Volume 5 Supplement 1

Proceedings of the 12-th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI)

Open Access

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

  • Ulas Darda Bayraktar1,
  • Eileen Bernal1,
  • Lisa Cabral1,
  • William J HarringtonJr.1,
  • Dirk P Dittmer2 and
  • Juan Carlos Ramos1Email author
Infectious Agents and Cancer20105(Suppl 1):A81

https://doi.org/10.1186/1750-9378-5-S1-A81

Published: 11 October 2010

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

:

Age

Lymphoma type

Stage

PS

HIV

CD4

Alternating regimen

RT

Sustained Response (months)

Progression (months)

Death (months)

34

DLBCL

IVB

3

+

4

-

-

PD

1.0

1.3

49

BL

IVB

2

+

91

EPOCH

-

CR (50)

-

-

40

BL

IIA

2

-

-

hCVAD

+

CR (57)

-

-

51

DLBCL

IVB

2

+

47

EPOCH

-

CR (65)

-

-

40

BL

IVB

2

+

214

hCVAD

-

PD

2.0

-

34

PBL

IVB

2

+

16

-

-

PD

1.0

4.5

33

PBL

IIA

1

+

166

EPOCH

-

CR (18)

-

-

44

PBL

IVA

1

+

458

EPOCH

-

CR (19)

-

-

52

PBL

IIB

1

+

57

EPOCH

+

CR (20)

-

-

51

Solid PEL

IVB

2

+

113

-

-

CR (31), 2nd CR (10)

After 1st line: 31.1

-

PS: ECOG performance score; RT: radiotherapy; DLBCL: diffuse large B-cell lymphoma; PEL: primary effusion lymphoma; PBL: plasmablastic lymphoma. EPOCH: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; hyper cVAD: dexamethasone and fractionated vincristine, doxorubicin cyclophosphamide; CR: complete remission; PR: partial remission; PD: progressive disease.

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.

Declarations

Acknowledgements

This article has been published as part of Infectious Agents and Cancer Volume 5 Supplement 1, 2010: Proceedings of the 12th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI).The full contents of the supplement are available online at http://www.biomedcentral.com/1750-9378/5?issue=S1.

Authors’ Affiliations

(1)
Division of Hematology/Oncology, University of Miami Miller School of Medicine
(2)
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill

Copyright

© Ramos et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.

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