title: Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi.
abstract: Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken.
  
  
  BACKGROUND
  Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted.
  
  
  METHODS
  Children 3-15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome.
  
  
  RESULTS
  We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course.
  
  
  CONCLUSIONS
  We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral loads that decreased over the course of their treatment, suggesting that phase II studies should investigate this correlation further. This study paves the way for a phase II efficacy trial of combined valacyclovir and CPM in the treatment of endemic Burkitt lymphoma.
authors.affiliation: University of North Carolina Project, Lilongwe, Malawi. daniel.olson@childrenscolorado.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Olson
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gulley
authors.forename: Weihua
authors.initials: W
authors.lastname: Tang
authors.forename: Clifford
authors.initials: C
authors.lastname: Wokocha
authors.forename: Oren
authors.initials: O
authors.lastname: Mechanic
authors.forename: Mina
authors.initials: M
authors.lastname: Hosseinipour
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Gold
authors.forename: Nelson
authors.initials: N
authors.lastname: Nguluwe
authors.forename: Charles
authors.initials: C
authors.lastname: Mwansambo
authors.forename: Carol
authors.initials: C
authors.lastname: Shores
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000821:virology; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D008295:Malawi; D008297:Male; D059039:Standard of Care; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D003520:Cyclophosphamide; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir