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REAL-WORLD ANALYSIS OF THE RISKS OF THROMBOTIC AND BLEEDING EVENTS IN PATIENTS RECEIVING PEGYLATED ASPARAGINASE FOR TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Benjamin Mautner
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Benjamin Brewer
Affiliations:
Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,États-unis;Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,Vereinigte Staaten;Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,Stati U
,
Joseph Mort
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Eric Pierce
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Farid Ghamsari
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Samantha Dibenedetto
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Emily Morse
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Leah Wells
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Amy Morris
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Cecily Allen
Affiliations:
Hematology and Oncology,Yale University,New Haven,États-unis;Hematology and Oncology,Yale University,New Haven,Vereinigte Staaten;Hematology and Oncology,Yale University,New Haven,Stati Uniti;Hematology and Oncology,Yale University,New Haven,United States;Hematology and Oncology,Yale University,New Haven,Estados Unidos;Hematology and Oncology,Yale University,New Haven,Verenigde Staten;Hematology a
,
Imari Patel
Affiliations:
Hematology and Oncology,University of Maryland Medical Center,Baltimore,États-unis;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Vereinigte Staaten;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Stati Uniti;Hematology and Oncology,University of Maryland Medical Center,Baltimore,United States;Hematology and Oncology,University of Maryland Medical C
,
Darren D'Souza
Affiliations:
Hematology and Oncology,University of Maryland Medical Center,Baltimore,États-unis;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Vereinigte Staaten;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Stati Uniti;Hematology and Oncology,University of Maryland Medical Center,Baltimore,United States;Hematology and Oncology,University of Maryland Medical C
,
Clayton Jackson
Affiliations:
Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,États-unis;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,Vereinigte Staaten;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,Stati Uniti;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Cen
,
Matthew Perciavalle
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Bradley Yelvington
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Ryan Miller
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Karin Abernathy
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Katherine Walsh
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Heather Wolfe
Affiliations:
Hematology and Oncology,Duke Cancer Institute,Durham,États-unis;Hematology and Oncology,Duke Cancer Institute,Durham,Vereinigte Staaten;Hematology and Oncology,Duke Cancer Institute,Durham,Stati Uniti;Hematology and Oncology,Duke Cancer Institute,Durham,United States;Hematology and Oncology,Duke Cancer Institute,Durham,Estados Unidos;Hematology and Oncology,Duke Cancer Institute,Durham,Verenigde S
,
Susan Locke
Affiliations:
Hematology and Oncology,Duke Cancer Institute,Durham,États-unis;Hematology and Oncology,Duke Cancer Institute,Durham,Vereinigte Staaten;Hematology and Oncology,Duke Cancer Institute,Durham,Stati Uniti;Hematology and Oncology,Duke Cancer Institute,Durham,United States;Hematology and Oncology,Duke Cancer Institute,Durham,Estados Unidos;Hematology and Oncology,Duke Cancer Institute,Durham,Verenigde S
,
Daniel Reed
Affiliations:
Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,États-unis;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,Vereinigte Staaten;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Center,Winston-Salem,Stati Uniti;Hematology and Oncology,Wake Forest Baptist Medical Comprehensive Cancer Cen
,
Vu Duong
Affiliations:
Hematology and Oncology,University of Maryland Medical Center,Baltimore,États-unis;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Vereinigte Staaten;Hematology and Oncology,University of Maryland Medical Center,Baltimore,Stati Uniti;Hematology and Oncology,University of Maryland Medical Center,Baltimore,United States;Hematology and Oncology,University of Maryland Medical C
,
Bhagirathbhai Dholaria
Affiliations:
Hematology and Oncology,Vanderbilt University Medical Center,Nashville,États-unis;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Vereinigte Staaten;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,Stati Uniti;Hematology and Oncology,Vanderbilt University Medical Center,Nashville,United States;Hematology and Oncology,Vanderbilt University Medical Center
,
Thomas LeBlanc
Affiliations:
Hematology and Oncology,Duke Cancer Institute,Durham,États-unis;Hematology and Oncology,Duke Cancer Institute,Durham,Vereinigte Staaten;Hematology and Oncology,Duke Cancer Institute,Durham,Stati Uniti;Hematology and Oncology,Duke Cancer Institute,Durham,United States;Hematology and Oncology,Duke Cancer Institute,Durham,Estados Unidos;Hematology and Oncology,Duke Cancer Institute,Durham,Verenigde S
,
Rory Shallis
Affiliations:
Hematology and Oncology,Yale University,New Haven,États-unis;Hematology and Oncology,Yale University,New Haven,Vereinigte Staaten;Hematology and Oncology,Yale University,New Haven,Stati Uniti;Hematology and Oncology,Yale University,New Haven,United States;Hematology and Oncology,Yale University,New Haven,Estados Unidos;Hematology and Oncology,Yale University,New Haven,Verenigde Staten;Hematology a
,
Michael Keng
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
,
Bethany Horton
Affiliations:
Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,États-unis;Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,Vereinigte Staaten;Public Health Sciences, Division of Translational Research and Applied Statistics,University of Virginia,Charlottesville,Stati U
Firas El Chaer
Affiliations:
Hematology and Oncology,University of Virginia,Charlottesville,États-unis;Hematology and Oncology,University of Virginia,Charlottesville,Vereinigte Staaten;Hematology and Oncology,University of Virginia,Charlottesville,Stati Uniti;Hematology and Oncology,University of Virginia,Charlottesville,United States;Hematology and Oncology,University of Virginia,Charlottesville,Estados Unidos;Hematology and
(Abstract release date: 05/12/22) EHA Library. El Chaer F. 06/10/22; 357217; P354
Firas El Chaer
Firas El Chaer
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P354

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The prognosis of younger adult patients with acute lymphoblastic leukemia (ALL) has improved with the adoption of pediatric-inspired chemotherapy regimens. PEGylated asparaginase (PEG-Asp) is essential to these regimens but is associated with an increased risk of coagulopathy, venous thromboembolism, and depletion of antithrombin III (AT3). There are limited data evaluating the risk of clinical coagulopathy (thrombosis and bleeding) and the optimal antithrombotic interventions in these patients are unknown.

Aims
We aimed to assess the risk of thrombotic and bleeding events in patients with ALL treated with PEG-Asp and compare the treatment modalities with either AT3 + fibrinogen repletion vs the addition of prophylactic anticoagulation (AC) with either subcutaneous heparin 5000 TID or subcutaneous lovenox 30-40mg/day.

Methods
We performed a multicenter retrospective analysis of patients ≥ 18 yo who received PEG-Asp for B- or T-ALL as part of multiagent chemotherapy from 2015-2020 treated across 6 US academic institutions. Categorical variables were summarized using means and standard deviations. The former was compared using Fisher’s exact test; the latter was compared using either the Wilcoxon text (for two groups) or the Kruskal-Wallis (for more than two groups) as appropriate. One way ANOVA test was used to compare continuous variables.


Results
Our study included 129 treated patients who met eligibility criteria for induction and 73 patients who underwent post-induction therapy. During induction, the majority of the patients (90%) had AT3 and fibrinogen repletion, while only 10% received additional prophylactic anticoagulation. The rates of any thrombotic events were lower in the AT3/cryoprecipitate-only treatment group (18% vs 50%, p=0.015). Venous thromboembolism accounted for the majority of the thrombotic events (91% and 100% in the AT3/cryoprecipitate vs AT3/cryoprecipitate + prophylactic anticoagulation, respectively). Bleeding rates were numerically higher in patients who received AT3/cryoprecipitate + prophylactic anticoagulation (33% vs 14%, p=0.18). The rates of thromboses or bleeding events were not different when either prednisone or dexamethasone were included in the induction treatment regimen. During the post-induction phase, the rates of thrombotic and bleeding events were similar across all groups. The median time to thrombotic event was 11 days after the last PEG-Asp administration during induction, and 123 days during post-induction.

Conclusion
Although the increased thrombotic risk in adult patients receiving PEG-Asp is well-characterized, rates of reported thromboses vary widely. Studies examining bleeding risk associated with PEG-Asp regimens are even scarcer and with more variable outcomes. In our study, there was both a statistically significant increase in the rate of any thrombotic event as well as a trend towards increased bleeding in patients receiving AT3/cryoprecipitate + prophylactic anticoagulation versus those receiving AT3/cryoprecipitate alone. More investigation into the relative thrombotic and bleeding risks associated with PEG-Asp is needed to determine optimal antithrombotic interventions in adult patients with ALL.

Keyword(s): Acute lymphoblastic leukemia, Asparaginase, Thrombosis

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P354

Type: Poster presentation

Session title: Acute lymphoblastic leukemia - Clinical

Background

The prognosis of younger adult patients with acute lymphoblastic leukemia (ALL) has improved with the adoption of pediatric-inspired chemotherapy regimens. PEGylated asparaginase (PEG-Asp) is essential to these regimens but is associated with an increased risk of coagulopathy, venous thromboembolism, and depletion of antithrombin III (AT3). There are limited data evaluating the risk of clinical coagulopathy (thrombosis and bleeding) and the optimal antithrombotic interventions in these patients are unknown.

Aims
We aimed to assess the risk of thrombotic and bleeding events in patients with ALL treated with PEG-Asp and compare the treatment modalities with either AT3 + fibrinogen repletion vs the addition of prophylactic anticoagulation (AC) with either subcutaneous heparin 5000 TID or subcutaneous lovenox 30-40mg/day.

Methods
We performed a multicenter retrospective analysis of patients ≥ 18 yo who received PEG-Asp for B- or T-ALL as part of multiagent chemotherapy from 2015-2020 treated across 6 US academic institutions. Categorical variables were summarized using means and standard deviations. The former was compared using Fisher’s exact test; the latter was compared using either the Wilcoxon text (for two groups) or the Kruskal-Wallis (for more than two groups) as appropriate. One way ANOVA test was used to compare continuous variables.


Results
Our study included 129 treated patients who met eligibility criteria for induction and 73 patients who underwent post-induction therapy. During induction, the majority of the patients (90%) had AT3 and fibrinogen repletion, while only 10% received additional prophylactic anticoagulation. The rates of any thrombotic events were lower in the AT3/cryoprecipitate-only treatment group (18% vs 50%, p=0.015). Venous thromboembolism accounted for the majority of the thrombotic events (91% and 100% in the AT3/cryoprecipitate vs AT3/cryoprecipitate + prophylactic anticoagulation, respectively). Bleeding rates were numerically higher in patients who received AT3/cryoprecipitate + prophylactic anticoagulation (33% vs 14%, p=0.18). The rates of thromboses or bleeding events were not different when either prednisone or dexamethasone were included in the induction treatment regimen. During the post-induction phase, the rates of thrombotic and bleeding events were similar across all groups. The median time to thrombotic event was 11 days after the last PEG-Asp administration during induction, and 123 days during post-induction.

Conclusion
Although the increased thrombotic risk in adult patients receiving PEG-Asp is well-characterized, rates of reported thromboses vary widely. Studies examining bleeding risk associated with PEG-Asp regimens are even scarcer and with more variable outcomes. In our study, there was both a statistically significant increase in the rate of any thrombotic event as well as a trend towards increased bleeding in patients receiving AT3/cryoprecipitate + prophylactic anticoagulation versus those receiving AT3/cryoprecipitate alone. More investigation into the relative thrombotic and bleeding risks associated with PEG-Asp is needed to determine optimal antithrombotic interventions in adult patients with ALL.

Keyword(s): Acute lymphoblastic leukemia, Asparaginase, Thrombosis

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