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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

The use of high-dose azidothymidine in combination with chemotherapy upfront is an effective... Bayraktar et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A81 http://www.infectagentscancer.com/content/5/S1/A81 MEETING ABSTRACTS 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 1 1 1 1 2 1* Ulas Darda Bayraktar , Eileen Bernal , Lisa Cabral , William J Harrington Jr. , Dirk P Dittmer , Juan Carlos Ramos th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 Background lymphomas is an attractive concept given that this drug is Azidothymidine (AZT), a thymidine analogue, is an excel- preferentially phosphorylated by EBV and HHV-8 TKs as lent substrate for gamma-herpes virus thymidine kinases compared to non-thymidine nucleoside analogues. The (TKs). Our group previously demonstrated that AZT drugs methotrexate (MTX) and doxorubicin (DOX) also alone can inhibit NF-B and disrupt EBV latency in pri- induce lytic expression of gamma-herpes viruses. MTX mary low-passage Type I latency EBV+ Burkitt lines. The inhibits thymidylate synthase, thus blocking de novo addition of hydroxyurea, which increases the intracellular synthesis of dTMP and increasing the likelihood of AZT levels of AZT monophosphate, synergized with AZT in incorporation into DNA. We have found that the combi- Type III latency EBV+ immunoblastic lymphoma cell nation of high-dose AZT with MTX, used alone or with lines. The use of AZT in targeting gamma-herpes virus alternating standard chemotherapy, can result in dramatic Table 1 Lymphoma Alternating Sustained Response Progression Death Age type Stage PS HIV CD4 regimen RT (months) (months) (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) - - nd 51 Solid PEL IVB 2 + 113 - - CR (31), 2 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. *Correspondence: jramos2@med.miami.edu Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL, USA Full list of author information is available at the end of the article © 2010 Ramos et al; licensee BioMed Central Ltd. Bayraktar et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A81 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A81 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/m IV on day 1) and AZT 1.5 g IV infu- sion 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/m (Day 1) , MTX 5 g/m (Day 2), and AZT 750 mg twice daily with hydro- xyurea 1 g daily (Days 2-5) under our new clinical trial. 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 promis- ing 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 pre- sented at the meeting. Acknowledgements This article has been published as part of Infectious Agents and Cancer th Volume 5 Supplement 1, 2010: Proceedings of the 12 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. Author details Submit your next manuscript to BioMed Central Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. Department of Microbiology and Immunology, and take full advantage of: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. • Convenient online submission Published: 11 October 2010 • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance doi:10.1186/1750-9378-5-S1-A81 • Inclusion in PubMed, CAS, Scopus and Google Scholar Cite this article as: Bayraktar et al.: The use of high-dose azidothymidine in combination with chemotherapy upfront is an effective treatment • Research which is freely available for redistribution approach for gamma-herpes virus-related non-Hodgkin’s lymphomas. Infectious Agents and Cancer 2010 5(Suppl 1):A81. 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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

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Springer Journals
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Copyright © 2010 by Ramos et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-5-S1-A81
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Abstract

Bayraktar et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A81 http://www.infectagentscancer.com/content/5/S1/A81 MEETING ABSTRACTS 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 1 1 1 1 2 1* Ulas Darda Bayraktar , Eileen Bernal , Lisa Cabral , William J Harrington Jr. , Dirk P Dittmer , Juan Carlos Ramos th From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010 Background lymphomas is an attractive concept given that this drug is Azidothymidine (AZT), a thymidine analogue, is an excel- preferentially phosphorylated by EBV and HHV-8 TKs as lent substrate for gamma-herpes virus thymidine kinases compared to non-thymidine nucleoside analogues. The (TKs). Our group previously demonstrated that AZT drugs methotrexate (MTX) and doxorubicin (DOX) also alone can inhibit NF-B and disrupt EBV latency in pri- induce lytic expression of gamma-herpes viruses. MTX mary low-passage Type I latency EBV+ Burkitt lines. The inhibits thymidylate synthase, thus blocking de novo addition of hydroxyurea, which increases the intracellular synthesis of dTMP and increasing the likelihood of AZT levels of AZT monophosphate, synergized with AZT in incorporation into DNA. We have found that the combi- Type III latency EBV+ immunoblastic lymphoma cell nation of high-dose AZT with MTX, used alone or with lines. The use of AZT in targeting gamma-herpes virus alternating standard chemotherapy, can result in dramatic Table 1 Lymphoma Alternating Sustained Response Progression Death Age type Stage PS HIV CD4 regimen RT (months) (months) (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) - - nd 51 Solid PEL IVB 2 + 113 - - CR (31), 2 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. *Correspondence: jramos2@med.miami.edu Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL, USA Full list of author information is available at the end of the article © 2010 Ramos et al; licensee BioMed Central Ltd. Bayraktar et al. Infectious Agents and Cancer 2010, 5(Suppl 1):A81 Page 2 of 2 http://www.infectagentscancer.com/content/5/S1/A81 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/m IV on day 1) and AZT 1.5 g IV infu- sion 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/m (Day 1) , MTX 5 g/m (Day 2), and AZT 750 mg twice daily with hydro- xyurea 1 g daily (Days 2-5) under our new clinical trial. 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 promis- ing 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 pre- sented at the meeting. Acknowledgements This article has been published as part of Infectious Agents and Cancer th Volume 5 Supplement 1, 2010: Proceedings of the 12 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. Author details Submit your next manuscript to BioMed Central Division of Hematology/Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. Department of Microbiology and Immunology, and take full advantage of: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. • Convenient online submission Published: 11 October 2010 • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance doi:10.1186/1750-9378-5-S1-A81 • Inclusion in PubMed, CAS, Scopus and Google Scholar Cite this article as: Bayraktar et al.: The use of high-dose azidothymidine in combination with chemotherapy upfront is an effective treatment • Research which is freely available for redistribution approach for gamma-herpes virus-related non-Hodgkin’s lymphomas. Infectious Agents and Cancer 2010 5(Suppl 1):A81. Submit your manuscript at www.biomedcentral.com/submit

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Infectious Agents and Cancer – Springer Journals

Published: Oct 11, 2010

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