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ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia: A Retrospective Study of 523 Patients Terry Mizrahi, MD,* Jean-Marie Leclerc, MD,* Miche`le David, MD,* Thierry Ducruet, MSc,w and Nancy Robitaille, MD*

Summary: Children with acute lymphoblastic leukemia (ALL) are at high risk of thrombotic complications, resulting from multiple risk factors (malignancy, chemotherapy, central venous access devices, and inherent host characteristics). Non-O blood groups have been associated with an increased risk of venous thromboembolism (VTE) in adults, with a compounding effect in the presence of thrombophilia or cancer. We hypothesized that among children with ALL receiving a standardized protocol, there would be an increased risk of thrombotic events in non-O compared with O blood group patients. In a retrospective study of 523 children with ALL from June 1995 to April 2013, there were 56 (10.7%) thromboembolic events. Patients with VTE were compared with the whole cohort, based on blood group, age, sex, leukemia phenotype, and clinical risk category. Among children with VTE, 42 (75%) had non-O and 14 (25%) had O blood group, compared with 302 (57.7%) non-O and 221 (42.3%) O blood groups in the cohort. Non-O blood group was confirmed as an independent risk factor for VTE in multivariate analysis. This is the first study to report a significant association between non-O blood groups and VTE in children with cancer. Key Words: ABO blood group system, thrombosis, pediatrics, acute lymphoblastic leukemia, risk factors

(J Pediatr Hematol Oncol 2015;37:e328–e332)

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hildren with acute lymphoblastic leukemia (ALL) are at high risk of thrombotic complications, resulting from multiple risk factors (including malignancy, medication, central venous access devices [CVADs], and inherent host characteristics). Several studies have investigated the role of ABO blood groups in the occurrence of venous thromboembolic events in adults. Non-O blood groups (A, B, and AB) have been associated with an increased risk of venous thromboembolism (VTE), with a compounding effect in the presence of thrombophilia or cancer. To date, no large study has been conducted in children with cancer. We hypothesized that among children with ALL receiving a

Received for publication April 10, 2014; accepted February 26, 2015. From the *Department of Pediatrics, Division of Pediatric Hematology-Oncology; and wApplied Clinical Research Unit, CHU SainteJustine, University of Montreal, Montreal, QC, Canada. T.M.: main author, writing of the manuscript, and retrospective review of all medical charts. N.R.: main supervisor, coauthor, and correction of the manuscript. J.-M.L. and M.D.: supervisor, coauthor, and correction of the manuscript. T.D.: statistician, coauthor, and statistics. The authors declare no conflict of interest. Reprints: Terry Mizrahi, MD, Department of Pediatrics, Division of Pediatric Hematology-Oncology, CHU Sainte-Justine, 3175 chemin de la Coˆte-Sainte-Catherine, Montreal, QC, Canada H3T 1C5 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

standardized protocol, there would be an increased risk of thrombotic events in non-O blood group as compared with O blood group patients.

MATERIALS AND METHODS Patient Records A retrospective review of medical charts of all children with ALL treated at CHU Sainte-Justine, a tertiary care center, was performed between June 1995 and April 2013. Patients were followed until December 2013, that is, for a minimum of 9 months after diagnosis. Patients with an objectively confirmed VTE (including cerebral venous thrombosis) were identified. Radiologic imaging included Doppler ultrasound, CT scan or MRI, cardiac ultrasound, and ventilation/perfusion lung scan. Children were included in 3 sequential similar multiagent protocols: Dana-Farber Cancer Institute (DFCI) 95-01 (1995 to 2000), 00-01 (2000 to 2005), and 05-01 (2005 to 2013). Regimens consisted of steroids (prednisone during the induction phase, followed by dexamethasone), doxorubicin, vincristine, asparaginase, methotrexate, and 6-mercaptopurine. All patients received repeated triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), except during the induction phase, where they received intrathecal cytarabine alone. Patients on high-risk protocols received more doxorubicin and higher doses of steroids than patients on standard-risk protocols. Asparaginase doses were increased from 20 doses in DFCI 95-01 to 30 doses in DFCI 00-01. In DFCI 00-01, patients were randomized to prednisone or dexamethasone; asparaginase was given either as a fixed or as an adjusted dose for 30 weeks. In DFCI 05-01, patients were randomized to IV or IM asparaginase and Escherichia coli asparaginase was replaced by PEG asparaginase. Patients with confirmed VTE received standard therapy. Patients were subdivided into O and non-O blood groups (A, B, and AB). Leukemia phenotype, risk category, age, sex, timing, localization of thrombosis, and thrombotic workup were collected. After 1995, all patients had peripherally inserted central catheters at diagnosis. The study was approved by the local Ethics Committee at CHU Sainte-Justine (Montreal, Canada).

Statistical Analysis The primary outcome was defined as the occurrence of VTE. Thrombosis-free survival curves were compared with the Log-Rank test and Cox regression models. If thrombosis did not occur, patients were censored at to the last date of clinical follow-up or death. Baseline variables (sex, phenotype [pre-T, pre-B], and ABO blood group [non-O, O]) were used as independent predictors in the model. As the variable “age”

e328 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 37, Number 5, July 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

J Pediatr Hematol Oncol



Volume 37, Number 5, July 2015

ABO Group and Thrombotic Risk in Childhood ALL

is included in the risk category (children 10 y and above being at high risk), a 3-level statistical cutoff was used: age Z10; age

ABO Group as a Thrombotic Risk Factor in Children With Acute Lymphoblastic Leukemia: A Retrospective Study of 523 Patients.

Children with acute lymphoblastic leukemia (ALL) are at high risk of thrombotic complications, resulting from multiple risk factors (malignancy, chemo...
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