Ibrutinib Monotherapy Research Articles

Applicability of the Chronic Lymphocytic Leukemia (CLL)-IPI on Patients Treated with Front-Line Ibrutinib in the Real World: The Case for New Prognostic Models

Background: CLL is a heterogeneous disease with several prognostic models proposed for risk stratification. The validated CLL-IPI model (Lancet Oncology; 2016) integrates weighted key markers: TP53 dysfunction (del17p or TP53 mutation) = 4 points, unmutated IGHV= 2 points, β2M >3.5 mg/L = 2 points, Binet stage ≥B or Rai stage ≥I = 1 point, and age >65 years = 1 point. The CLL-IPI divides patients into 4 risk groups with differential survival outcomes, but it was developed based on patients receiving chemoimmunotherapy, not novel agents, such as ibrutinib. Whether the CLL-IPI applies to patients receiving ibrutinib is unknown. We sought to examine how the CLL-IPI impacts pts receiving ibrutinib monotherapy in the front line setting.Patients and Methods: A retrospective cohort analysis of CLL pts treated with front-line ibrutinib across 19 community and academic centers was conducted. We analyzed demographics, prognostic factors, CLL-IPI scores, and survival outcomes. The primary endpoint was progression-free survival (PFS) measured from the time of ibrutinib initiation until CLL progression, death, or last follow up as estimated by the Kaplan Meier method. Using Cox regression, we examined the CLL-IPI score and its individual components as predictors of PFS. Descriptive statistics were used for demographic data.Results: A total of 326 CLL pts treated with front-line ibrutinib monotherapy were included in this analysis. Median age at ibrutinib initiation was 68 years (range, 36-96), 63% were males. Median follow up on ibrutinib was 12 months (range, 1-76). Frequency of the CLL-IPI adverse variable testing and presence is displayed in Table 1. Of pts tested, 32% had TP53 dysfunction (del17p or TP53 mutation), 67% were IGHV unmutated, 76% had β2M >3.5 mg/L, 96% had advanced clinical stage, and 45% were age >65 years. In total, 79 pts (24%) had all variables available to accurately calculate the CLL-IPI. Of these, 2.5% were low risk, 20% intermediate risk, 49.5% high risk, and 28% very high risk. The 12 month PFS on frontline ibrutinib for intermediate, high, and very high risk groups was 86%, 94%, and 94%, respectively. These differences were not significant (Figure). On univariate analyses of individual CLL-IPI variables, only the presence of del17p and/or TP53 mutation was significantly associated with inferior PFS (HR 2.2, p=.01).Conclusions: In the largest cohort of 326 frontline ibrutinib-treated CLL pts reported to date, only 79 patients had all CLL-IPI variables available. β2M was missing in 63% and IGHV mutational analysis was missing in 44%. Contrary to pts treated with chemoimmunotherapy, CLL-IPI did not distinguish 12 month PFS in ibrutinib-treated pts. Only del17p and/or TP53 mutation was associated with inferior PFS. Our analysis suggests the need for different prognostic models in pts treated with ibrutinib and confirms that testing of all CLL-IPI prognostic variables is not commonly performed in the real world. [Display omitted] DisclosuresBrander:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy. Pagel:Gilead: Consultancy; Pharmacyclics: Consultancy. Tam:Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding. Shadman:Gilead: Research Funding; AbbVie: Other: advisory board; Emergent: Research Funding; PLEXXIKON: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Other: advisory board, Research Funding. Ujjani:Genentech: Consultancy; Abbvie: Research Funding, Speakers Bureau; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding. Skarbnik:Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Novartis: Speakers Bureau. Cheson:AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy; Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support . Barr:AbbVie: Consultancy, Research Funding; Celgene: Consultancy; Infinity: Consultancy; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy; Gilead: Consultancy. Dwivedy Nasta:Takeda: Research Funding; Incyte: Research Funding; Immunogen: Research Funding. Furman:Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy; Abbvie: Consultancy, Honoraria; Genentech: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Mato:Janssen: Consultancy; Kite: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Regeneron: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Pharmacyclics: Research Funding.

Predicting Mechanisms of Ibrutinib-Resistance in Chronic Lymphocytic Leukemia (CLL) Using Computational-Based Modeling for Personalized Therapy with Clinical Validation

Background: Bruton's tyrosine kinase (BTK), a mediator of B cell receptor signaling, has been effectively exploited as a therapeutic target in Chronic lymphocytic leukemia (CLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, relapsed/refractory, and high-risk CLL. However, concerns regarding ibrutinib resistance have emerged and characterizing the underlying mechanisms may aid in identifying patients with increased risk of resistance/disease progression. Moreover, understanding the interplay between determinants of ibrutinib resistance may reveal alternate therapeutic targets. Using a computational biology modeling (CBM) simulation-based method, we reverse-engineered the salient molecular architecture of a CLL patient progressing on ibrutinib to identify potential drug combinations to overcome drug resistance and induce remission.Methods: For validation of the computational biological modeling (CBM) software (Cellworks group), we selected a cohort of 15 ibrutinib resistant CLL patients from previously published studies (Table 1). Genomic data derived from whole exome sequencing (WES), targeted next-generation sequencing (NGS), copy number variation (CNV), and/or karyotype data were used in this study. All available genomic data for each profile was entered into the CBM, which generates a disease-specific protein network map using PubMed and other online resources. Disease-biomarkers that are unique to each patient were identified within the protein network maps by using CBM technology. Ibrutinib was selected from a digital drug library and simulated on every relapsed CLL patient case. Drug impact was assessed by quantitatively measuring the drug's effect on a cell growth score, which is a composite of cell proliferation, viability, and apoptosis, along with the simulated impact on each disease-specific biomarker score. Each patient-specific map was digitally screened to identify any Ibrutinib resistance mechanism(s).Results: In our modeled patient set, 4 different resistance mechanisms were identified across 14/15 ibrutinib- refractory CLL cases. 1) BTK C481S mutation (n=4) impacts ibrutinib binding affinity; 2) PLCG2 mutations (n=4) lead to activation of PRKCB and AKT1 signaling; 3) CARD11 mutation (n=2) results in constitutive activation of BTK downstream effectors; and 4) decreased G-protein coupled receptor (GPCR) pathway signaling, an upstream activator of BTK (n=5), was found to be a novel resistance mechanism identified by CBM. Knockdown (KD) of ALOX5AP, ARRB1 and CYSLTR2 reduced GPCR pathway signaling, resulting in reduced BTK activity (Table 1). After validating the CBM algorithm, we rendered a digital avatar for a relapsed-refractory CLL patient (Del17p+); progressing on ibrutinib. The patient had rapidly escalating ALC and lymphadenopathy; with the largest node measuring ~16cm. In addition to p53 loss, simulation modeling accounted for BTK C481S mutation (BAF 0.69) expressed in the patients tumor cells. CBM predicted venetoclax would be the most effective therapeutic for the patient due to several upstream signaling pathways converging on Bcl-2. Indeed, addition of venetoclax to the ongoing ibrutinib monotherapy dramatically reduced the patients ALC (from 113 to 3.3 x 109/L) by day 4 post-treatment, accompanied by reduction in lymphadenopathy (left axillary node decreased to ~3cm). Ibrutinib was discontinued within 1 month of starting the combination, with venetoclax monotherapy continued per dosing guidelines thereafter. Notably, the patient maintained remission status on venetoclax monotherapy alone.Conclusions: Computational modeling was used to identify ibrutinib resistance mechanisms in CLL patients. Using this novel approach, we identified an effective therapy (venetoclax) for a high-risk CLL patient who was progressing on ibrutinib. CBM-based approaches can be used to predict alternative therapeutic regimens for drug-refractory patients, targeting the disease-specific biomarkers unique to each patient. Altogether, our study demonstrates proof-of-principle on the use of computational predictive algorithms to simulate multiple protein-interaction networks operational in a tumor cell to exploit individualized therapeutic vulnerabilities. [Display omitted] DisclosuresYsebaert:Janssen: Consultancy, Research Funding, Speakers Bureau. Kumar:Cellworks: Employment. Singh:Cellworks Research India Pvt. Ltd: Employment. Ullal:Cellworks Research India: Employment. Bhargav:Cellworks: Employment. Azam:cellworks: Employment. Abbasi:Cellworks Group Inc.: Employment. Vali:Cellworks Group Inc.: Employment. Cogle:Celgene: Other: Membership on Steering Committee for Connect MDS/AML Registry.

Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy

Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy

Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia

Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax. To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax. A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older. Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4. Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate. Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation. The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL. ClinicalTrials.gov Identifier: NCT02756897.

Cardiac risk factors and adverse events among patients receiving first-line CLL treatment in a real-world community practice setting.

e24044 Background: First-line (1L) ibrutinib monotherapy (IM) is commonly prescribed for CLL but is associated with cardiovascular adverse events (CVAEs) that may lead to discontinuation. Existing data are largely from clinical trials (both 1L and relapsed/refractory), and real-world evidence is limited. The aim of this study was to compare baseline cardiac risk factors and CVAEs in patients (pts) receiving 1L IM vs intensive therapy (IT; aggressive, less tolerable, majority were bendamustine plus anti-CD20 antibody) or non-intensive therapy (NIT; less aggressive, more tolerable, majority were anti-CD20 antibody alone). Methods: We compared 3 treatment groups (IM, IT, and NIT) in terms of clinical characteristics, baseline CV risk factors, and subsequent CVAEs. Pts were selected from the Flatiron Health database based on the following criteria: aged ≥18 years, CLL/SLL diagnosis, had ≥2 clinic encounters, and initiated 1L treatment between 1/1/2016 and 12/31/2019. Baseline characteristics and subsequent CVAEs were descriptively compared between IM and IT/NIT groups; significance was assumed if p < 0.05. Results: Data on 515 pts were included (IM, 191; IT, 195; NIT, 129). Age at baseline differed significantly between the IM group (mean 71.2 years) and the other 2 groups (IT, 66.2 years; NIT, 74.5 years). The proportion of del(17p) was significantly higher in the IM group vs IT/NIT groups (IM, 26.7%; IT, 3.6%; NIT, 3.1%). Significant differences between IM and IT groups were seen in baseline ECOG (ECOG 0: IM, 28.8%; IT, 43.1%), diabetes mellitus (IM, 56.0%; IT, 44.1%), and hypercholesterolemia (IM, 68.6%; IT, 58.0%). Significant differences between IM and NIT groups were seen in baseline angina/coronary revascularization (2.6% vs 8.5%), atrial fibrillation/atrial flutter (AF; 14.1% vs 26.4%), and cerebrovascular disease (8.9% vs 20.2%). The rate of any CVAE was significantly higher in IM (35.6%) vs IT and NIT groups (IT, 20.0%; NIT, 24.8%) (Table). For IM vs IT treated pts, significant differences were observed in new or worsening (N/W) AF (11.5% vs 5.1%), other arrhythmias (9.4% vs 3.1), and hypertension (HTN; 20.4% vs 8.2%). Conclusions: This is one of the first real-world studies focused specifically on 1L CLL to describe baseline CV risk factors and compare CVAE events in CLL pts treated with IM as compared to IT or NIT. Results show higher CVAE rates of AF, other arrhythmias, and HTN for IM vs IT. [Table: see text]

Serious infections and cardiovascular complications among patients with chronic lymphocytic lymphoma treated with first-line ibrutinib or bendamustine/rituximab.

e19503 Background: Clinical trials have shown positive outcomes associated with ibrutinib monotherapy (IM) and bendamustine / rituximab combination (BR) therapy in patients with chronic lymphocytic lymphoma (CLL) compared to other standard treatments, but limited real-world data exist. This study evaluated serious infections and cardiovascular complications in CLL patients treated with first-line IM or BR therapy using US real-world data. Methods: Administrative claims from the MarketScan® Research Databases were used to identify adult patients enrolled in commercial or Medicare supplemental insurance plans based on a first prescription fill of IM or BR therapy (the index date) from 2/1/14 to 9/1/19. Patients were diagnosed with CLL, treatment naïve, and continuously enrolled for ≥12 months prior to and following the index date. Serious infections and cardiovascular complications requiring hospitalization (diagnosis code in any position) were evaluated during a fixed 12-month follow-up period. Statistical differences in outcome distributions between the treatment groups were tested. Multivariate logistic regression models for lower respiratory tract infection (LRTI) and atrial fibrillation (AF) were also conducted to determine the adjusted odds of hospitalization. Results: Of 2,138 CLL patients, 810 had IM and 512 had BR as index therapy with ≥12 months of follow-up data. Patients receiving IM were older and more likely to have had an LRTI during baseline compared to BR patients, otherwise both groups had similar baseline characteristics. Hospitalization for serious infections was more common during follow-up among IM patients than BR patients (17.7% vs. 13.1%; p = 0.027). Specifically, 10.2% of IM patients had a bacterial infection hospitalization compared to 5.7% of BR patients (p = 0.004) and 10.7% of IM patients had a LRTI hospitalization compared to 6.6% of BR patients (p = 0.012). After adjusting for baseline characteristics, IM patients did not have significantly higher odds of a LRTI hospitalization (OR = 1.51; p = 0.069). Hospitalization for cardiovascular complications was more common during follow-up among IM patients than BR patients (18.3% vs. 11.9%; p = 0.002). Specifically, 8.4% of IM patients had an AF-related hospitalization versus 2.7% of BR patients (p < 0.001). After adjusting for baseline characteristics, IM patients were more likely to have a hospitalization for AF versus BR patients (OR = 3.89; p < 0.001). Conclusions: In a real-world setting, serious infections and cardiovascular complications were more common among CLL patients treated with first-line IM compared to BR during 12 months of follow-up. IM patients were more likely than BR patients to have an inpatient admission due to AF after adjusting for other patient characteristics.

Real-world incidence and costs of serious infections and cardiovascular complications among patients with indolent non-Hodgkin lymphoma treated with first-line ibrutinib or bendamustine/rituximab.

e19528 Background: Patients with Indolent non-Hodgkin lymphoma (iNHL) have shown positive outcomes with ibrutinib monotherapy (IM) as well as bendamustine/rituximab combination (BR) therapy, but no studies have reported on patient outcomes using real-world data. The current analysis evaluated serious infections and cardiovascular complications in iNHL patients treated with first-line IM or BR therapy using US real-world data. Methods: Administrative claims from the MarketScan® Research Databases were used to identify adult patients enrolled in commercial or Medicare supplemental insurance plans based on a first prescription fill of IM or BR therapy (the index date) from 2/1/14 to 9/1/19. Patients included in the study were diagnosed with iNHL, were treatment naïve, and were continuously enrolled for ≥12 months both prior to and following the index date. Serious infections and cardiovascular complications requiring hospitalization (diagnosis code in any position) and associated inpatient costs were evaluated during a fixed 12-month follow-up period. Statistical differences in outcome distributions and costs (reported per patient per month [PPPM]) between the groups were tested. Results: Of 1,948 iNHL patients, 147 had IM and 1,058 had BR as index therapy with ≥12 months of follow-up data. Patients receiving IM were older, more often male, and more likely to have had a lower respiratory tract infection (LRTI) or atrial fibrillation (AF) during baseline compared to BR patients, otherwise the groups had similar baseline characteristics. Hospitalization for serious infections was similar for IM and BR patients during the follow-up period (17.0% vs. 14.4%; p = 0.397); among hospitalized patients, the IM and BR groups incurred similar PPPM inpatient costs ($2,839 vs. $3,954; p = 0.188). Specifically, 7.5% of IM patients had a bacterial infection hospitalization and incurred $2,561 PPPM vs 7.6% of BR patients who incurred $3,975 PPPM (both p > 0.05); 8.8% of IM patients had a LRTI hospitalization and incurred $3,629 PPPM vs 6.1% of BR patients who incurred $4,980 PPPM (both p > 0.05). Hospitalization for cardiovascular complications was similar during follow-up for IM and BR patients (15.6% vs. 12.2%; p = 0.237); among hospitalized patients, the IM and BR groups incurred similar PPPM costs ($3,777 vs. $3,862; p = 0.948). Specifically, 7.5% of IM patients had a hospitalization for AF and incurred $4,481 PPPM vs 3.6% of BR patients who incurred $4,860 PPPM (p = 0.025 and p = 0.875, respectively). Conclusions: In a real-world setting, serious infections and cardiovascular complications requiring hospitalization, including associated costs, were similar among iNHL patients treated with first-line IM or BR over 12 months, although IM patients were more likely to have an AF-related complication.

Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.

7526 Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]

Overall survival, adverse events, and economic burden in patients with chronic lymphocytic leukemia receiving systemic therapy: Real-world evidence from the medicare population.

BackgroundInformation on overall survival (OS) and adverse events (AEs) in patients with chronic lymphocytic leukemia (CLL) is mostly available from clinical trials. We therefore conducted a population‐based retrospective cohort study to assess OS, incidence of AEs, and economic burden in real‐world practice among Medicare patients treated for CLL.MethodsPatients with CLL receiving ≥1 systemic therapy from 2013 to 2015 were selected from the Medicare claims database and followed from the start of first observed systemic therapy (index date) through December 2016 or death. OS for patients receiving each of the most commonly observed treatments was estimated by the Kaplan–Meier method. AEs were assessed among patients receiving these treatments across all observed lines of therapy. All‐cause direct medical costs were assessed from the Medicare system perspective.ResultsAmong 7,965 eligible patients across all observed therapy lines, ibrutinib monotherapy (Ibr; n = 2,708), chlorambucil monotherapy (Clb; n = 1,620), and bendamustine/rituximab (BR; n = 1,485) were the most common treatments. For first observed therapy, 24‐month OS estimates for Ibr, Clb, and BR recipients were 69% (95% CI = 68%–71%), 68% (95% CI = 65%–71%), and 79% (95% CI = 77%–81%) respectively. The most frequently recorded AEs in patients receiving these treatments in any observed line of therapy were neutropenia, hypertension, anemia, and infection. For all patients, the mean monthly all‐cause cost during the follow‐up period was $8,974 (SD = $11,562); cost increased by the number of AEs, from $5,144 (SD = $5,409) among those with 1–2 AEs to $10,077 (SD = $12,542) among those with ≥6 AEs.ConclusionOver two‐thirds of patients survived at least 2 years after starting their first observed therapy for CLL. Our findings highlight considerable susceptibility to AEs and unmet medical need in Medicare patients with CLL treated in routine practice. Medicare incurred substantial economic burden following initiation of systemic therapy, and patients with greater numbers of AEs accounted disproportionately for the high overall cost of CLL management.

Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial

Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. TG Therapeutics.

Real-world healthcare resource utilization and costs in patients with chronic lymphocytic leukemia: differences between patients treated with first-line ibrutinib or bendamustine + rituximab

Background This study evaluated the real-world healthcare resource utilization and costs in chronic lymphocytic lymphoma (CLL) patients treated with first-line ibrutinib monotherapy (IbM) therapy or bendamustine plus rituximab (BR) combination therapy. Methods Treatment-naïve CLL patients in the IBM MarketScan Research Databases were identified based on the first prescription of either IbM or BR therapy between 1 February 2014 and 30 August 2017. Results A total of 1866 patients with 12 months of continuous enrollment (IbM n = 1157; BR=n = 729) were identified. Thirty-four percent of IbM patients had at least one inpatient admission compared to 24% of BR patients. A total of 31% of IbM patients had at least one CLL-related inpatient admission compared to 20% of BR patients. Among patients with an ER visit, IbM patients visited the emergency room (ER) more frequently than BR patients. There were no differences in total cost, both all-cause and CLL-related, between the IbM and BR cohorts. However, IbM patients had significantly higher all-cause and CLL-related inpatient costs than BR patients as well as all-cause outpatient pharmacy prescriptions costs, while BR patients had significantly higher PPPM outpatient medical costs Conclusion The results of this study suggest that further research on the real-world effectiveness of IbM in comparison to BR combination therapy, given the comparatively higher rates of inpatient admissions, longer lengths of stay, and more ER visits observed in IbM patients relative to the BR patients is needed. Given the differences in costs, it is important to further examine the impact these healthcare expenditures have on the cost-effectiveness of IbM first line treatment.

Inhibition of Bruton\u2019s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness

Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. We investigated the effects of Bruton’s tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.

Impact of Adherence to Ibrutinib on Clinical Outcomes in Real-World Patients With Chronic Lymphocytic Leukemia.

BackgroundChronic lymphocytic leukemia (CLL) is a B-cell neoplasm with clonal expansion of small lymphocytes. Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a first-line treatment option, and recent data suggest that strict adherence is directly related to clinical outcomes.ObjectivesThe primary objective of this study was to quantify ibrutinib adherence rates in real-world patients with CLL on ibrutinib; secondary outcomes included progression-free survival and overall survival.MethodsThis retrospective study included subjects who were treated at a large academic medical center over approximately 5 years. Subjects were at least 18 years, diagnosed with CLL or small lymphocytic lymphoma, and treated with ibrutinib monotherapy for at least 6 months. Adherence was quantified using the medication possession ratio (MPR), which is the ratio of the sum of days’ supply of medication in a period over the number of days in that period, and was based on fill history from the medical center’s specialty pharmacy.ResultsFor the 32 subjects in this study, the mean ibrutinib adherence rate was 91.7% (range, 84.4%–100%). Only 3 subjects had disease progression, and 1 death was recorded while on therapy (all with MPR < 95%); therefore, analyses of clinical outcomes were unable to be assessed due to a low number of events. There were no statistically significant differences in rates of adherence based on baseline characteristics and adverse drug events.ConclusionIn patients with CLL treated with ibrutinib, mean adherence was 91.7%, which is lower than rates seen in clinical trials.

Ibrutinib Monotherapy in Relapsed or Refractory, Transformed Diffuse Large B-cell Lymphoma

BackgroundHistologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment. Patients and MethodsWe prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate. ResultsTwenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib. ConclusionsIbrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.

Clinical characteristics and prognosis of Waldenström's macroglobulinemia: a clinical data report from a single center

目的总结51例华氏巨球蛋白血症（WM）患者的临床特征及预后，重点评估伊布替尼治疗WM的疗效和不良反应，为WM诊疗提供经验和借鉴。方法回顾性分析2008年11月至2019年10月海军军医大学附属长征医院收治的51例初诊WM患者的基线临床特征、疗效及预后。结果51例患者男女比例为2.64∶1，中位年龄65（46~84）岁。ISSWM危险分层：低危组9例（18%）、中危组21例（41%）、高危组21例（41%），27例（73%）存在MYD88L265P突变。中位随访时间38.6（0.3~120.0）个月，中位无进展生存时间为46.4个月，中位总生存时间未达到。接受伊布替尼治疗的16例患者总体缓解率为87%，主要缓解率为80%，起效速度快，达到至少部分缓解的中位时间为8周，与其他药物组相比差异有统计学意义（P<0.05）。结论WM多见于老年男性，多数患者合并MYD88L265P突变。伊布替尼治疗WM疗效确切，即使是高龄、ISSWM高危患者，也有较高的总体缓解率、主要缓解率。伊布替尼起效速度较快，严重不良反应少见，是一种安全、有效的治疗方案。

Ibrutinib and Obinutuzumab in CLL: MRD Responses Sustained for Several Years with Deepest MRD Depletion in Patients with >1 Year Prior Ibrutinib Exposure

Ibrutinib and Obinutuzumab in CLL: MRD Responses Sustained for Several Years with Deepest MRD Depletion in Patients with >1 Year Prior Ibrutinib Exposure

Efficacy and Safety Analysis of Ibrutinib-Containing Therapy for Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results from a Real-World Study in China

Background: Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for the treatment of relapsed/refractory (R/R) Mantle cell lymphoma (MCL). Both single-agent ibrutinib and combination of ibrutinib with rituximab have achieved great efficacy with manageable toxicity (Wang,NEJM2013; Wang,Lancet Oncol2015; Dreyling,Lancet2015). This study, for the first time, analyzed the real-world effectiveness and tolerability of ibrutinib for MCL patients in China. Methods: This multi-center, retrospective cohort study enrolled adult patients (pts) with pathologically confirmed MCL who initiated ibrutinib-containing treatment between November 2017 (date of commercialization) and April 2020. Eligible patients were retrospectively divided into 3 subgroups to receive ibrutinib-containing treatments for different purposes: R/R MCL group, newly diagnosed MCL group and maintenance therapy group. This analysis reports the baseline characteristics, efficacy and safety profiles in R/R MCL patients. Results: A total of 67 R/R MCL pts receiving ibrutinib-containing treatment from 9 medical centers in China were included in this analysis. At ibrutinib initiation, the median age was 61.0 (range 39-81) years, 68.7% were male and 81.8% had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Approximately three-quarters of pts (72.3%) had 1 previous line of therapy before ibrutinib. Baseline characteristics are summarized in Table 1. Of all patients enrolled, 53.7% (36/67) of pts received ibrutinib monotherapy and 46.3% (31/67) received ibrutinib-containing combination therapy. IR (ibrutinib and rituximab) (16/31, 51.6%) and IR2 (ibrutinib, rituximab and lenalidomide) (5/31, 16.1%) were the two most common combination regimens. Nine patients (29.0%) received ibrutinib plus R-chemotherapy. Although no statistically significant difference was found in listed baseline characteristics between these two groups, a larger percentage of pts with bone marrow involvement (58.1% vs 35.7%) and bulky mass (largest diameter) ≥5 cm (46.4% vs 27.3%) were observed in combination therapy group. Best overall response rate (ORR) was 65.7% (20.9% complete remission [CR]). Median time to response (TTR) was 4.1 months and median duration of response (DOR) was 18.4 months. With a median follow-up of 10.2 months, median progression-free survival (PFS) was 21.3 months (95% confidence interval [CI], 15.2 - not available [NA]) (Figure 1A). PFS rates were 86.0%, 69.8% and 47.6% at 6 months, 1 year and 2 years. With a median follow-up of 11.2 months, median overall survival (OS) was not reached with OS rates of 98.5%, 87.9% and 76.3% at 6 months, 1 year and 2 years (Figure 1B). Compared with ibrutinib monotherapy, combination therapy showed higher ORR (50.0% vs 83.9%), CR rate (8.3% vs 35.5%) and shorter TTR (median TTR, 6.0 vs 2.2 months; Logrank,p=0.0012) (Figure 2A). Although the combination therapy had a trend for better PFS, no statistically significant benefit in PFS or OS was observed (Figure 2B, C). Safety analysis focused on 55 R/R MCL pts from 3 centers with adequate adverse events information. The most common treatment emergent adverse events (TEAEs) of interest were infection (8/55, 14.6%), rash (8/55, 14.6%), bleeding (5/55, 9.1%; 1/5 was major bleeding [subdural hemorrhage]) and atrial fibrillation (3/55, 5.5%). Four pts (7.3%) experienced grade 3-4 TEAE (neutropenia, n=2; neutropenia and lung infection, n=1; subdural hemorrhage, n=1). Six pts (10.9%) had ≥1 temporary ibrutinib discontinuation due to TEAE (infection, n=3; neutropenia, n=1; rash, n=1; vomiting, n=1). One patient discontinued ibrutinib permanently due to TEAE (subdural hemorrhage). Combination therapy group showed a higher incidence of hematological TEAE (60.9% vs 39.1%) and infection (20.7% vs 7.7%). No TEAE-related death or new safety signals was recorded. Conclusion: This real-world analysis demonstrates that ibrutinib is effective and tolerable for R/R MCL in China. Ibrutinib-containing combination therapy outperformed ibrutinib monotherapy in response rate and TTR, but showed no survival benefits. The response rate data of ibrutinib monotherapy obtained from our study was different to existing clinical trial data, which may be mainly due to the short follow-up time of our study. Further analysis with longer follow-up is needed to validate these findings. Disclosures No relevant conflicts of interest to declare.

Ibrutinib As a Promising Treatment for Heavily Pretreated Waldenström Macroglobulinemia: A Real World Data

Background:Waldenström Macroglobulinemia (WM) remains an incurable disease with a heterogeneous course, relapse following initial treatment happens in virtually all patients. Ibrutinib, a Bruton Tyrosine Kinase inhibitor, is a promising drug used in WM, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease. Ibrutinib first received FDA approval in WM as a monotherapy in January 2015 and expanded the approved use of ibrutinib with rituximab in August 2018.Ibrutinib-related prior data in Waldenström Macroglobulinemia (WM) remain sparse, particularly outside of clinical trials. Herein, we share a real-life experience using off-label ibrutinib in the treatment of heavily pretreated WM. Methods:This multicenter retrospective study conducted in eight different sites included 13 adult patients diagnosed with WM and used off-label ibrutinib monotherapy or with rituximab from April 2016 to November 2019. Disease-refractoriness to prior therapy was defined as progression on therapy or within 2 months of treatment interruption. The response rates were assessed by the modified Third International Workshop on WM Response Criteria. Results:TwelveRRWM patients received ibrutinib monotherapy for active/symptomatic WM during the study period; median follow up of the entire cohort was 29 months for the subset that received ibrutinib as salvage therapy. The median time on therapy for the entire cohort was 12.5 months. WM IPSS score was calculated intermediate in three patients and high in nine patients. MYD88 mutation status was assessed in five patients and detected positive at the time of WM diagnose. Before therapy, six of the 12 (50%) had a serum level of 3000 mg per deciliter or higher; after treatment, at the time of best response, two of the 12 patients (16.6%) had a serum IgM level of 3000 mg per deciliter or higher. ECOG performance score was 1 in 75% of our cohort. The median lines of prior therapy for the RRWM were 3 (range: 2-8). Only two patients had received autologous stem cell transplantation (ASCT) prior to ibrutinib monotherapy. Responses included a complete response in three patients, a very good response in 1 patient and a partial response in six patients, representing overall response of 83.3%. The remaining two patients discontinued ibrutinib due to progressive disease. No several adverse events due to ibrutinib were observed in our cohort. At the time of data collection, one patient had deceased. Conclusion:Ibrutinib is an effective drug, associated with durable responses, and safety for both previously-treated and newly diagnosed WM. Our study has several limitations that should be considered when reviewing the results, including the retrospective design and inclusion of a small number of patients. Nevertheless, because of the rarity of the diseases, our data provide useful information on the use of ibrutinib in patients with heavily pretreated WM. Disclosures Ferhanoglu: Janssen: Other: Advisory Board; Roche: Other: Advisory Board; Abbvie: Other: Advisory Board; Takeda: Other: Advisory Board. Beksac:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen&amp;janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: ibrutinib were used off-label

A Clinical Practice Comparison of Overall Survival, Time-to-Next-Treatment, and Time-to-Treatment-Discontinuation Among CLL/SLL Patients Receiving First-Line Ibrutinib with and without a Del(17p) Mutation

A Clinical Practice Comparison of Overall Survival, Time-to-Next-Treatment, and Time-to-Treatment-Discontinuation Among CLL/SLL Patients Receiving First-Line Ibrutinib with and without a Del(17p) Mutation

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results