Title

Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

2018-07-15

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cancer Biology | Enzymes and Coenzymes | Hemic and Lymphatic Diseases | Immune System Diseases | Immunology and Infectious Disease | Nervous System | Neuroscience and Neurobiology | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.

Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV(+) PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m(2) was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.

Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.

Conclusions: EBV(+) PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach.

Keywords

PCNS, PTLD, EBV, AZT, Lytic infection

DOI of Published Version

10.1158/1078-0432.CCR-17-2685

Source

Clin Cancer Res. 2018 Jul 15;24(14):3273-3281. doi: 10.1158/1078-0432.CCR-17-2685. Epub 2018 Apr 9. Link to article on publisher's site

Journal/Book/Conference Title

Clinical cancer research : an official journal of the American Association for Cancer Research

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

29632007

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