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Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 7 5 e7 7
Official Journal of the European Paediatric Neurology Society
Case study
Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation €rn-Sven Ku¨hl a, Wolfram Ebell a, Andreas Peyrl a,b,*, Nina Weichert a, Jo iz Driever a Pablo Herna a b
€tsmedizin Berlin, Berlin, Germany Department of Pediatric Oncology/Hematology, Charite Universita Department of Pediatrics, Medical University of Vienna, Vienna, Austria
article info
abstract
Article history:
Background: Levetiracetam is increasingly used as antiepileptic drug (AED) of choice in
Received 30 October 2013
children as well as in adults with complex diseases due to its lack of interactions and a
Received in revised form
large spectrum of action. Secondary graft failure, i.e. loss of donor cells after initial
22 September 2014
engraftment, is a relatively uncommon but serious and life-theatening complication after
Accepted 11 October 2014
pediatric hematopoietic stem cell transplantation. Methods and results: We report a case of secondary graft failure after hematopoietic stem
Keywords:
cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic
Levetiracetam
treatment with levetiracetam.
Allogenic hematopoietic stem cell
Exclusion of all other possible etiologies left levetiracetam as the most likely cause of
transplantation
the imminent complete secondary graft failure after hematopoietic stem cell trans-
Myelosuppression
plantation. Furthermore, the blood cell count improved just a few days after cessation of
Secondary graft failure
levetiracetam medication. Conclusion: Thus, we recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should carefully be excluded, including adverse events through new generation AED agents. Switching to different AEDs with less harming effect on bone marrow function should strongly be considered. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a relatively new antiepileptic drug (AED), increasingly used as monotherapy or part of combination therapy for partial and generalized seizures in children as
well as in adults.1,2 Levetiracetam is an increasingly used AED in patients with complex diseases due to lack of interactions and a large spectrum of action. Hematopoietic stem cell transplantation is a curative treatment option for children with treatment-related myelodysplastic syndrome.3,4 Secondary graft failure, the loss of donor cells after
* Corresponding author. Medical University of Vienna, Department of Pediatrics, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: þ43 1 40400 32320; fax: þ43 1 40400 61028. E-mail address: [email protected] (A. Peyrl). http://dx.doi.org/10.1016/j.ejpn.2014.10.004 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
76
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 7 5 e7 7
initial engraftment, is a relatively uncommon but serious and life-threatening complication after pediatric hematopoietic stem cell transplantation, occurring in 2.2% of patients.5 Here we report a case of secondary graft failure after hematopoietic stem cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic treatment with levetiracetam.
2.
Case study
A 16-year-old boy developed seizures due to an early isolated CNS-recurrence of acute lymphoblastic leukemia (ALL) 24 months after initial diagnosis. He was treated with phenytoin, followed by valproic acid and eventually became seizure free after switching antiepileptic medication to monotherapy with levetiracetam (30 mg/kg/day). Therapy for ALL relapse was performed according to the ALL-REZ-BFM 2002 protocol.6 He achieved 2nd complete remission but developed treatmentrelated myelodysplastic syndrome of complex karyotype as second malignancy 10 months later. Therefore, he underwent hematopoietic stem cell transplantation with unmanipulated bone marrow (total nucleated cells (TNC) 0.7 108/kg BW of recipient) from a matchedunrelated donor. The preparative regimen consisted of total body irradiation (TBI, 2 2 Gy/d, days 7 to 5), etoposide (1800 mg/m2/d, day 4), and ATG rabbit (Fresenius, 20 mg/kg/
d, days 3 to 1, Fresenius Biotech, Graefelfing, Germany). Treatment-related toxicities included mucositis, pneumonia with partial pulmonary insufficiency, and fever during neutropenia with septicemia due to Klebsiella pneumoniae. Supportive care included broad antimicrobial medication (ceftazidime, teicoplanin, meropenem, tobramycin), red blood cell and platelet transfusions. The bone marrow was stimulated with G-CSF, starting on day þ5. First neutrophil engraftment was documented on day þ21. On day þ33 the patient developed secondary graft failure. There was no evidence of viral infection or autoimmune manifestations. STR analysis revealed 100% donor cells of all cell lines. On day þ50, antiepileptic treatment with levetiracetam was tapered off and phenobarbital was commenced, as we considered a possible myelosuppressive effect of levetiracetam. Second neutrophil engraftment was documented on day þ54 (see Fig. 1) and the patient's blood cell counts remained stable until discharge on day þ 70. In addition, phenobarbital maintained seizure freedom.
3.
Discussion
Children with treatment-related myelodysplastic syndrome (t-MDS) carry a poor prognosis with limited curative options.7 Chemotherapy alone leads to dismal results, whereas allogenic hematopoietic stem cell transplant seems to offer the highest probability of survival.3,4
Fig. 1 e Blood levels of leucocytes, neutrophils and reticulocytes before and after allogenic hematopoietic stem cell transplantation.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 7 5 e7 7
Levetiracetam is a new antiepileptic drug that binds to the synaptic vesicle protein 2A, thereby interfering with the recycling of synaptic vesicles and neurotransmitter release.8 Levetiracetam has almost complete oral bioavailability, does not depend on the P450 cytochrome system, shows <10% protein binding and has no significant interactions with other drugs.9 This absence of drug interactions has led to use of levetiracetam especially in medical settings in which polytherapy is necessary. For children undergoing hematopoietic stem cell transplantation conditioned with busulfan, levetiracetam is used as an effective anti-convulsant to prevent seizures.10 Most common side effects of levetiracetam include aggression, mood swings, irritability, and depression.2 Thrombocytopenia or even pancytopenia are rare adverse events of levetiracetam therapy.11,12 In our institution, levetiracetam is used frequently to treat or prevent partial or generalized seizures since more than ten years. Levetiracetam has been generally well tolerated within this period, and especially not been suspected to be involved in pancytopenia in any patient so far. In our patient, we carefully considered other potential etiologies of secondary pancytopenia. The infused TNC count was relatively small compared to the body weight of the patient, which may be a critical factor determining the speed of engraftment. Nonetheless, first engraftment was documented on day þ21. None of the antimicrobials (aciclovir, voriconazole, ciprofloxacin, trimethoprim/sulfamethoxazole) were discontinued when the patient developed secondary graft failure, and maintained beyond improvement. Exclusion of all other possible etiologies left levetiracetam as the most likely cause of the imminent complete secondary graft failure after hematopoietic stem cell transplantation. This explanation is further supported as the blood cell count improved just a few days after cessation of levetiracetam medication. We recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should be carefully excluded, including adverse activity of new generation AED agents. Switching to different AEDs with less probable effect on the bone marrow should strongly be considered.
Conflict of interest The authors declare no conflict of interest.
77
references
1. Goldberg-Stern H, Feldman L, Eidlitz-Markus T, et al. Levetiracetam in children, adolescents and young adults with intractable epilepsy: efficacy, tolerability and effect on electroencephalogramea pilot study. Eur J Paediatr Neurol 2013;17:248e53. 2. Stephen LJ, Kelly K, Parker P, Brodie MJ. Levetiracetam monotherapy-outcomes from an epilepsy clinic. Seizure 2011;20:554e7. 3. Barnard DR, Lange B, Alonzo TA, et al. Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 2002;100:427e34. 4. Kobos R, Steinherz PG, Kernan NA, et al. Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant 2012;18:473e80. 5. Woodard P, Tong X, Richardson S, et al. Etiology and outcome of graft failure in pediatric hematopoietic stem cell transplant recipients. J Pediatr Hematol Oncol 2003;25:955e9. 6. Eckert C, Henze G, Seeger K, et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 2013;31:2736e42. 7. Smith SM, Le Beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003;102:43e52. 8. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861e6. 9. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77e85. 10. Soni S, Skeens M, Termuhlen AM, et al. Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 2012;59:762e4. 11. Elouni B, Ben Salem C, Biour M. Levetiracetam-induced pancytopenia. Ann Pharmacother 2009;43:985. 12. Sahaya K, Goyal MK, Sarwal A, Singh NN. Levetiracetaminduced thrombocytopenia among inpatients: a retrospective study. Epilepsia 2010;51:2492e5.
Official Journal of the European Paediatric Neurology Society
Case study
Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation €rn-Sven Ku¨hl a, Wolfram Ebell a, Andreas Peyrl a,b,*, Nina Weichert a, Jo iz Driever a Pablo Herna a b
€tsmedizin Berlin, Berlin, Germany Department of Pediatric Oncology/Hematology, Charite Universita Department of Pediatrics, Medical University of Vienna, Vienna, Austria
article info
abstract
Article history:
Background: Levetiracetam is increasingly used as antiepileptic drug (AED) of choice in
Received 30 October 2013
children as well as in adults with complex diseases due to its lack of interactions and a
Received in revised form
large spectrum of action. Secondary graft failure, i.e. loss of donor cells after initial
22 September 2014
engraftment, is a relatively uncommon but serious and life-theatening complication after
Accepted 11 October 2014
pediatric hematopoietic stem cell transplantation. Methods and results: We report a case of secondary graft failure after hematopoietic stem
Keywords:
cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic
Levetiracetam
treatment with levetiracetam.
Allogenic hematopoietic stem cell
Exclusion of all other possible etiologies left levetiracetam as the most likely cause of
transplantation
the imminent complete secondary graft failure after hematopoietic stem cell trans-
Myelosuppression
plantation. Furthermore, the blood cell count improved just a few days after cessation of
Secondary graft failure
levetiracetam medication. Conclusion: Thus, we recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should carefully be excluded, including adverse events through new generation AED agents. Switching to different AEDs with less harming effect on bone marrow function should strongly be considered. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a relatively new antiepileptic drug (AED), increasingly used as monotherapy or part of combination therapy for partial and generalized seizures in children as
well as in adults.1,2 Levetiracetam is an increasingly used AED in patients with complex diseases due to lack of interactions and a large spectrum of action. Hematopoietic stem cell transplantation is a curative treatment option for children with treatment-related myelodysplastic syndrome.3,4 Secondary graft failure, the loss of donor cells after
* Corresponding author. Medical University of Vienna, Department of Pediatrics, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: þ43 1 40400 32320; fax: þ43 1 40400 61028. E-mail address: [email protected] (A. Peyrl). http://dx.doi.org/10.1016/j.ejpn.2014.10.004 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
76
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 7 5 e7 7
initial engraftment, is a relatively uncommon but serious and life-threatening complication after pediatric hematopoietic stem cell transplantation, occurring in 2.2% of patients.5 Here we report a case of secondary graft failure after hematopoietic stem cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic treatment with levetiracetam.
2.
Case study
A 16-year-old boy developed seizures due to an early isolated CNS-recurrence of acute lymphoblastic leukemia (ALL) 24 months after initial diagnosis. He was treated with phenytoin, followed by valproic acid and eventually became seizure free after switching antiepileptic medication to monotherapy with levetiracetam (30 mg/kg/day). Therapy for ALL relapse was performed according to the ALL-REZ-BFM 2002 protocol.6 He achieved 2nd complete remission but developed treatmentrelated myelodysplastic syndrome of complex karyotype as second malignancy 10 months later. Therefore, he underwent hematopoietic stem cell transplantation with unmanipulated bone marrow (total nucleated cells (TNC) 0.7 108/kg BW of recipient) from a matchedunrelated donor. The preparative regimen consisted of total body irradiation (TBI, 2 2 Gy/d, days 7 to 5), etoposide (1800 mg/m2/d, day 4), and ATG rabbit (Fresenius, 20 mg/kg/
d, days 3 to 1, Fresenius Biotech, Graefelfing, Germany). Treatment-related toxicities included mucositis, pneumonia with partial pulmonary insufficiency, and fever during neutropenia with septicemia due to Klebsiella pneumoniae. Supportive care included broad antimicrobial medication (ceftazidime, teicoplanin, meropenem, tobramycin), red blood cell and platelet transfusions. The bone marrow was stimulated with G-CSF, starting on day þ5. First neutrophil engraftment was documented on day þ21. On day þ33 the patient developed secondary graft failure. There was no evidence of viral infection or autoimmune manifestations. STR analysis revealed 100% donor cells of all cell lines. On day þ50, antiepileptic treatment with levetiracetam was tapered off and phenobarbital was commenced, as we considered a possible myelosuppressive effect of levetiracetam. Second neutrophil engraftment was documented on day þ54 (see Fig. 1) and the patient's blood cell counts remained stable until discharge on day þ 70. In addition, phenobarbital maintained seizure freedom.
3.
Discussion
Children with treatment-related myelodysplastic syndrome (t-MDS) carry a poor prognosis with limited curative options.7 Chemotherapy alone leads to dismal results, whereas allogenic hematopoietic stem cell transplant seems to offer the highest probability of survival.3,4
Fig. 1 e Blood levels of leucocytes, neutrophils and reticulocytes before and after allogenic hematopoietic stem cell transplantation.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 7 5 e7 7
Levetiracetam is a new antiepileptic drug that binds to the synaptic vesicle protein 2A, thereby interfering with the recycling of synaptic vesicles and neurotransmitter release.8 Levetiracetam has almost complete oral bioavailability, does not depend on the P450 cytochrome system, shows <10% protein binding and has no significant interactions with other drugs.9 This absence of drug interactions has led to use of levetiracetam especially in medical settings in which polytherapy is necessary. For children undergoing hematopoietic stem cell transplantation conditioned with busulfan, levetiracetam is used as an effective anti-convulsant to prevent seizures.10 Most common side effects of levetiracetam include aggression, mood swings, irritability, and depression.2 Thrombocytopenia or even pancytopenia are rare adverse events of levetiracetam therapy.11,12 In our institution, levetiracetam is used frequently to treat or prevent partial or generalized seizures since more than ten years. Levetiracetam has been generally well tolerated within this period, and especially not been suspected to be involved in pancytopenia in any patient so far. In our patient, we carefully considered other potential etiologies of secondary pancytopenia. The infused TNC count was relatively small compared to the body weight of the patient, which may be a critical factor determining the speed of engraftment. Nonetheless, first engraftment was documented on day þ21. None of the antimicrobials (aciclovir, voriconazole, ciprofloxacin, trimethoprim/sulfamethoxazole) were discontinued when the patient developed secondary graft failure, and maintained beyond improvement. Exclusion of all other possible etiologies left levetiracetam as the most likely cause of the imminent complete secondary graft failure after hematopoietic stem cell transplantation. This explanation is further supported as the blood cell count improved just a few days after cessation of levetiracetam medication. We recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should be carefully excluded, including adverse activity of new generation AED agents. Switching to different AEDs with less probable effect on the bone marrow should strongly be considered.
Conflict of interest The authors declare no conflict of interest.
77
references
1. Goldberg-Stern H, Feldman L, Eidlitz-Markus T, et al. Levetiracetam in children, adolescents and young adults with intractable epilepsy: efficacy, tolerability and effect on electroencephalogramea pilot study. Eur J Paediatr Neurol 2013;17:248e53. 2. Stephen LJ, Kelly K, Parker P, Brodie MJ. Levetiracetam monotherapy-outcomes from an epilepsy clinic. Seizure 2011;20:554e7. 3. Barnard DR, Lange B, Alonzo TA, et al. Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 2002;100:427e34. 4. Kobos R, Steinherz PG, Kernan NA, et al. Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant 2012;18:473e80. 5. Woodard P, Tong X, Richardson S, et al. Etiology and outcome of graft failure in pediatric hematopoietic stem cell transplant recipients. J Pediatr Hematol Oncol 2003;25:955e9. 6. Eckert C, Henze G, Seeger K, et al. Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 2013;31:2736e42. 7. Smith SM, Le Beau MM, Huo D, et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003;102:43e52. 8. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861e6. 9. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77e85. 10. Soni S, Skeens M, Termuhlen AM, et al. Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 2012;59:762e4. 11. Elouni B, Ben Salem C, Biour M. Levetiracetam-induced pancytopenia. Ann Pharmacother 2009;43:985. 12. Sahaya K, Goyal MK, Sarwal A, Singh NN. Levetiracetaminduced thrombocytopenia among inpatients: a retrospective study. Epilepsia 2010;51:2492e5.