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. Patients and 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.

Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target

“… 43 On the basis of this proposition, a phase I study recently evaluated the concomitant use of valacyclovir and cyclophosphamide in endemic Burkitt lymphoma and showed that this combination was safe. 44 Further clinical testing of this concept is needed.…”

“…Except when used together with epigenetically active agents, 41 , 42 , 43 , 44 antiviral drugs exhibit no direct effect on EBV+ LPD. However, when used prophylactically, antiviral drugs appear to suppress EBV replication and hence decrease the occurrence of PTLD after HSCT or solid organ allografting.…”

Combining an antiviral with rituximab in EBV-related haemophagocytic lymphohistiocytosis led to rapid viral clearance; and a comprehensive review

“…In answering (1), valacyclovir was used successfully mostly in combination with other therapies, and on grounds of immune dysregulation— including post-transplant patients, HIV, etc— in EBV-related cases of encephalitis/various forms of CNS infection,36 37 severe/complicated (eg, with hepatic involvement)/chronic infectious mononucleosis,38 hepatitis,39 chronic fatigue syndrome,40 hairy leukoplakia,41 hydroa vacciniforme,42 various types of LPDs (eg, Burkitt lymphoma),43 oral papulosis,44 periodontitis45 and lymphocytic myocarditis 46. For these conditions, which may coexist, other antiherpetics have also been used.…”