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Hemorrhagic complications of l -asparaginase therapy
Volume 102 Number 3
Editorial correspondence
ably reflects more the biases of the authors than anything else. This paper is written in a summary form without any discussion of the problems in conducting these studies and specific examples. Some of the statistics they showed (for example, correlation coefficients between biostatisticians and neonatologists) are inappropriate, considering that the reviewers for each study "met to discuss any differences in their answers." I would challenge these authors to submit the same 86 manuscripts to a different biostatistician and neonatologist and have them score them independently. An experienced biostatistician who has published much in the area of treatment and management and is aware of real world problems would probably find that many more than 10% of the studies had appropriate T / M recommendations and conclusions.
Richard F. Mattingly, M.D. Editor Obstetrics and Gynecology Alfred A. Rimm, Ph.D. Head, Division of Biostatistics/ Clinical Epidemiology The Medical College of Wisconsin Milwaukee, WI 53226
an adequate treatment for thrombosis during asparaginase treatment, because heparin requires AT III to become effective. We have treated 10 patients as described above. In all patients treatment was given for at least five days. In all patients the hemostatic imbalances were corrected (i.e., fibrinogen and AT Ill levels were maintained within the normal range). No patient had bleeding or thrombosis, and in all patients asparaginase therapy was continued. No side effects were observed from the replacement therapy. Intensive therapy of the hemostatic imbalances observed during asparaginase therapy might be worthwhile.
VK Muntean, M.D. Department of Pediatrics University of Graz Graz, Austria REFERENCES
1.
2.
REFERENCE 1.
Tyson JE, Furzan JA, Reisch JS, Mize SG: An evaluation of the quality of therapeutic studies in perinatal medicine. J PEDIATR 102:10, 1983.
3.
4.
Hemorrhagic complications of L-asparaginase therapy To the Editor. We read with interest the articles by Priest et al. 1'2 regarding the imbalances in the hemostatic system during asparaginase therapy. We use a protocol for treatment of acute lymphoblastic leukemia in children that includes asparaginase daily for three weeks? Changes in the hemostatic system occur in almost every patient during therapy? Severe bleeding has been observed during asparaginase therapy, s so we adopted a more aggressive approach to correct the hemostatic imbalances. In all patients a coagulation profile, including fibrinogen and antithrombin lII (AT III) determinations, is done every two to three days. When fibrinogen drops below 100 mg/dl, treatment with fresh-frozen plasma is started. Simultaneously, AT III concentrate (Behring Corp.) is given in a continuous infusion as long as replacement therapy with fresh-frozen plasma is needed to maintain fibrinogen levels > 100 mg/dl. When fibrinogen is > 100 mg/dl and AT I l I < 80% of normal, only AT III concentrate is given in a continuous infusion, until levels are > 80%. We added AT III infusions to the replacement regimen because replacement with procoagulant material alone with the freshfrozen plasma might lead to thrombosis in leukemic patients with high cell counts, some degree of liver failure, and an asparaginaseinduced drop in AT lit. Heparinization alone does not seem to be
483
5.
Priest JR, Ramsay NKC, Steinberg PG, et ah A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J PEI)~A'rR 100:984, 1982. Priest JR, Ramsay NKC, Bennett A J, Krivit W, Edson JR: The effect of L-asparaginase on antithrombin, plasmogen, and plasma coagulation during therapy for acute lymphoblastic leukemkia. J PEDIATR 100:990, 1982. Riehm H, Gadner H, Welte K: Die West-Berliner Studie zur Behandlung der akuten Iymphoblastischen Leuk~imie des Kindes. Klin Padiatr 189:89, 1977. Gadner H, Riehm H: Ver/inderungen der H~imostase wfihrend der lnduktionstherapie akuter lymphoblastischer Leuk~imien im Kindesalter. In G6beI U, editor: Erworbene Gerinnungsst6rungen im Kindesalter. Stuttgart, 1979, Enke. Urban Ch, Sager WD: Intracranial bleeding during therapy with L-asparaginase in childhood acute lymphocytic leukemia. Eur J Pediatr 137:323, 1982.
Reply We have considered therapies as suggested by Dr. Muntean for children receiving L-asparaginase. Thrombotic or hemorrhagic events were recognized in 18 of 1,547 (1.2%) patients. One child receiving asparaginase a second time had a second central nervous system event (seizures), but neither hemorrhage nor thrombosis could be documented by computerized tomographic scan. Two other children uneventfully received courses of asparaginase either before or after the course associated with the intracranial event. Thus the syndrome occurs infrequently in patients treated with the regimens we used (nine intramuscular asparaginase doses in three weeks), and patients affected once can safely receive asparaginase at other times. Therefore we have not deemed it necessary to subject every child to the risks of prophylactic plasma component replacement therapy, as Dr. Muntean suggests may be worthwhile. Furthermore, the antithrombin concentrate used by Dr. Muntean is not approved for use in this country at present. The daily intravenous administration of asparaginase for four weeks used in the European induction regimen ~ may affect the
Editorial correspondence
ably reflects more the biases of the authors than anything else. This paper is written in a summary form without any discussion of the problems in conducting these studies and specific examples. Some of the statistics they showed (for example, correlation coefficients between biostatisticians and neonatologists) are inappropriate, considering that the reviewers for each study "met to discuss any differences in their answers." I would challenge these authors to submit the same 86 manuscripts to a different biostatistician and neonatologist and have them score them independently. An experienced biostatistician who has published much in the area of treatment and management and is aware of real world problems would probably find that many more than 10% of the studies had appropriate T / M recommendations and conclusions.
Richard F. Mattingly, M.D. Editor Obstetrics and Gynecology Alfred A. Rimm, Ph.D. Head, Division of Biostatistics/ Clinical Epidemiology The Medical College of Wisconsin Milwaukee, WI 53226
an adequate treatment for thrombosis during asparaginase treatment, because heparin requires AT III to become effective. We have treated 10 patients as described above. In all patients treatment was given for at least five days. In all patients the hemostatic imbalances were corrected (i.e., fibrinogen and AT Ill levels were maintained within the normal range). No patient had bleeding or thrombosis, and in all patients asparaginase therapy was continued. No side effects were observed from the replacement therapy. Intensive therapy of the hemostatic imbalances observed during asparaginase therapy might be worthwhile.
VK Muntean, M.D. Department of Pediatrics University of Graz Graz, Austria REFERENCES
1.
2.
REFERENCE 1.
Tyson JE, Furzan JA, Reisch JS, Mize SG: An evaluation of the quality of therapeutic studies in perinatal medicine. J PEDIATR 102:10, 1983.
3.
4.
Hemorrhagic complications of L-asparaginase therapy To the Editor. We read with interest the articles by Priest et al. 1'2 regarding the imbalances in the hemostatic system during asparaginase therapy. We use a protocol for treatment of acute lymphoblastic leukemia in children that includes asparaginase daily for three weeks? Changes in the hemostatic system occur in almost every patient during therapy? Severe bleeding has been observed during asparaginase therapy, s so we adopted a more aggressive approach to correct the hemostatic imbalances. In all patients a coagulation profile, including fibrinogen and antithrombin lII (AT III) determinations, is done every two to three days. When fibrinogen drops below 100 mg/dl, treatment with fresh-frozen plasma is started. Simultaneously, AT III concentrate (Behring Corp.) is given in a continuous infusion as long as replacement therapy with fresh-frozen plasma is needed to maintain fibrinogen levels > 100 mg/dl. When fibrinogen is > 100 mg/dl and AT I l I < 80% of normal, only AT III concentrate is given in a continuous infusion, until levels are > 80%. We added AT III infusions to the replacement regimen because replacement with procoagulant material alone with the freshfrozen plasma might lead to thrombosis in leukemic patients with high cell counts, some degree of liver failure, and an asparaginaseinduced drop in AT lit. Heparinization alone does not seem to be
483
5.
Priest JR, Ramsay NKC, Steinberg PG, et ah A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J PEI)~A'rR 100:984, 1982. Priest JR, Ramsay NKC, Bennett A J, Krivit W, Edson JR: The effect of L-asparaginase on antithrombin, plasmogen, and plasma coagulation during therapy for acute lymphoblastic leukemkia. J PEDIATR 100:990, 1982. Riehm H, Gadner H, Welte K: Die West-Berliner Studie zur Behandlung der akuten Iymphoblastischen Leuk~imie des Kindes. Klin Padiatr 189:89, 1977. Gadner H, Riehm H: Ver/inderungen der H~imostase wfihrend der lnduktionstherapie akuter lymphoblastischer Leuk~imien im Kindesalter. In G6beI U, editor: Erworbene Gerinnungsst6rungen im Kindesalter. Stuttgart, 1979, Enke. Urban Ch, Sager WD: Intracranial bleeding during therapy with L-asparaginase in childhood acute lymphocytic leukemia. Eur J Pediatr 137:323, 1982.
Reply We have considered therapies as suggested by Dr. Muntean for children receiving L-asparaginase. Thrombotic or hemorrhagic events were recognized in 18 of 1,547 (1.2%) patients. One child receiving asparaginase a second time had a second central nervous system event (seizures), but neither hemorrhage nor thrombosis could be documented by computerized tomographic scan. Two other children uneventfully received courses of asparaginase either before or after the course associated with the intracranial event. Thus the syndrome occurs infrequently in patients treated with the regimens we used (nine intramuscular asparaginase doses in three weeks), and patients affected once can safely receive asparaginase at other times. Therefore we have not deemed it necessary to subject every child to the risks of prophylactic plasma component replacement therapy, as Dr. Muntean suggests may be worthwhile. Furthermore, the antithrombin concentrate used by Dr. Muntean is not approved for use in this country at present. The daily intravenous administration of asparaginase for four weeks used in the European induction regimen ~ may affect the