Burkitt lymphoma (BL) is the most common pediatric cancer in sub-Saharan Africa and is associated with Epstein-Barr Virus (EBV). In a proof of principle study, we demonstrated increased EBV viral particles in tumor biopsies after the first dose of cyclophosphamide, suggesting that the virus had converted to a lytic infection. During the lytic cycle, EBV expresses proteins that make it susceptible to antiviral therapy. Dr Dan Olson is currently conducting a phase I clinical trial of valacyclovir and cyclophosphamide in children with BL at Kamuzu Central Hospital. We are awaiting funding for a phase 2 trial.

The Phase I trial has been completed and submitted for presentation with the follow abstract:

Title

Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi

Authors

Dan Olson, Oren Mechanic, Stuart Gold, Clifford Wokocha, Charles Mwansambo, Weihua Tang, Margaret Gulley, Mina Hosseinipour, Carol Shores

Introduction

Endemic Burkitt lymphoma (BL), an Epstein-Barr virus (EBV)-associated malignancy, is the most common paediatric cancer in sub-Saharan Africa. In central Malawi, BL 2 year survival rates remain approximately 50% with cytotoxic chemotherapy. We have shown that the Kamuzu Central Hospital (KCH) standard of care single agent, cyclophosphamide (CPM), increases EBV viral load and activates lytic phase genes, indicating a switch from latent to lytic EBV infection in the tumor. It has long been speculated that the addition of antiviral agents that target lytic EBV proteins may improve survival in a variety of tumors including BL. Antiviral nucleoside analogs have an established safety record, with oral valacyclovir FDA approved for children as young as 2 years of age.

Objective

Determination of the maximally tolerated dose or the recommended phase II dose and toxicity profile of combination CPM and valacyclovir in children with endemic Burkitt lymphoma. Descriptive analysis of response to treatment and serum EBV viral load in children treated with CPM alone compared to CPM and valacyclovir

Study Design

Phase 1, 3+3 design of fixed dose CPM with escalating doses of valacyclovir, enrolling patients with facial manifestation of BL. Because conditions vary at KCH, a control group treated with CPM alone was enrolled for direct comparison of toxicity. 40 mg/kg CPM was given IV on day 1 and 60 mg/kg given days 8, 18 and 28. Oral valacyclovir was given 3 times a day from day -2 to 35 at 15 mg/kg/dose in the first cohort and 30 mg/kg/dose in the second cohort. Patients were assessed for adverse events, dose limiting toxicity and response to treatment. Serum was collected throughout treatment for determination of EBV viral loads.

Results

Patients ranged from 3 to 16 years of age with 4 boys and 9 girls. One patient in the 30mg/kg/dose cohort absconded for social reasons after the 2nd dose of CPM following near resolution of the tumor and was replaced. Six control, three 15 mg/kg/dose and four 30 mg/kg/dose patients were enrolled. No dose limiting toxicities or grade 3 or 4 adverse events attributable to valacyclovir or CPM were observed. Vomiting, abdominal pain, tumor site pain and anemia accounted for the majority of grade 1 and 2 adverse events and were seen in all groups. One subject in the control arm and one in the 30 mg/kg/dose cohort had progressive disease at the end of therapy. All remaining patients had either complete resolution of the tumor or shrinkage to what appeared to be only scar. In patients with high viral loads prior to therapy in all groups, viral load plummeted with 2 or 3 cycles of treatment.

Conclusions

Combination therapy with CPM and valacyclovir at both doses had a comparable safety profile to CPM monotherapy in children with endemic Burkitt lymphoma. The valacyclovir recommended Phase II dose is 30 mg/kg, 3 times daily.

Publications and Presentations

• Tang W, Harmon P, Gulley ML, Mwansambo C, Kazembe PN, Martinson F, Wokocha C, Kenney SC, Hoffman I, Sigel C, Maygarden S, Hoffman M and Shores C. Viral Response to Chemotherapy in Endemic Burkitt Lymphoma. Clin Cancer Res. 2010 Apr 1;16(7):2055-64 PMID: 20233888
• Harmon P, Gulley M; Tang W; Kazembe P; Wokocha C; Mwansambo C; Martinson F; Hoffman M, Hoffman I; Shores C. Viral Response to Chemotherapy in Endemic Burkitt Lymphoma American Head and Neck Society Meeting, San Francisco, July 2008 (preliminary data), American Academy of Otolaryngology Annual Meeting, Washington DC, September 2009

Grants

NIH Fogarty International Center                                                      7/1/10-7/1/11

Fogarty International Research Fellowship for Dan Olson MD        $85,000

Title: Phase 1 trial of valacyclovir and cyclophosphamide therapy in Burkitt Lymphoma.

Advisors: Carol Shores and Mina Hosseinipour

3R01CA066519-09S1                                                                        2/13/1995-1/31/2008

National Cancer Institute

PI- Shannon Kenney MD PhD, Carol Shores took over as PI for this portion of the grant when Dr Kenney left UNC.

The Effect of Cytotoxic Therapy on Inducing Lytic Epstein-Barr Virus in EBV-Associated Malignancy

The major goals of this project are to determine if chemotherapy induces EBV lytic infection in Burkett lymphoma

Agency # not defined                                                                          7/1/2007-6/30/2008

American Academy of Otolaryngology/Head and Neck Surgery

Resident Research Award to Paula Harmon PGY2

Viral response to therapy in endemic Burkett’s lymphoma

Advisor: Carol Shores