Abstract
Thromboembolism (TE) and hemorrhage are known complications following L-asparaginase (L-asp) therapy, but the incidence and epidemiology of these events in children are not clearly defined. POG protocols 9201, 9605, and 9406 were phase III studies for low, standard, and higher risk patients with acute lymphoblastic leukemia (ALL). Protocol 9201 enrolled 649 patients, 9605: 1087, and 9406: 911. All 3 studies used a common 4 week induction protocol (POG 9400) of native L-asp (6000 IU/m2 IM x 6 doses), weekly vincristine, and daily prednisone. Doxorubicin was added for patients meeting higher risk criteria based on age, initial white blood cell count, and CNS/testicular status. Patients on 9201 and 9605 received no L-asp after induction. 9406 patients received 3 doses of PEG L-asp (1000 or 2500 IU/m2 IM) during consolidation. The incidence of TE and hemorrhage on 9201 was 2.2% (14/649), on 9605 1.9% (21/1087) and on 9406 5.3% (48/911). In all three protocols, TE was more common than hemorrhage. Hemorrhages were more frequent in POG 9406.
| # Patients | # Thromboses | # Hemorrhages | # Total Events | # in Induction | |
|---|---|---|---|---|---|
| 9201 | 649 | 13 | 1 | 14 | 6 |
| 9605 | 1087 | 17 | 4 | 21 | 10 |
| 9406 | 911 | 34 | 14 | 48 | 27 |
| Total | 2647 | 64 | 19 | 83 | 43 |
| # Patients | # Thromboses | # Hemorrhages | # Total Events | # in Induction | |
|---|---|---|---|---|---|
| 9201 | 649 | 13 | 1 | 14 | 6 |
| 9605 | 1087 | 17 | 4 | 21 | 10 |
| 9406 | 911 | 34 | 14 | 48 | 27 |
| Total | 2647 | 64 | 19 | 83 | 43 |
The largest proportion of events occurred during the month of induction therapy. 70% of induction events (30/43) occurred in patients who received 4 drug therapy. Of the 43 induction events, 21/26 patients with reported coagulation studies had abnormal fibrinogen levels <100mg/dL, 7 of those were <50mg/dL. Antithrombin levels were not reported. 28 of 64 TE were likely central venous line (CVL) related [6 tip of catheter, 16 axillary/subclavian vein, 2 superior vena cava, 2 atrium, 1 internal jugular vein, 1 basilic vein]. Locations of remaining TE included: 13 CNS [4 venous sinus, 9 cerebral]; 10 lower extremity; 4 upper extremity; 1 pulmonary embolism; 8 site not specified. Locations of hemorrhages included: 8 CNS [7 intracranial, 1 subdural]; 2 GI [1 gastric, 1 esophageal perforation]; 2 acute epistaxis; 2 site not specified; and 1 of each of the following: CVL site, pulmonary, splenic, vitreous eye, and hemothorax. Statistical analyses correlating number of L-asp doses to induction events and correlates with gender, age, race, and congenital abnormality are being evaluated.
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