many potential candidates cannot be progressed easily to optimization. Here, we demonstrated that a combination of state-of-the-art technologies used to benchmark hit compounds from phenotypic screens versus known bio-annotated compound libraries represent a viable approach to perform target deconvolution of hits from phenotypic screening approaches. In this work, a phenotypic screen and subsequent deconvolution identified a novel target in combination with a novel compound, making a suitable starting point for progression into a potential kidney therapeutic agent.

BACKGROUND: Hyperkalemia is a common electrolyte abnormality in patients with CKD, which is associated with worse outcomes and limits use of renin–angiotensin–aldosterone system inhibitors (RAASi). This post hoc subgroup analysis of three clinical trials evaluated the efficacy and safety of the sodium-free, potassium-binding polymer, patiromer, for the treatment of hyperkalemia in adults with nondialysis CKD. METHODS: Data from the 4-week treatment periods of AMETHYST-DN, OPAL-HK, and TOURMALINE studies were combined. Patients had baseline diagnosis of CKD, hyperkalemia (serum potassium >5.0 mEq/L), and received patiromer 8.4–33.6 g/day. Patients were stratified by baseline eGFR into two subgroups: severe/end-stage CKD (stage 3b–5; eGFR

Altres ajuts: Pharmacyclics LLC; AbbVie Company. Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features. Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Aims: In patients with current or a history of hyperkalaemia, treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) is often compromised. Patiromer, a novel potassium (K+ ) binder, may improve serum K+ levels and adherence to RAASi. Methods: The DIAMOND trial will enroll ∼820 patients with heart failure with reduced ejection fraction (HFrEF; ejection fraction ≤40%). Patients meeting the screening criteria will enter a single-blinded run-in phase where they will be started or continued on a mineralocorticoid receptor antagonist (MRA) titrated to 50 mg/day and other RAASi therapy to ≥50% target dose, and patiromer. Patiromer will be titrated up to a maximum three packs/day (8.4 g/pack) to achieve optimal doses of RAASi without hyperkalaemia. The run-in phase will last up to 12 weeks, following which patients will undergo double-blind randomization in a 1:1 ratio to receive either continued patiromer or placebo (patiromer withdrawal). The primary endpoint is the mean difference in serum K+ from randomization between patiromer and placebo arms. Secondary endpoints will include hyperkalaemia events with K+ value >5.5 mEq/L, durable enablement of MRA at target dose, investigator-reported adverse events of hyperkalaemia, hyperkalaemia-related clinical endpoints and an overall RAASi use score (using a 0-8-point scale) comprising all-cause death, occurrence of cardiovascular hospitalization or usage of comprehensive heart failure medication. Conclusion: The DIAMOND trial is designed to determine if patiromer can favourably impact K+ control in patients with HFrEF with hyperkalaemia or a history of hyperkalaemia leading to RAASi therapy compromise, and in turn improve RAASi use.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Steroid-refractory (SR) chronic graft-versus-host disease (cGVHD) is a major obstacle in recipients of allogeneic stem cell transplantation (HCT). Ruxolitinib is the first agent to demonstrate superior efficacy to the best available therapy, but real-life data are still lacking. Here we describe the results of ruxolitinib compassionate use for the treatment of SR/steroid-dependent cGVHD in a tertiary care university hospital. In this retrospective single-center study, we evaluated the outcomes of 48 patients diagnosed with SR-cGVHD who were treated with ruxolitinib. Forty-seven (98%) had moderate-severe disease, and 27 (56%) had received ≥2 lines of prior therapy (excluding steroids). Results were analyzed using SPSS version 26.0.01 and R version 3.4.3. The overall response rate was 77% (37 of 48), with 15% (7 of 37) in complete remission. The median time to response was 2 months (range, 0.5 to 8 months). Steroid tapering was achieved in 26 patients (54%) and definitive discontinuation was achieved in 10 patients (21%) after a median of 20 months (range, 1.5 to 60 months). Toxicity was predominantly hematologic, including a 33% rate of anemia and a 17% rate of thrombocytopenia. Overall survival at 2 years was significantly higher in responders compared with nonresponders (88% [95% confidence interval (CI), 65% to 96%] versus 49% [95% CI, 12% to 78%]; P = .01). At last follow-up, tapering of ruxolitinib had been started in 8 of 37 responders (22%). Our experience supports the efficacy of ruxolitinib in the treatment of SR-cGVHD, along with its steroid-sparing effect and manageable toxicity. Gradual tapering of ruxolitinib seems feasible without cases of GVHD flare. More studies and longer follow-up are needed to confirm these data, as well as to identify the ideal dose adjustments in cases of toxicity.

Purpose of review The treatment landscape of chronic lymphocytic leukaemia (CLL) has tremendously evolved in the last decades, from chemo to chemoimmunotherapy (CIT) and, eventually, to pathway inhibitors that target critical pathways for leukaemic cells survival. Also, treatment goals are moving towards achieving undetectable minimal residual disease with little toxicity. Recent findings We performed a thorough review of the history of treatment approvals by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This review especially focuses on therapies that are currently approved by both agencies. The indications and particular characteristics of each drug are examined. Summary Currently available treatment approaches for CLL offer the opportunity to individualize therapy for every single patient with CLL. Inhibitors of B-cell receptor (BCR) signalling pathways and antiapoptotic proteins are nowadays the treatment of choice for most CLL patients, but CIT can be an option for younger and fit patients with low-risk disease [mutated IGHV, no del(11q) or del(17p)/TP53 mutations].

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with

7519 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of 1L I+V in CLL. The primary analysis (PA) evaluating FD tx with I+V was previously presented (Ghia et al., ASCO 2021). Here we present 3-y follow-up results from the FD cohort. Methods: Patients (pts) aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; -4) was measured by 8-color flow cytometry. Serious AEs (SAEs) deemed related to I reported >30 d after last dose of study drug were collected. Results: 159 pts were enrolled (median age 60 y), including pts with high-risk features of del(17p)/ TP53 mutation (17%), unmutated IGHV (uIGHV; 56%), and complex karyotype (19%). 147 (92%) and 149 (94%) pts completed tx with I and V, respectively. With 1 y of additional follow-up since PA, median time on study was 39 mo (range 1-41). ORR was 96% and was consistent (96%-97%) in pts with high-risk features (Table).The primary endpoint of complete response (CR) including CR with incomplete bone marrow recovery (CRi) rate in pts without del(17p) (n=136) increased nominally from 56% (95% CI, 48-64) to 58% (95% CI 50-66); in all pts, CR rate increased from 55% (95% CI 48-63) to 57% (95% CI 50-65). In pts achieving CR, 93% had durable responses lasting ≥12 mo post-tx. Of pts with uMRD in peripheral blood at 3 mo post-tx, 66/85 (78%) evaluable pts maintained uMRD through 12-mo post-tx. At 36 mo, PFS was 88% (95% CI 82‒92) and OS was 98% (95% CI 94‒99); similar rates were seen in pts with high-risk features (Table). All pts are off tx; no new SAEs of any kind have occurred since the PA. Available data on relevant mutations in BTK, PLCɣ2, or BCL-2 at time of PD will be presented. As of January 2022, 12 pts were retreated with single-agent I after PD (tx duration range 3-29 mo); of evaluated pts, 7/9 had partial responses and 2/9 had stable disease. Conclusions: Fixed duration I+V continues to provide deep, durable responses and clinically meaningful PFS, including in pts with high-risk disease features, representing an all-oral, once-daily, chemotherapy-free FD regimen for previously untreated pts with CLL/SLL. With an additional 1 y of follow-up, no OS events or SAEs occurred. Manageable safety profile is unchanged as previously reported. To date, successful single-agent I retreatment responses are observed. Clinical trial information: NCT02910583. [Table: see text]

iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinutuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P0.0001). The best overall rate of undetectable minimal residual disease (0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of progression- free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574.

Background and Aims Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is an orally-administered, non-absorbable, inorganic, selective potassium (K+) binder for the treatment of adults with hyperkalaemia. SZC entraps K+ throughout the gastrointestinal tract in exchange for hydrogen and sodium ions. In addition to serum K+ reduction, phase 2 clinical trial data have shown an increase in serum bicarbonate and a decrease in serum urea. This may be due to SZC trapping of ammonium ions (which are of a similar size to K+ ions) in the gastrointestinal tract. Maintaining serum bicarbonate ≥22 mmol/L preserves kidney function and reduces metabolic bone disease. Thus, SZC-induced increase in serum bicarbonate may represent an effect of clinical significance. We present a post hoc analysis of central laboratory-measured serum bicarbonate, urea, and urine pH data from three randomized, placebo-controlled, phase 3 studies of SZC among patients with hyperkalaemia (ZS-003, HARMONIZE, and HARMONIZE-Global). Method In all studies, patients initially received up to 10 g SZC three times a day (TID) for 48 hours for correction of hyperkalaemia (randomized placebo-controlled in ZS-003, open-label in HARMONIZE and HARMONIZE-Global), followed by randomization to maintenance therapy with SZC up to 15 g once a day (QD) versus placebo for up to 29 days among those who achieved normokalaemia during the correction phase. Results The analysis included 753 patients from the initial 48-hour correction phase of ZS-003, and 208 and 214 patients who completed the 29-day maintenance phase of HARMONIZE and HARMONIZE-Global, respectively. Significant dose-dependent increases from baseline in serum bicarbonate of 0.3–1.5 mmol/L occurred within 48 hours of SZC TID in ZS-003 (Figure A), which occurred regardless of chronic kidney disease (CKD) stage (Figure B). Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days with SZC ≥10 g (Figure C) and ≥5 g QD (Figure D), respectively. Mixed-model least-squares mean serum bicarbonate increases from baseline versus placebo over 15–29 weeks with SZC were 2.2 mmol/L (p Conclusion SZC consistently and dose-dependently increases serum bicarbonate concentrations, reduces the proportions of patients with serum bicarbonate

BACKGROUND Chronic kidney disease (CKD) is a major global health burden, and is associated with increased adverse outcomes, poor quality of life, and substantial health care costs. While there is an increasing need to build patient-centered pathways for improving CKD management in clinical care, data in this field are scarce. OBJECTIVE The aim of this study was to understand patient-reported experiences, symptoms, outcomes, and treatment journeys among patients with CKD through a retrospective and qualitative approach based on data available through PatientsLikeMe (PLM), an online community where patients can connect and share experiences. METHODS Adult members (aged ≥18 years) with self-reported CKD within 30 days of enrollment, who were not on dialysis, and registered between 2011 and 2018 in the PLM community were eligible for the retrospective study. Patient demographics and disease characteristics/symptoms were collected from this retrospective data set. Qualitative data were collected prospectively through semistructured phone interviews in a subset of patients, and questions were oriented to better understand patients’ experiences with CKD and its management. RESULTS The retrospective data set included 1848 eligible patients with CKD, and median age was 56 years. The majority of patients were female (1217/1841, 66.11%) and most were US residents (1450/1661, 87.30%). Of the patients who reported comorbidities (n=1374), the most common were type 2 diabetes (783/1374, 56.99%), hypertension (664/1374, 48.33%), hypercholesterolemia (439/1374, 31.95%), and diabetic neuropathy (376/1374, 27.37%). The most commonly reported severe or moderate symptoms in patients reporting these symptoms were fatigue (347/484, 71.7%) and pain (278/476, 58.4%). In the qualitative study, 18 eligible patients (13 females) with a median age of 60 years and who were mainly US residents were interviewed. Three key concepts were identified by patients to be important to optimal care and management: listening to patient needs, coordinating health care across providers, and managing clinical care. CONCLUSIONS This study provides a unique source of real-world information on the patient experience of CKD and its management by utilizing the PLM network. The results reveal the challenges these patients face living with an array of symptoms, and report key concepts identified by patients that can be used to further improve clinical care and management and inform future CKD studies.

Background In chronic lymphocytic leukemia, a better understanding of leukemic cell characteristics after treatment would help to design specific therapeutic approaches aimed at preventing clinical relapse. Gene arrays have become a powerful approach to perform gene expression profiling; nevertheless, to work with residual cells entails an intensive labor. The aim of this study was to set forth an effective gene expression approach to analyze residual leukemic cells. Methods Leukocytes from CLL patient's samples were sorted by flow cytometry using a 6-color panel. The quality and quantity of RNA isolated from different inputs of cells were compared by two silica column protocols: RNeasy Micro and RNeasy Mini. RNA amplifications were carried out according to two manufacturer's protocols: Ovation Pico SL and Ovation Pico WTA. A total of 3.5 mu g of cDNA was labeled and hybridized to Human Gene 2.0 ST arrays. Results RNA extracted from low number of input cells by RNeasy Micro showed similar RNA integrity number to that obtained from RNeasy Mini; however, the RNA quantity was higher using the RNeasy Micro Kit. In addition, those RNA samples obtained with RNeasy Micro and amplified with Ovation Pico WTA showed good quality to proceed for a gene array study, independently of the number of input cells (range: 1 x 10(4)-5 x 10(5) cells). Conclusions We observed that this workflow is a feasible approach to obtain genomic material extracted from leukemic cells as little as 1 x 10(4) cells and it can be useful to carry out gene expression profile experiments to characterize residual leukemic cells in chronic lymphocytic leukemia.

Background The diagnosis of CLL is supported by a typical morphology and immunophenotype and usually does not present difficulties. Nevertheless, some patients with CLL can show an atypical phenotype, this raising the possibility of a lymphoproliferative disorder other than CLL. It has been recently shown that the expression of CD200 could be a rather consistent marker for CLL. Methods The expression of CD200 was investigated in 120 consecutive patients with B-cell chronic lymphoproliferative disorders (B-CLPD) (65 cases diagnosed as typical CLL, 16 atypical CLL, and 39 non-CLL before entering the study) by using multiparametric flow cytometry with four color combinations. CD200 was analyzed as percentage of positive cells (>= 30%) and MFIR expression. ROC curves were used to determine the cut-off for the CD200 MFIR. Matutes score (MS) was used as comparator. Results All 81 (100%) patients classified as CLL and 25 of 39 (64.1%) classified as non-CLL expressed high CD200 expression (>= 30%). CD200 expression showed a high sensitivity (100%) and a low specificity (35.9%), and the accuracy was similar to that of Matutes score markers (range: 79.2%-86.7%); except SmIg that was 59.1%. The addition of CD200 to the Matutes score correctly identified 74 of 81 (91.4%) CLL cases including 9 of 16 atypical CLL cases. As per non CLL cases, 37 of 39 (94.9%) were correctly diagnosed by the modified system. Altogether, CD200 improved the diagnostic accuracy of Matutes score from 86.7% to 92.5% (P < .01). Conclusion These results show that CD200 is a valuable, albeit not specific, CLL diagnostic marker. (c) 2018 International Clinical Cytometry Society

Despite significant effort, patients with kidney disease have not seen their outcomes improved significantly over the past two decades. This has motivated clinicians and researchers to consider alternative methods to identifying risk factors, disease progression markers, and effective therapies. Genome-scale data sets from patients with renal disease can be used to establish a platform to improve understanding of the molecular basis of disease; however, such studies require expertise and resources. To overcome these challenges, we formed an academic-industry consortium to share molecular target identification efforts and expertise across academia and the pharmaceutical industry. The Renal Pre-Competitive Consortium (RPC2) aims to accelerate novel drug development for kidney diseases through a systems biology approach. Here, we describe the rationale, philosophy, establishment, and initial results of this strategy.

Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P

Introduction: The BCL-2 inhibitor venetoclax (Ven) has been approved on monotherapy or combined with rituximab in relapsed/refractory CLL patients (pts) and combined with obinutuzumab in previously untreated CLL pts. However, evidence from clinical trials can be difficult to generalize to real-world patient populations. The VENARES study assesses the real-world use of Ven following approval to inform of subpopulations underrepresented in clinical trials. Methods: This is Spanish non-interventional retrospective, multicenter post-marketing observational study. The main objective was to evaluate the effectiveness of Ven in adult CLL pts by the overall response rate (ORR) at 9 months (mo) after the first Ven dose administration. Secondary objective was to evaluate the effectiveness for the Ven monotherapy and the Ven combined with rituximab subpopulations. Consecutive adult pts with diagnosis of CLL who have initiated Ven at least 9 mo before the inclusion in the study were included. Data of pts are retrospectively reviewed until the date of last follow-up or death. Results: 125 pts diagnosed with CLL and who met the eligibility criteria were analyzed. The median age was 72 years (67 - 77) with 76.8% being older than 65 years. Most patients were male (68.8%), had a concurrent disease (65.6%). ECOG PS was recorded in 76 pts: 40 pts (32%) had PS 0, 30 pts (24%) PS 1 and 6 pts (4.8%) PS 2. Pts had received a median of 4 prior lines of therapy (range 1-13 lines). At baseline, among the 92 pts with known Binet stage, 31 (33.7%) had stage C and 38 (41.3%) had stage B; bulky nodes ≥ 5 cm were present in 20 of 87 pts; 49 pts (39.2%) had an absolute lymphocyte count ≥ 25 x 10 9/L and 33 of 54 pts (61%) baseline beta-2 microglobulin value above of 3500 ng/mL. In total, 29 of 90 patients (32%) assessed had Cr 17p deletion, 28 of 86 patients (32%) tested had TP53 mutations, and 46 of 56 patients (82%) who were tested had unmutated immunoglobulin heavy-chain variable (IGHV) status. Ven was administered as monotherapy in 71 pts (57.6%), combined with rituximab in 36 pts (28.8%), combined with obinutuzumab in 5 pts (4%) and combined with other drugs in 13 pts (10.4%). 83 of 125 patients included were evaluable for the primary objective of the study: the ORR at 9 mo was 84.3% (70 patients): CR/CRi in 44 (53%) pts, PR/nPR in 26 pts (31.3%), SD in 9 pts (10.8%) and PD in 4 pts (4.8%). By treatment, in the evaluable patients, ORR at 9 months were 79.2% (38 of 48 patients) in the Ven monotherapy group, with 45% of CR/CRi, and 92.3% (24 of 26 patients) in the Ven combined with rituximab, with 61% CR/Cri. The median duration of PFS was not reached at the time of the analysis (1-June-2021). Kaplan-Meier estimates of the probability of PFS at 24 mo was 75.4% (95% CI, 58.2 - 86.3). Disease progression occurred in 21 pts. Assessment of minimal residual disease (MRD) was available for 32 patients (25.6%) on the basis of peripheral-blood samples, bone marrow or both. Best undetectable MRD was reached in fourteen patients (43.8%). uMRD was more common in pts treated with Ven combined with R (83.3%, 5 of 6 pts) than in pts treated with Ven monotherapy (33.3%, 7 of 21 pts). Adverse events (AEs) were reported during Ven therapy in all 125 patients, 93 of these pts reported AEs related to Ven. Related to Ven, 67 patients (53.6%) experienced at least one AE: 52 pts (41.6%) had neutropenia being grade 3 and 4 in 22 (42.3%) and 9 (17.3%) pts, respectively. 9 pts (7.2%) had febrile neutropenia. Thrombocytopenia and anemia were less common occurring in 5.6% and 2.4%, respectively. Tumor lysis syndrome (TLS) occurred in 4 of 125 pts during ramp-up (3 laboratory and 1 clinical), 2 of them were related to Ven both lab TLS. None of the pts discontinued therapy due to TLS. Richter transformation was observed in 6 pts (4.8%). Other common AEs was diarrhea (10.4%), but most cases were mild. Conclusions: Our first real-world data show that Ven monotherapy or combined with rituximab is effective in highly pre-treated CLL patients, ORR at 9 mo was 84.3% in all population and PFS estimate at 24 mo was 75.4% with similar outcomes to those in the pivotal clinical trials. The safety profile of Ven was consistent with prior experience of Ven in monotherapy or combined with rituximab and no new safety signals were detected. Disclosures Baltasar: Janssen, Abbvie: Consultancy. Terol: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees. Osorio: Janssen, Abbvie, Roche: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Serna: AbbVie, AstraZeneca, Roche: Speakers Bureau; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy. Arguiñano: Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Speakers Bureau; Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Consultancy. Loscertales: Janssen, Abbvie, Roche, Gilead: Speakers Bureau; Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy. García: Janssen, Roche, Gilead, Celgene: Consultancy; Janssen, AbbVie: Research Funding; Janssen, Roche, Gilead, AbbVie, Celgene: Other: medical meetings funding. Pérez Persona: BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Pérez-Encinas: Janssen: Consultancy. Caballero: Celgene, Janssen, Novartis, Abbvie: Speakers Bureau; Celgene, Janssen, Amgen: Consultancy. Ruiz-Zorrilla: Abbvie: Current Employment. Moreno: abbvie: Current Employment. Ferrà: Janssen, Roche, Gilead, Takeda, Abbvie: Consultancy; Janssen, Roche, Gilead, AbbVie: Other: medical meetings funding.

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 < 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 >6 or creatinine clearance 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 < 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 PFS by MRD Status at 10 -4 : In the Ibr+Ven arm, PFS rate during the first 12 months after EOT was >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.

Objective: Report RESONATE-2 phase 3 study extended long-term follow-up of first-line ibrutinib vs chlorambucil in older patients with CLL/SLL. Methods: Patients (≥65 years [y]) with previously untreated CLL/SLL (without del[17p]) were randomly assigned 1:1 to once-daily ibrutinib 420 mg, until disease progression (PD) or unacceptable toxicity (n=136); or chlorambucil 0.5–0.8 mg/kg, up to 12 cycles (n=133). Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for patients treated with ibrutinib vs chlorambucil (HR 0.160 [95% CI: 0.111–0.230]). At 6.5y, PFS was 61% vs 9% for ibrutinib vs chlorambucil. PFS benefit was observed consistently, including ibrutinib-treated patients with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). With ibrutinib, 6.5y OS was 78%; ORR was 92%, and complete response (CR/CRi) rate increased to 34%. Ongoing rates of grade ≥3 AEs of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage in 5–7y. One patient (1%) had dose reduction due to grade ≥3 AEs during years 5–6/6–7. Of 31 patients with dose reductions due to any-grade AEs over full follow-up, 22 (71%) had AE resolution/improvement. Primary reason for discontinuation was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were 3% (n=2) in 5–6y and none in 6–7y. With up to 7y of follow-up, 47% of patients remain on single-agent ibrutinib. Conclusions: Long-term RESONATE-2 data demonstrate sustained PFS and OS benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. Responses continued to deepen over time. Rates of grade ≥3 AEs of interest continued to be low with rare further discontinuations and dose reductions due to AEs; most AEs leading to dose reduction resolved/improved. Ibrutinib remains well tolerated with no new safety signals. Funding: Pharmacyclics LLC, an AbbVie Company.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of similar to 9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or TP53 status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing >= 8 consecutive days of ibrutinib had a shorter median PFS vs those missing