Pharmacyclics LLC Research Articles

Retrospective Single-Institution Analysis of Patients with Chronic Lymphocytic Leukemia with TP53 alterations Treated First-Line with Bruton's Tyrosine Kinase Inhibitor-Based Therapy

Retrospective Single-Institution Analysis of Patients with Chronic Lymphocytic Leukemia with TP53 alterations Treated First-Line with Bruton's Tyrosine Kinase Inhibitor-Based Therapy

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

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

BRUIN CLL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Background: Covalent Bruton Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and many patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). The purpose of this randomized phase 3 study is to demonstrate the superiority of continued BTK pathway inhibition with pirtobrutinib compared to other available therapies in patients with BTKi-treated CLL/SLL.Study Design and Methods: BRUIN CLL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL/SLL who have been treated with a prior covalent BTKi. Prior therapy with venetoclax is permitted. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior venetoclax (yes/no). Patients receiving investigator's choice are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 (determined by IRC).Eligible patients are adults aged ≥18 years with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who have received prior covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation any time pre-enrollment, a major bleeding event on prior covalent BTKi and history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization.The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients (NCT04666038). DisclosuresSharman: BeiGene: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Hill: Loxo Oncology at Lilly: Current Employment. Wang: Loxo Oncology at Lilly: Current Employment. Ku: Loxo Oncology at Lilly: Current Employment, Current holder of stock options in a privately-held company. Guntur: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Ghia: Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Mato: Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Nurix: Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding.

Long-Term Outcome of Treatment-Naïve and Relapsed/Refractory Patients with CLL and TP53 Aberrations Treated with Ibrutinib, with or without Rituximab

Long-Term Outcome of Treatment-Naïve and Relapsed/Refractory Patients with CLL and TP53 Aberrations Treated with Ibrutinib, with or without Rituximab

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Normal FISH CLL Represents a Heterogeneous Subgroup Where Prognosis Can be Refined with IGHV Mutational Status

Normal FISH CLL Represents a Heterogeneous Subgroup Where Prognosis Can be Refined with IGHV Mutational Status

Utilizing Clinical Features of Progression to Predict Richter's Syndrome in Patients with CLL Progressing after Ibrutinib

Background:Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib.Methods:We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model.Results:We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9).Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither.Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A).To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither.Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01).Conclusions:Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. [Display omitted] DisclosuresKittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Clinical and Economic Burden of Tumor Lysis Syndrome Among Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Introduction: Tumor lysis syndrome (TLS) can be a life-threatening complication in patients with hematologic malignancies. In chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), treatment guidelines identify a high risk of TLS for regimens containing anti-CD20-based chemoimmunotherapy (CIT), lenalidomide, obinutuzumab, or venetoclax. Patients who develop TLS require intensive care, adding to the overall clinical and economic burden of CLL/SLL. This study aimed to evaluate the clinical and economic burden of treatment-emergent TLS among patients with CLL/SLL treated with regimens with high risk of TLS.Methods: The IBM MarketScan Research Databases (01/01/2006-04/30/2020) were used to identify adults with CLL/SLL who initiated a CIT-, lenalidomide-, obinutuzumab-, or venetoclax-based regimen on or after 01/01/2007 or upon treatment approval date if post-2007 (index date) and had ≥12 months and ≥30 days of continuous eligibility pre- and post-index date, respectively. Treatment-emergent TLS was defined as developing TLS in the first 90 days of active treatment (based on claims with a TLS diagnosis or laboratory test results). The post-index period was divided into 30-day intervals until the end of the index regimen (earliest of start of next regimen or end of eligibility). Intervals pre-TLS were non-TLS intervals and all intervals starting from the TLS diagnosis were TLS intervals. If TLS occurred after the first 90 days of active treatment (non-treatment-emergent TLS), all intervals were non-TLS intervals and the post-index period was censored at TLS diagnosis. Per-patient-per-month (PPPM) healthcare resource utilization (HRU) and payer paid costs during TLS and non-TLS intervals were compared using rate ratios (RRs) and mean monthly cost differences (MMCDs), respectively, obtained from generalized linear models adjusted for baseline and time-varying confounders. The proportion of patients switching to a next therapy in the first 90 days post-index was compared between patients developing versus not developing TLS using Kaplan-Meier rates with log-rank P-value.Results: Among 6,343 patients with CLL/SLL, 71 (1.1%, mean age: 66.4 years, 26.8% females; 22 treated with venetoclax; mean [median] duration of the entire index regimen: 16.0 [10.0] months) developed TLS during the first 90 days of active treatment and 6,272 (98.9%, mean age: 65.9 years, 34.1% female; 170 treated with venetoclax; mean [median] duration of the entire index regimen: 22.0 [14.5] months) did not. Among all 6,343 patients, there were 1,129 TLS intervals and 138,429 non-TLS intervals observed post-index. All patients incurred considerable cumulative costs over the entire index regimen duration (TLS cohort: $201,200; non-TLS cohort: $158,590). Developing TLS was associated with 1.7 times more inpatient (IP) admissions (P<0.001; Fig. 1a), 2.0 times more days of IP stay (P=0.012), 22% fewer days of antineoplastic drug administration (P=0.020; Fig. 1a), and $3,062 PPPM higher healthcare costs (P=0.016), driven by significantly higher IP costs PPPM (MMCD=$1,688; P=0.044; Fig. 1b) vs. not developing TLS. Higher costs during TLS intervals were observed for patients initiated on a venetoclax-based regimen (TLS intervals: $24,170 PPPM; non-TLS intervals: $20,091 PPPM) and patients initiated on a non-venetoclax-based regimen (TLS intervals: $8,746 PPPM; non-TLS intervals: $6,915 PPPM). In the first 90 days post-index, HRU and costs were higher than when averaged over the entire duration of the index regimen, regardless of developing TLS or not (Table 1). Among patients not developing TLS, those treated with a venetoclax-based regimen had numerically higher cumulative TLS prevention costs during the first 90 days post-index ($4,398) than those treated with a non-venetoclax-based regimen ($2,879). Patients developing TLS switched more quickly to a next line of therapy in the first 90 days of treatment compared to those not developing TLS (12.6% vs. 5.1%, P=0.006; Table 2).Conclusions: In this study of CLL/SLL patients treated with CIT-, lenalidomide-, obinutuzumab-, or venetoclax-based regimens, TLS led to a significant HRU and cost burden (mostly driven by IP admissions) and a higher rate of treatment switching. Consideration of available treatment options based on patient goals and treatment expectations is warranted before selecting a treatment with a high risk of developing TLS. [Display omitted] DisclosuresRogers: AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Innate Pharma: Consultancy; Pharmacyclics LLC: Consultancy; Janssen Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Emond: GlaxoSmithKline: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Côté-Sergent: GlaxoSmithKline: Consultancy; Janssen: Consultancy. Kinkead: Janssen: Consultancy; Otsuka: Consultancy. Lafeuille: Pharmacyclics: Consultancy; Janssen Scientific Affairs, LLC: Consultancy; Pfizer: Consultancy; GlaxoSmithKline: Consultancy. Lefebvre: Pfizer: Consultancy; Pharmacyclics: Consultancy; Otsuka: Consultancy; Janssen Scientific Affairs, LLC: Consultancy; GlaxoSmithKline: Consultancy; Novartis: Consultancy; Regeneron: Consultancy. Huang: Johnson & Johnson: Current equity holder in publicly-traded company; Janssen Scientific Affairs, LLC: Current Employment.

SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome: Updated Results of a Phase II Trial

Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia and Myelodysplastic Syndrome: Updated Results of a Phase II Trial

Variance in Practice between Experts and Oncology Healthcare Professionals for Follicular Lymphoma: Analysis of an Online Treatment Decision Tool

Variance in Practice between Experts and Oncology Healthcare Professionals for Follicular Lymphoma: Analysis of an Online Treatment Decision Tool

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

Proteomic Profiling Based Classification of CLL Provides Prognostication for Modern Therapy and Identifies Novel Therapeutic Targets

The availability of targeted therapy and improved molecular characterization of Chronic Lymphocytic Leukemia (CLL) require a re-evaluation of treatment paradigms. As CLL heterogeneity is dependent on molecular and environmental factors, there is a need to create a new classification based on the integration of several factors. Here, we accomplish this goal by identifying CLL signatures using Reverse Phase Protein Array. Protein expression for 384 total and post translationally modified proteins was assessed in 871 CLL and Mature Small B Cell Leukemia (MSBL: HCL, HCLV, LGL-T, MCL, MZL, PLL, Richter's, T-Cell PLL) patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteins were categorized into 40 protein functional groups (PFGs) based on literature and intra-dataset protein correlations and patients clustered based on PFG expression patterns into 6 recurrent protein expression signatures (PES) (Figure 1A). Individual protein expression (58/384 proteins), PFG expression (32/40) and overall PES were all highly prognostic of survival (OS) and time to first or second treatment (TTFT, TTST) (Figures 1B-C). The adhesion, apoptosis-occurring, apoptosis-regulating, heat shock, histone1 (marks), histone 2 (modifiers) and the STP-regulation PFGs were prognostic for all 3 outcome measures. Notably SG-A contained most of the MSBL and 15/16 cases of hairy cell leukemia, but the CLL cases within this SG fared very poorly. For OS, groups A and C had markedly inferior survival (P<0.0001) (10.3 and 20.3 median years) relative to the other 4 groups, which were statistically similar to each other. First treatment occurred sooner for Groups A and C (5.8 and 5.23 median years). Additionally, the TTST was also inferior for Group A (median 3.5 years). There were significant differences in age, hemoglobin, platelets, % BM and PB lymphocytes and β2M between the SG, but not for race (p = 0.84) or gender (p = 0.72). , Historically adverse cytogenetic aberrations del 11q and del17p events (23% overall) were less common in SG A, B, D and E (15, 14, 16, 17%) and overrepresented in SG C (32%), while historically favorable 13q changes were seen across all groups as was Trisomy 12 (14% overall), although SGs A and E were enriched (25%, 22%) while SG-F was low (5%) for Trisomy 12. SG membership superseded other traditional prognostic factors (Rai Staging, IGHV Status) and were prognostic for modern (BTK inhibition) and older CLL therapies. SGs A and C responded poorly to chemotherapy regimens compared to the other groups, whereas all groups responded well to BTK inhibitors except for SG-A. SGs and PFGs membership provided novel drug targets (see our other abstracts on TP53BP1 and ASNS) and defined optimal candidates for Watch and Wait (WaW) vs. early intervention. A model based on the accumulation of irregularities in ANXA1, TFRC, and SMAD2.p245 expression, optimally predicted TTFT overall and in early stage CLL patients. Patients with < 1 negative level of either of the 3 proteins, have a median TTFT of 14.59 years, whereas patients having 2-3 have a median of 5-6.27 years (P<0.0001). CHEK1.pS345, GAB2, IGFBP2, S100A4, WEE1.pS642, and ZAP70 were universally overexpressed by all SGs, suggesting them as ideal targets for inhibition. Collectively proteomics demonstrates promise for improving classification, therapy strategy determination, and identifying novel therapeutic targets. [Display omitted] DisclosuresFerrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Burger: Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Wierda: Xencor: Research Funding; Karyopharm: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Janssen: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding.

Phase II Trial of Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia: Updated Outcomes in Genomic Subgroups

Phase II Trial of Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia: Updated Outcomes in Genomic Subgroups

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for Treatment for Patients with Richter Transformation

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for Treatment for Patients with Richter Transformation

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Venetoclax, Obinutuzumab and Atezolizumab (PD-L1 Checkpoint Inhibitor) for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Evaluation of the Incidence and Risk Factors Associated with Bleeding Events in Patients Receiving Acalabrutinib Therapy

Background:Acalabrutinib is a more selective, second generation covalent binding Bruton tyrosine kinase (BTK) inhibitor. It was designed with the intent to mitigate adverse events (AEs) associated with ibrutinib, such as bleeding and cardiovascular events. In the phase 3 trial that that led to acalabrutinib approval in the front line setting for chronic lymphocytic leukemia (CLL), 37% and 2% of patients who received acalabrutinib monotherapy experienced grade 1-2 or ≥3 bleeding events, respectively. Currently, there are no long term studies evaluating the incidence of bleeding events associated with acalabrutinib. Therefore, the purpose of this study was to assess the incidence of bleeding events, and risk factors associated with bleeding events for patients treated with acalabrutinib for hematologic malignancies.Methods:This was a single center retrospective study conducted at The Ohio State University. Patients were included if they were ≥18 years old, diagnosed with a hematologic malignancy, and initiated on acalabrutinib (monotherapy or combination therapy) between January 1, 2010 and August 31, 2019. The International Society on Thrombosis and Haemostasis (ISTH) bleeding scale (no bleed, clinically non-relevant bleed, and clinically relevant/major bleed) and Common Terminology Criteria for Adverse Events V5.0 (CTCAE) were used to evaluate the grade and class of bleed events. Descriptive statistics were used to summarize demographic information and bleed events; univariable analysis was used to assess risk factors.Results:We analyzed 289 patients who received acalabrutinib for a hematologic malignancy. The main source of acalabrutinib was from clinical trials (85%) and the median acalabrutinib exposure time for all patients was 40.8 months (range: 0-81.6 months). 89% of patients had CLL, 2% had mantle cell lymphoma, and 9% had other non-Hodgkin's lymphoma. Additionally, 18% of patients had a prior bleed history and 51% were continued on concomitant medications that increase bleeding (Table 1). There were a total of 241 (83%) patients who experienced at least one bleed event. Per ISTH categorization, 143 (59%) patients' most severe bleed event was clinically non-relevant and 98 (41%) patients' was clinically relevant/major; cutaneous bleeds were most common in both groups, 71% and 31%, respectively. Only 6% of patients had a major bleed, hence, clinically relevant and major bleeds were analyzed together for the purpose of this study.There were a total of 633 bleed events that occurred in this study population; 76% were clinically-non relevant and only 3% (n=17) were CTCAE grade ≥3. Acalabrutinib was not discontinued or held for any clinically non-relevant bleeds, was discontinued for six (1%) clinically relevant/major bleeds, and held for 44 (7%) clinically relevant/major bleeds. Clinically relevant /major bleeds also resulted in discontinuations of concomitant anticoagulation and antiplatelet therapy in only 4% (n=24) of cases. 1263 procedures were identified and the incidence of clinically non-relevant and clinically relevant/major bleeds related to surgeries/procedures was 1% (n=12) and 1.3% (n=16), respectively.10% of clinically non-relevant and 57% of clinically relevant/major bleeds led to hospitalizations, emergency room visits, or physician office visits; including two major CNS bleed events which resulted in death. The overall survival (OS) was not reached in the clinically non-relevant and clinically relevant/major bleed groups and was 14 months (95% CI 6-40) in the no bleed group (p=0.021). Univariate analysis showed that risk factors associated with a clinically relevant/major bleed included concomitant medications (OR 3.06, 95% CI 1.49-6.26) and prior bleed history (OR 4.40, 95% CI 1.45-13.40) (Table 3).Conclusions:Overall, our study had a long acalabrutinib exposure time and demonstrated a low incidence of grade ≥3 bleeds. There was also a low risk of bleeds related to procedures. The majority of bleeds were clinically non-relevant that did not result in significant treatment adjustments, hospitalizations, or death. This study identified prior bleed history and concomitant medications that increase bleeding as risk factors for bleeds and should be evaluated prior to starting acalabrutinib therapy. Our data supports acalabrutinib as a safe long-term treatment in regards to bleeds for patients with hematologic malignancies. [Display omitted] DisclosuresWiczer: BTG Specialty Pharmaceuticals: Consultancy. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; AstraZeneca: Consultancy; Onclive: Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rogers: Janssen Pharmaceuticals, Inc: Research Funding; Pharmacyclics LLC: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Innate Pharma: Consultancy; ovartis Pharmaceuticals Corporation: Research Funding; AbbVie Inc.: Consultancy, Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

Very Few Interventions after Tumor Lysis Monitoring in Patients with Chronic Lymphocytic Leukemia Who Are Started on Venetoclax in the Real-World Setting- Suggests Less Intensive Monitoring Maybe Safe for Low-Risk Patients

Very Few Interventions after Tumor Lysis Monitoring in Patients with Chronic Lymphocytic Leukemia Who Are Started on Venetoclax in the Real-World Setting- Suggests Less Intensive Monitoring Maybe Safe for Low-Risk Patients

Expansion of T Follicular Helper Cells in NLC Co-Cultures Reinforces the Concept of Co-Evolution of CLL and Supportive T Helper Cell Clones

Expansion of T Follicular Helper Cells in NLC Co-Cultures Reinforces the Concept of Co-Evolution of CLL and Supportive T Helper Cell Clones