The great antiepileptic debate

From the Martin Laboratory, Clinical Research Division

Before patients with hematologic malignancies can receive allogeneic hematopoietic stem cell therapy (HCT), clinicians treat them with a conditioning regimen. One common method utilizes high doses of two chemotherapeutic drugs—busulfan followed by cyclophosphamide. As busulfan can cause seizures, patients take antiepileptic medications (AEM) as a precaution. Phenytoin, one of the most common AEMs, induces enzymes that increase plasma levels of cyclophosphamide metabolites, such as 5-hydroxycyclophosphamide (4HCY). 4HCY then decomposes into phosphoramide mustard which damages cells by cross-linking DNA. The effects of enzymes induced by phenytoin might act as a double-edged sword, helping to eliminate malignant cells while also harming healthy tissues. Newer AEMs, including levetiracetam, do not increase levels of 4HCY and overall have fewer toxicities and interactions with other drugs. Doctors considered how these new AEMs might affect the efficacy of HCT. Dr. Paul Martin (Clinical Research Division) recalled a discussion of AEMs at Fred Hutch: “In 2014, members of the transplant program debated whether to replace phenytoin with levetiracetam to prevent seizures during treatment with busulfan.  Due to lack of evidence, the debate was lengthy and inconclusive. Some investigators were concerned that replacement of phenytoin with levetiracetam would make the pretransplant conditioning regimen less effective in eliminating malignant cells in recipients before transplantation.”

Phenytoin induces expression of the enzymes CYP2B6, CYP2C and CYP3A, which increase the metabolism of cyclophosphamide into plasma 4HCY.
Phenytoin induces expression of the enzymes CYP2B6, CYP2C and CYP3A, which increase the metabolism of cyclophosphamide into plasma 4HCY. Image provided by Dr. Paul Martin

In order to find answers to the questions raised, Dr. Martin collaborated with transplantation centers around the world in a large retrospective study using registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study, published in Biology of Blood and Marrow Transplantation, reviewed outcomes of patients who received busulfan/cyclophosphamide before allogeneic HCT from 2004 to 2014. The data covered a cohort of 2155 patients, 1460 of whom were given phenytoin while 695 were given alternative AEMs to prevent BU-caused seizures. The patients were treated for a variety of blood cell cancers including acute myelogenous leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia. The authors found no significant difference in risk of relapse in adults when comparing patients treated with phenytoin verses alternative AEMs. Further analysis of pediatric patients revealed a slight trend towards a higher risk of relapse in children who received alternative AEMs. In adults treated with busulfan intravenously, those given phenytoin were at greater risk for kidney failure and required dialysis more frequently compared to those given AEMs.

On the significance of this study, Dr. Martin said, “Results of this retrospective analysis suggest that agents other than phenytoin can be used safely to prevent seizures during treatment of adults with high-dose busulfan before allogeneic hematopoietic cell transplantation.” Clinicians can now look to this study as a guide for whether they should give phenytoin or alternative AEMs for patients treated with busulfan. As for the concern that alternative AEMs would increase the risk of relapse, Dr. Martin said, “The current study shows no evidence to support this concern in adults.  Some question about this concern still remains in children.” Dr. Martin said, “It would be of interest to examine this question in more detail as it applies to transplantation in pediatric patients, but the question cannot be answered with the number of pediatric patients available for testing.”

This work was supported by the National Cancer Institute.

Fred Hutch/UW Cancer Consortium members Drs. Jeannine McCune and Paul Martin contributed to this research.

McCune JS, Wang T, Bo-Subait K, Aljurf M, Beitinjaneh A, Bubalo J, Cahn JY, Cerny J, Chhabra S, Cumpston A, Dupuis LL, Lazarus HM, Marks DI, Maziarz RT, Norkin M, Prestidge T, Mineishi S, Krem MM, Pasquini M, Martin PJ. 2019. Association of Antiepileptic Medications with Outcomes after Allogeneic Hematopoietic Cell Transplantation with Busulfan/Cyclophosphamide Conditioning. Biol Blood Marrow Transplant. 2019 Mar 11;. doi: 10.1016/j.bbmt.2019.03.001. [Epub ahead of print]