Risk of Major Bleeding with Ibrutinib in Patients with Thrombocytopenia - a Retrospective Single-Center Canadian Study

Abstract Introduction: Ibrutinib, an oral Bruton Kinase inhibitor, is a highly effective treatment for patients with chronic lymphocytic leukemia (CLL). Previous studies reported an increased risk of bleeding due to impaired platelet function. Patients with CLL experience significant thrombocytopenia, which increases their risk for bleeding. This population was excluded from major trials and data is lacking to inform management in this setting. Methods: This is a single center retrospective study of all adult patients with CLL who received single agent ibrutinib in London, Ontario, Canada between January 2014 to December 2020. The primary objective was to investigate the risk of major bleeding associated with thrombocytopenia. Secondary objective was to investigate potential predictors of bleeding. Bleeding events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading system. A major bleed was defined as CTCAE grade 3 or higher as well as bleeding in the central nervous system. To assess the effect of independent variables on the outcome of bleeding, univariate analysis using chi square and t-tests was performed. Multivariate analysis was then preformed with the variables that were significant (p<0.05) on univariate analysis, using logistic and cox regression models. Results: A total of 170 patients were included in this study. There were 54 bleeding events documented in 42 patients (24.7 %) of which 19(35 %) were major bleeding occurring in 17 patients. Median time to major bleeding was 2.4 months. Of the patients with major bleeding, 4(21%) were on anticoagulation, 2(10%) were on antiplatelet and 2(10%) were on combined anticoagulation and antiplatelet. There were 8 central nervous system (CNS) bleeding and 2 of them died. The mean platelet (PLT) nadir, defined as lowest PLT count at any point during ibrutinib treatment, was 73 x 10 9/Lin patients with major bleeding compared to 116 x 10 9/L in patients with minor and 91 x 10 9/L in patients with no bleeding events. On the univariate analysis, when compared patients with major bleeding to patients with no bleeding, potential predictors of major bleeding included PLT nadir (p=0.09), haemoglobin (Hb) < 100 g/L at ibrutinib initiation (p=0.027) and anticoagulation (p=0.009). When compared patients with major bleeding to patients with minor or no bleeding, potential predictors of major bleeding included PLT nadir (p=0.045), Hb <100 (p=0.036) and anticoagulation (p=0.06). Grade 3 thrombocytopenia, defined as PLT nadir < 50 at any point during treatment with ibrutinib was not associated with increased risk of major bleeding (p=0.2). To confirm the significance of these variables, multivariate analysis was performed. When compared patients with major bleeding to patients with no bleeding, PLT nadir (OR= 0.9, p=0.008) and anticoagulation (OR=4.02, p=0.001) were confirmed to be the potential predictors of major bleeding. When compared patients with major bleeding to patients with minor or no bleeding, PLT nadir (OR=0.9 p=0.005) and Hb <100 (OR=2.34, p=0.005) were the potential predictors of major bleeding. Conclusions: Although not common, Ibrutinib is associated with increased risk of bleeding and identifying high risk patients is essential to prevent major bleeding events. This retrospective Canadian study was done with the primary objective to assess the association between PLT count and major bleeding in patients on ibrutinib for treatment of CLL. In this analysis patients with major bleeding tend to have lower PLT counts compared to patients with minor or no bleeding, with mean PLT nadir of 73x 10 9/L. However, grade 3 thrombocytopenia (PLT nadir<50) was not associated with increased risk of major bleeding. Other important predictors of increased risk of major bleeding while on ibrutinib include anticoagulation and anemia (Hb <100). Figure 1 Figure 1. Disclosures Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Lam: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria.

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Management and Outcomes of Atrial Fibrillation in Patients Receiving Ibrutinib for Hematologic Malignancies at a Single Center

Blood ◽

10.1182/blood.v128.22.2040.2040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2040-2040 ◽

Cited By ~ 2

Author(s):

Tracy E Wiczer ◽

Lauren B Levine ◽

Jessica Brumbaugh ◽

Jessica Coggins ◽

Qiuhong Zhao ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Antiplatelet Therapy ◽

Major Bleeding ◽

Stroke Prevention ◽

Research Funding ◽

Bleeding Events ◽

Advisory Committees ◽

Major Bleeding Events ◽

Grade 3

Abstract Background Ibrutinib (IB) is Food and Drug Administration approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM). High overall response rates, extended progression free survival, and an acceptable adverse event profile make IB an impactful therapy for these malignancies. Atrial fibrillation (AF) has been identified as a less common but serious adverse effect of IB with reported incidence ranging from 2-16% in clinical trials and post-marketing experience. AF can be associated with significant morbidity and mortality, including congestive heart failure and embolic events such as stroke. Data regarding the management of AF in this patient population is thus far limited. Embolic stroke prevention poses a particular clinical challenge as IB carries an inherent bleeding risk that may be increased by antiplatelet therapy and therapeutic anticoagulation. We report the management and outcomes of a large cohort of patients who developed AF while on IB therapy. Methods Patients with hematological malignancies and incident or recurrent AF while on IB therapy at the Ohio State University were identified retrospectively. Incident AF was defined as new onset AF in patients without a history AF and recurrent AF as an AF event requiring new intervention in patients with a prior history of AF. Data pertaining to patient demographics, comorbid conditions, AF events, AF management, stroke prevention strategies, and complications of AF therapy were collected. AF events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 andcongestive heart failure, hypertension, age, diabetes mellitus, stroke (CHADs2) scores were calculated. Major bleeding was defined as a decrease in hemoglobin of 2g/dL or more, requiring a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding events were graded according to CTCAE criteria. Management strategies and outcomes are summarized. Results Seventy-two patients with incident or recurrent AF were identified. Fifty-nine patients developed incident AF while 13 patients developed recurrent AF while on IB. Baseline characteristics are presented in Table 1.Patients with recurrent AF were older, had worse baseline ECOG performance status, and longer baseline PR interval on electrocardiogram assessment.Patients were followed for a median of 4.3 years from the start of ibrutinib and 1.7 years from AF event.Ninety-three percent of the AF events were grade 1-2 and 7% were grade 3. First-line therapy forAF included rate-control for 54 (75%) patients, interventional procedural strategies for 8 (11.1%), and rhythm-control for 3 (4.2%). Seven (9.7%) patients required no intervention. Twenty-two patients (30.5%) required a second and 4 (5.5%) required third-line AF management intervention. Among those with a secondary AF management strategy, rhythm control was the most frequently utilized (n=10, 45.5%). During the AF events, 31 (43.1%) patients continued IB, 35 (48.6%) temporarily held IB, 5 (6.9%) discontinued IB, and one patient had the dose reduced. Stroke prevention strategies are described in Table 2. Patients with recurrent AF were less likely to be treated with anticoagulation when compared to patients with incident AF. Six (8.3%) patients had a major bleeding event and 2 of these patients went on to have a second major bleed. Of the 8 major bleeding events, 3 occurred with concomitant antiplatelet therapy and no patients were on anticoagulation therapy at the time of bleeding. Eighteen (25%) patients developed a total of 25 clinically relevant non-major bleeding events (9 grade 1 events, 13 grade 2 events, 2 grade 3 events, and 1 could not be graded). Only one potential embolic event occurred in a patient with a CHADs2 score of 1 on aspirin 325mg who developed symptoms consistent with stroke. Conclusions AF events in patients being treated with IB are generally manageable and in the majority of cases did not result in IB discontinuation. Clinically relevant bleeding events are common, and caution must be exercised when initiating routine antiplatelet therapy and/or anticoagulation in patients with IB. Risk of ischemic stroke was low in our patient population, though follow up was limited. The optimum strategy for stroke prophylaxis in patients with concurrent IB is unclear. Disclosures Christian: Pharmacyclics: Research Funding; Janssen: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy.

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Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽

10.1182/blood-2019-122930 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2441-2441

Author(s):

Alex C. Spyropoulos ◽

Gary E. Raskob ◽

Alexander T Cohen ◽

Walter Ageno ◽

Jeffrey I. Weitz ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

Bayer Healthcare ◽

Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

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The Risk of Bleeding in Patients Receiving Ibrutinib Combined with Novel Direct Oral Anticoagulants

Blood ◽

10.1182/blood-2019-125356 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4314-4314

Author(s):

Michal Ariela Raz ◽

Jon E. Arnason ◽

Osnat Bairey ◽

Lev Shvidel ◽

Ariel Aviv ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Lymphoproliferative Disorders ◽

Bleeding Events ◽

Concurrent Administration ◽

Risk Of Bleeding ◽

Grade 3

Introduction: Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction and concurrent treatment with ibrutinib and warfarin was shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, considering their expanding employment together with the lack of data regarding their safety in patients receiving ibrutinib. Methods: We conducted a retrospective cohort study to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders (CLL, MCL, DLBCL, MZL or WM) that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy, between January 2010 and October 2018 in 5 participating centers. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage (including the adjustment for renal function), blood count and chemistry tests, bleeding site and grade. Results: The study included 30 patients, median age at starting concurrent administration of ibrutinib and DOACs was 71.58 years (range 50.9-88.2). Most patients were treated for CLL (n=18, 60%) and MCL (n=8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63.3% and 30% of patients respectively. None of the patients received an additional antiplatelet agent. Twenty-three patients were treated with apixaban (76.7%), 4 with rivaroxaban (13.3%) and 3 (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). The median follow-up after initiation of the ibrutinib-DOAC combination was 13.4 months (range 1.8-47.9 months). Bleeding was reported in 22 patients (73.3%), mostly mucocutaneous (n=12, 40%) and gastrointestinal tract (n=7, 23.3%), followed by CNS bleeding (n=4, 13.3%). Mucocutaneous bleedings were all grade 1-2 and gastrointestinal tract and CNS bleeding events were grade 1-4. Major bleeding events, defined as grade 3 or 4, occurred in 5 patients (16.6%) and did not result in death of any of the patients. The median time for bleeding following ibrutinib-DOAC initiation was 5.6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% (Figure 1). Incidence of bleeding events (including all grades) was quite similar between all DOAC subtypes (73.9% with apixaban, 75% with rivaroxaban and 66.7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in 8 patients (26.7%) due to grade 1 to 4 bleeding events and was re-initiated in 6 patients, resulting in recurrent grade 3 and 4 bleeding events in 2 patients. Conclusions: Concurrent administration of DOACs and ibrutinib appears to be feasible. However, risk of bleeding is not neglectable, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

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Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Blood ◽

10.1182/blood.v128.22.4387.4387 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4387-4387 ◽

Cited By ~ 4

Author(s):

Aaron Pavlik ◽

Hallie Barr ◽

Emily Dotson ◽

John C. Byrd ◽

Kristie A. Blum ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Event ◽

Antiplatelet Agents ◽

Bleeding Complications ◽

Bleeding Events ◽

Advisory Committees ◽

Major Bleeding Events

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th16-10-0810 ◽

2017 ◽

Vol 117 (06) ◽

pp. 1164-1170 ◽

Cited By ~ 33

Author(s):

Frederikus A. Klok ◽

Stefano Barco ◽

Stavros V. Konstantinides

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Major Bleeding ◽

External Validation ◽

Chronic Phase ◽

Bleeding Risk ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk ◽

Study Population

SummaryOne of the main determinants of establishing the optimal treatment duration of patients with venous thromboembolism (VTE) is the risk of major bleeding during long-term anticoagulant therapy. The 6-variable VTE-BLEED score was recently developed to enable estimation of this bleeding risk. This study aimed at externally validating VTE-BLEED. This was a post-hoc study of the randomised, double-blind, double-dummy, Hokusai-VTE study that compared edoxaban versus warfarin for treatment of VTE. VTE-BLEED was calculated in all 8,240 study patients. The numbers of adjudicated major bleeding events during ‘stable anticoagulation’, i. e. occurring after day 30, in patients with low (total score <2 points) and high risk of bleeding (total score ≥2 points) were compared for the overall study population, patients randomised to edoxaban or warfarin, and for important patient subcategories. During ‘stable’ anticoagulation, major bleeding occurred in 1.02% (40/3,903) and 0.82% (32/3,899) of patients treated with warfarin and edoxaban, respectively. For the overall study population, the risks of bleeding in the low and high risk groups were 0.51% and 2.03%, respectively, for an odds ratio (OR) of 4.04 (95% confidence interval [CI]: 2.51–6.48). ORs were 5.04 (95%CI: 2.62–9.69) and 3.09 (95%CI: 1.54–6.22) for warfarin and edoxaban, respectively. VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold higher bleeding risk across all the predefined subcategories, as well as for the treatment period between day 30 to day 180, and beyond day 180. In conclusion, patients identified as high risk by VTE-BLEED had a four-fold increased risk of bleeding during the chronic phase of treatment.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Ibrutinib Plus Obinutuzumab and Venetoclax in Relapsed/Refractory Mantle Cells Lymphoma Patients, Results of the OASIS Phase I Clinical Trial

Blood ◽

10.1182/blood-2018-99-113777 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4158-4158 ◽

Cited By ~ 5

Author(s):

Steven Le Gouill ◽

Franck Morschhauser ◽

Krimo Bouabdallah ◽

Guillaume Cartron ◽

Rene-Olivier Casasnovas ◽

...

Keyword(s):

Drug Resistance ◽

Phase I ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Primary Objective ◽

Clinical Relapse ◽

Advisory Committees ◽

Grade 3

Abstract Background. Mantle Cell Lymphoma (MCL) drug resistance are highly dependent on B-cell-receptor signaling, Bcl-2 and the microenvironment. Ibrutinib inhibits both tumor cell proliferation and binding to the microenvironment. Venetoclax is a Bcl-2 inhibitor and Bcl-2 family members like Mcl-1 and Bcl-xL confers resistance to Venetoclax and are upregulated by the tumor microenvironment but downregulated by Ibrutinib (Touzeau, 2011, Chiron, 2015). Ibrutinib plus venetoclax has recently demonstrated high efficacy in relapsed/refractory (R/R) MCL (Tam et al NEJM 2018). Preclinical investigations show that microenvironment-dependent long-term expansion and drug resistance to venetoclax are counteracted by obinutuzumab (type II glycoengineered humanized anti-CD20 antibody) and obinutuzumab/venetoclax/ibrutinib is highly active against primary MCL cells. (Chiron Blood 2016). All together these findings gave the rational to investigate Obinutuzumab/Ibrutinib (step A) and Obinutuzumab/Venetoclax/Ibrutinib (step B) combinations. The OAsIs trial (NCT02558816) has been designed to assess the safety, tolerability and efficacy of these two combos in R/R MCL. DLTs were assessed during the first 2 months (step A) and 3 months (step B) of treatment. Methods: Oasis is a multicenter, non-randomized, phase I study. Step A evaluates the safety of obinutuzumab (1000mg IV C1D1, 8,15, C2-6 D1 and every 2 months until C24) plus Ibrutinib (560mg/d until progression) (n=9). Step B primary objective is to determine the MTD of obinutuzumab/venetoclax/ibrutinib. Venetoclax is administered from C2 (C2W1 100mg/d, C2W2 200mg/d, C2W3 400mg/d and C2W4-C6: 400, 600 or 800mg/d). A continual reassessment method is used to allocate venetoclax doses (3 patients-pts- per dose-level). Enrolment in step A and B for R/R MCL started in November 2015 and October 2016, respectively. Results. Step A (Obinutuzumab/Ibrutinib) (n=9). Median age at inclusion was 64y (range 58-82) and median lines of treatment prior to inclusion is 1 (1-4), including ASCT in 7 patients and allo-SCT in one case. Median time from diagnosis to C1D1 is 46.5m (18.4-103). Two pts presented with blastoid variant. One of nine step A patients presented TP53 mutation. Median time from diagnosis to C1D1 is 46.5m (18.5-103). During the first 3 months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Eight grade 3-4 hematological AEs were reported in 4 pts (lymphopenia 4 ; neutropenia 4 ; thrombocytopenia 1). One patient progressed at end of C2 and died few weeks later while 7 (87%) were in CR according to Lugano criteria at end of C6. MRD status was assessed by ASO qPCR targeted to clonal immunoglobulin rearrangements in 6 /9 step A pts (one progressed before C6, data missing = 2). Of these, 4 were MRD negative in both blood and bone marrow after C6 (one remained MRD pos with no clinical relapse and underwent allo-SCT, one was not evaluated in BM). At the 12 months time point, the 3 evaluated pts remained MRD negative. With a median follow-up of 23,5m (8,9-31.6), 8 pts are alive (6 completed the 2y treatment program and are in CR). Step B (Obinutuzumab/ Ibrutinib/Venetoclax; Ven 400mg (n=3); at Ven=600mg (n=3) and Ven=800mg (n=6)). Median age at inclusion is 64.5y (range 45-74). Median lines of treatment prior inclusion is 2 (1-3), including ASCT in 8 patients. Five pts presented with blastoid MCL. TP53 status was assessed in 3/10 pts (2 ongoing). Of these 10, 3 presented TP53 mutations. Median time from diagnosis to C1D1 is 50.2m (12.8-123). The median follow-up for living pts (n=8) is 6.5m (2.5-15). During the first three months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Twenty-nine grade 3-4 hematological AEs were reported in 7 pts (febrile neutropenia 1, neutropenia 4 ; thombopenia 4, anemia 2 and lymphopenia 3). At end of C2 , 3 achieved CR, 5 PR and 4 pts had PD. Among 9 pts assessed after C6, 5 patients were in CR (MRD analysis ongoing) Conclusion. No DLT has been reported in both step A and B. Both combinations are well tolerated and provide high disease control including CR at the molecular level. Oasis step C (obinutuzumab/venetoclax/ibrutinib) for untreated MCL pts is now open for inclusion since July 2018. Disclosures Le Gouill: Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi: Honoraria; Janssen: Honoraria; Gilead Sciences: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gastinne:Millennium/Takeda: Honoraria. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Rule:Kite: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Metabolic PET/CT Analysis of Aggressive Non-Hodgkin Lymphoma Prior to Axicabtagene Ciloleucel CAR-T Infusion: Predictors of Progressive Disease, Survival, and Toxicity

Blood ◽

10.1182/blood-2021-153739 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2518-2518

Author(s):

William Breen ◽

Jason R. Young ◽

Matthew Hathcock ◽

Roman O. Kowalchuk ◽

Radhika Bansal ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Non Hodgkin Lymphoma ◽

Increased Risk ◽

Pet Ct ◽

Car T ◽

Grade 3

Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

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Bendamustine, Bortezomib and Dexamethasone (BVD) in Elderly Patients with Multiple Myeloma in First Relapse: Updated Results of the Intergroupe Francophone Du Myelome (IFM) 2009-01 Trial

Blood ◽

10.1182/blood.v120.21.4044.4044 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4044-4044 ◽

Cited By ~ 3

Author(s):

Philippe Rodon ◽

Cyrille Hulin ◽

Brigitte Pegourie ◽

Mourad Tiab ◽

Bruno Anglaret ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Board Of Directors ◽

Response Rate ◽

Progression Free Survival ◽

Primary Objective ◽

Advisory Committees ◽

Highly Active ◽

Line Therapy ◽

Grade 3

Abstract Abstract 4044 Background: Prognosis of relapse is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1st line treatment. Methods: Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0–2, ANC > 1.5×109/l, platelets > 100×109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 D1–8, V 1.3 mg/m2 D1–8-15–22 and D 20 mg D1–8-15–22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results: The present analysis is restricted to the 6 monthly cycles. From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66–86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: melphalan-prednisone (MP) in 12, MP-Thalidomide in 44, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 3. 49 pts (67.1%) achieved at least partial response [best response CR: 9 pts (12.3%), VGPR: 12 pts (16.5%), PR: 28 pts (38.3%), MR: 6 pts (8.2%), SD: 4 pts (5.5%), progression: 13 pts (17.8%), early discontinuation: 1 pt (1.3%)]. Adverse prognostic factors for response were 1st line regimen with IMiD (p=0.006) and del17p (p=0.036). At 6 months, PFS was 67.1% and OS 80.8%. Cause of death was MM in 9 pts, sepsis in 4 pts and renal failure in 1 pt. Grade 3–4 adverse events were neutropenia: 16 pts (21.9%), thrombocytopenia: 7 pts (9.6%), sepsis: 14 pts (19.2%), gastro-intestinal: 9 pts (12.3%), anaphylaxis: 1 pt (1.3%). Grade 2 peripheral neuropathy occurred in 10 pts (13.6%) and grade 3 in 2 pts (2.7%). At 6 months, treatment was discontinued in 33 pts (45.2%). Cause of discontinuation was progressive MM in 18 pts (24.6%), failure to achieve PR in 5 pts (6.8%), adverse event in 8 pts (10.9%), patient refusal or lost to follow-up 1 pt (1.3%) each. Conclusion: In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favorably with those achieved with VD or LD. Disclosures: Hulin: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Roussel:celgene: Honoraria; janssen: Honoraria.

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A Lysa Phase II Study of Oral JAK1/2 Inhibitor Ruxolitinib in Advanced Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Blood ◽

10.1182/blood.v128.22.4160.4160 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4160-4160 ◽

Cited By ~ 2

Author(s):

Eric W Van Den Neste ◽

Marc Andre ◽

Thomas Gastinne ◽

Aspasia Stamatoullas ◽

Corinne Haioun ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Study Drug ◽

Median Number ◽

Primary Objective ◽

Additional Treatment ◽

Advisory Committees ◽

Grade 3

Abstract Background: JAK2 constitutive activation/overexpression is frequent in classical HL tumor cells and many autocrine/paracrine cytokines stimulate HL cells by recognizing JAK1- or JAK2-bound receptors. Thus, JAKs blockade may be of therapeutic value in HL. Methods: A phase II study (HIJAK study)was conducted to evaluate safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in R/R HL, given at 20 mg bid for 6 cycles of 28 days. Dosage at 15 mg bid was planned for patients with platelets comprised between 75 and 200 x 109/L at inclusion. Patients with platelets < 75 x 109/L, neutrophils < 1000 x 109/L were excluded. Maintenance beyond 6 cycles was permitted if disease control. The primary objective was overall response rate (ORR, Cheson 2007) at 6 cycles. Secondary objectives were safety, B symptoms relief, best ORR, response duration, PFS and OS. To be evaluable for response and survivals, patients had to receive at least one cycle of the study drug. The safety set included all patients who received at least one dose of ruxolitinib. Median follow-up was 27.1 months (95% CI: 14.4-27.1). Results: 33 patients were included between Jul 2013 and Dec 2014 in 10 LYSA centers in France and Belgium: M/F, 21/12; median age 37 (range 19-80) years; stage III/IV, 75.8%; B symptoms, 51.5%; median number of prior lines, 5 (range 1-16); prior transplantation, 60.6%; prior radiotherapy, 54,5%; prior brentuximab vedotin (BV), 82%; refractory to last therapy, 81.8%. Overall, median number of ruxolitinib cycles was 4. Nine (27.3%) patients received at least 6 cycles and 6 (18.2%) maintenance. ORR at the end of induction was 3/32 (9.4%) patients, all PRs. Best ORR at any time during study was 18.8% (6/32) with five PRs and 1 patient who converted into CR beyond 6 cycles. Transient stable disease was noted in 11 patients. Rapid and durable alleviation of B-symptoms (pruritus, fever, sweating) was frequently noted, especially pruritus which was present in 35.5% of patients before treatment and 6.6% of them after one cycle of ruxolitinib. Median duration of response was 7.7 months (95% CI: 1.8-NA). Two patients remain on therapy. Median PFS was 3.5 months (95%CI: 1.9-4.6) and median OS was 27.1 months (95%CI: 14.4-27.1). Using bead-based immunoassays, plasma levels of 27 cytokines related to the immune system were measured at baseline and after cycle 1. Before ruxolitinib, there was no difference in cytokine levels between responders and non-responders. In responders, the only cytokine that significantly decreased was CX-CL10 (P.01). In patients presenting with pruritus (n=11), PDGF-BB, IL-5, IL-10, IL-12, IL-13, IL-17, eotaxin, FGF basic, MIP1b, rantes, and VEGF were significantly increased. In the latter patients, ruxolitinib treatment significanlty decreased PDGF-BB, IL-10, IL-12, IL-13, IL-17, FGF basic and VEGF. Among patients who were analyzable for JAK2 amplification in RS cells (n=12), polysomy was detected in all of them and specific JAK2 amplification in one. Further analysis of Jak2 targets by IHC will be performed. 40 adverse events (AEs) were reported in 14/33 patients (42.4%), of which 18 were related to ruxolitinib and 18 were grade ≥ 3. One AE led to permanent treatment discontinuation. No AE leading to death was reported. 87.5% of AEs recovered without sequelae. Eight SAEs (infection, 3; anemia, 1; diarrhea, 1; subdural hematoma, 1; bone pain, 1; pulmonary embolism, 1) were reported in 4 patients (12.1%), of which 2 were related to ruxolitinib. No grade 4 neutropenia and 1 grade 3/4 thrombocytopenia was observed. Five patients had grade 3 anemia. Twelve patients died due to lymphoma (83.3%) or toxicity of additional treatment (8.3%) or other reason (8.3%). Among 30 patients who progressed (initial site in 97% and/or new site in 60%), 25 (83.3%) were retreated: with chemotherapy in 19 (comprising bendamustine in 10) and/or immunotherapy in 9 (rituximab, n=4; BV, n=3; nivolumab, n=2). Transplantation was eventually performed in 5/25 (4 allogenic, 1 autologous). In the 25 patients who were retreated, CR/PR rates were 10/15%, respectively. Conclusions: Ruxolitinib shows hints of activity beyond simple anti-inflammatory action in highly advanced, mostly refractory, HL patients, although most responses are short-lived. Toxicity was limited suggesting potential to be combined with other modalities. Further treatment, beyond ruxolitinib, was possible in most patients, even with chemotherapy. Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Ghesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Roche France: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria.

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ASXL1 Mutation Is a Novel Risk Factor for Bleeding in Patients with Philadelphia-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽

10.1182/blood-2021-146384 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3637-3637

Author(s):

Amro Elshoury ◽

Han Yu ◽

Wenyan Ji ◽

James E. Thompson ◽

Elizabeth A. Griffiths ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Advisory Board ◽

Factor V ◽

Continuous Variables ◽

Bleeding Events ◽

Advisory Committees ◽

Risk Of Bleeding

Abstract Background: Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality. Although risk factors for thrombosis are well established, bleeding risk factors in these patients are poorly characterized. Identifying MPN patients at higher risk for bleeding could guide the duration of anticoagulation for patients with MPN associated thrombosis (balancing the risk between bleeding and thrombosis), select individuals at higher risk for bleeding during prophylactic anticoagulation, and predict for bleeding complications with surgical procedures. Methods: We performed a retrospective analysis of bleeding risk factors among consecutive adult MPN patients treated at Roswell Park Comprehensive Cancer Center. Bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH). The primary outcome of interest was time to initial bleeding after MPN diagnosis. Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables) (Table 1). Cox regression was used to examine the associations between candidate risk factors with identified bleeding events in univariate and multivariable analyses. Variables with p<0.1 in univariate analyses were selected for multi-variate analysis. A time-dependent variable of thrombosis status was included in the model. A stepwise feature selection based on Akaike Information Criterion was used for model selection. Continuous variables were dichotomized at median for the regression analyses. Results: A total of 170-consecutive adult MPN patients were identified between 2005 and 2021. Median follow-up was 43.5 months (range 0.66-485.72). The rate of bleeding (major and minor) was 4.9/100 patient-years and rate of thrombosis was 5.4/100 patient-years (5.4/100 patient-years for arterial thrombosis and 2.9/100 patient-years for venous thrombosis). In univariable analysis, predictors of bleeding included age > 60 years (HR 2.8; 95% CI 1.47-5.34; p=0.001), diagnoses of primary myelofibrosis (PMF) (HR 2.98; 95% CI 1.29-6.9; p=0.01) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS-MPN) overlap syndrome (HR 4.56, 95% CI1.91-10.88; p=0.0004), prior history of thrombosis (HR 3.3, 95% CI 1.27-8.8; p=0.01) and presence of ASXL1 (HR 4.13, 95% CI 2.13-8.04; p=0.0001), JAK2 V617F (HR 0.58; 95% CI 0.31-1.08; p=0.08) and TET2 mutations (HR 3.46; 95% CI 1.5-7.9; p=0.003). In multivariate analysis, the presence of JAK2 V617F (HR 4.8; 95% CI 1-21.5; p=0.03) and ASXL1 (HR 12.7, 95% CI 1.7-93; p=0.01) mutations were associated with increased risk of bleeding (Figure 2). Patients with polycythemia vera were at lower risk of bleeding (HR -3.5, 95% CI 0-0.8; p=0.03). Since ASXL1 mutation was associated with a higher risk of bleeding, we studied the association between ASXL1 mutation and other clinical variables. Patients with ASXL1 mutations were more likely to have a diagnosis of PMF and MDS-MPN overlap syndrome (p=0.0001), age > 60 years (p=0.0001), risk for thrombosis (p=0.04), lower hematocrit (p=0.009) and platelets (p=0.0003) but higher white blood cell count (WBC) (p= 0.04) (Figure 3). We then studied the correlation between ASXL1 mutation and factor VIII/Von Willebrand complex and factor V, the two most described abnormal coagulation factors in MPN. ASXL1 mutation was not associated with a statistically significant lower VWF Ag (p=0.07) or factor V (p=0.1) that could potentially explain the higher risk of bleeding seen with this mutation (figure 4). Conclusion: ASXL1 mutations are associated with a significantly higher risk of bleeding in adult MPN patients. The risk of bleeding with ASXL1 mutations was independent of prior thrombosis and was not associated with abnormalities in VWF profile or factor V. Confirmation of these findings in additional patients and studies of underlying platelet function to identify the possible mechanism of ASXL1 associated bleeding in these patients are ongoing. Figure 1 Figure 1. Disclosures Elshoury: Bristol Meyers Squibb: Other: advisory board. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Griffiths: Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

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