High-Dose Methotrexate and Azidothymidine in Combination with Alternating DA-EPOCH Is An Effective Regimen for the Treatment of EBV-Related Plasmablastic Lymphoma.

Plasmablastic lymphoma (PBL) is an aggressive and generally fatal, rare type of B-cell non-Hodgkin's lymphoma (NHL) with predilection to sino-oral mucosa. PBL is usually associated with human immunodeficiency virus (HIV) and displays an unusual phenotype lacking the expression of B-cell surface antigens. PBLs are infected by Epstein Barr virus (EBV) in approximately 80% of cases and exhibit a restricted pattern of EBV gene expression as they do not typically express latent membrane proteins (LMPs), which enforce viral latency. Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for EBV thymidine kinase, and is capable of inducing EBV lytic gene expression and apoptosis in primary Type I latency EBV+ Burkitt lymphoma (BL) cell lines. AZT was initially developed as an antineoplastic agent but was found to have low efficacy due to poor affinity to human DNA polymerase and low incorporation into DNA. The chemotherapy drug methotrexate (MTX), which also induces gamma-herpes virus lytic induction, inhibits thymidylate synthase thus blocking de novo synthesis of dTMP increasing the likelihood of AZT incorporation into DNA. Indeed, the combination of high-dose MTX and AZT was found to be clinically efficacious in HIV-infected patients with aggressive relapsed NHL. Similarly, at the University of Miami, we have found this drug combination to be highly effective when used in patients with aggressive gamma-herpes virus lymphomas including EBV+ BL and human herpes virus 8 (HHV-8) related primary effusion lymphoma (solid PEL). We report here the role of high dose MTX plus intravenous AZT with alternating infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin) in the treatment of HIV associated EBV+ plasmablastic lymphoma.

Three HIV+ patients with biopsy proven, EBV-encoded RNA (EBER)+ PBL in sino-oral mucosa were treated with high dose methotrexate (4.5 g/m² IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-3) alternating with dose-adjusted (DA) EPOCH chemotherapy for 6-8 cycles as first line therapy. Patients were started/kept on HAART and were administered prophylactic intrathecal MTX±cytarabine. Responses were evaluated by oral exam and CT scans.

Selected characteristics of patients are demonstrated in Table. Only Patient 2 was on HAART at the time of diagnosis. Patient 1 had intracranial extension of the large left maxillary lesion through sphenoid sinus with negative CSF cytology. All patients treated with HD-MTX/AZT and alternating EPOCH as above achieved a complete remission (CR). Patient 1 achieved CR after the 3^rd cycle. However, 19 days after the 4^th cycle he was found to have local recurrence, which was thought to be secondary to poor chemotherapy penetration to necrotic oral palate tissue, and was administered a total of 4620 cGy intensity-modulated radiotherapy to head and neck region followed by consolidation with the same chemotherapy regimen for 4 more cycles. He remains alive and free of disease after 14 months. Patient 2 and 3 received a total of 6 cycles of chemotherapy and remain disease-free after 12 and 13 months, respectively. No grade ≥3 toxicities were encountered during the treatment.

The combination of high dose MTX and AZT plus alternating DA-EPOCH chemotherapy is a tolerable and effective treatment for HIV related EBV+ plasmablastic lymphomas. The combination of MTX and AZT is a highly active, EBV lytic inducing and targeted regimen which deserves further investigation in the treatment of gamma-herpes virus associated malignancies.

No relevant conflicts of interest to declare.