The use of high-dose azidothymidine in combination with chemotherapy upfront is an effective treatment approach for gamma-herpes virus-related non-Hodgkin’s lymphomas

Background

Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for gamma-herpes virus thymidine kinases (TKs). Our group previously demonstrated that AZT alone can inhibit NF-κB and disrupt EBV latency in primary low-passage Type I latency EBV+ Burkitt lines. The addition of hydroxyurea, which increases the intracellular levels of AZT monophosphate, synergized with AZT in Type III latency EBV+ immunoblastic lymphoma cell lines. The use of AZT in targeting gamma-herpes virus lymphomas is an attractive concept given that this drug is preferentially phosphorylated by EBV and HHV-8 TKs as compared to non-thymidine nucleoside analogues. The drugs methotrexate (MTX) and doxorubicin (DOX) also induce lytic expression of gamma-herpes viruses. MTX inhibits thymidylate synthase, thus blocking de novo synthesis of dTMP and increasing the likelihood of AZT incorporation into DNA. We have found that the combination of high-dose AZT with MTX, used alone or with alternating standard chemotherapy, can result in dramatic clinical responses and even cures in patients with poor prognosis gamma-herpes virus-related lymphomas.

Materials and methods

Ten patients with EBV-positive (9 HIV-positive) non-Hodgkin’s lymphoma (NHL) were treated with first-line MTX (3.0-4.5 g/m² IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-4) every 3 weeks or alternated with other chemotherapy regimens, including EPOCH, or hyper cVAD between 2004-2009 at the discretion of the treating physician (Table 1). One patient (solid PEL) received AZT and MTX initially, and upon relapse 31 months later received DOX 20 mg/m² (Day 1) , MTX 5 g/m² (Day 2), and AZT 750 mg twice daily with hydroxyurea 1 g daily (Days 2-5) under our new clinical trial.

Table 1 :

Results

Clinical characteristics, response, and survival data of patients are summarized in Table 1. All patients were treated with high-dose AZT and MTX. Three patients with plasmablastic lymphoma (PBL) and 1 patient with BL also received alternating EPOCH; 2 BL patients received alternating hCVAD. Seven patients achieved CR. Two patients developed neutropenic fever. Median PFS in this cohort of patients has not been reached. Median OS was 31 months (95% CI: 0.0-84.8).

Conclusions

The combination of high-dose MTX/AZT is a promising and tolerable treatment for gamma-herpes virus-related lymphomas. A Phase II clinical trial with low-dose doxorubicin, MTX, AZT, and hydroxyurea for relapse EBV+ NHL is currently recruiting participants. Interim results and supporting laboratory data for using this gamma-herpes virus lytic approach will be presented at the meeting.