CMV Infection in Hematopoietic Stem Cell Transplant Recipients

Michael Boeckh, MD

This research project is focused on pharmacological and laboratory approaches to prevention of infection with CMV and other herpes viruses after hematopoietic stem cell transplantation. It is a sub-project of the Adult Leukemia Research Center grant. The project has two major components:

1. prevention and treatment of CMV infection by optimization of antiviral treatment strategies
2. investigation of the reconstitution of herpesvirus-specific (i.e. CMV, HSV, VZV) T-cell immunity after tranplantation

The introduction of ganciclovir (GCV) has resulted in a major reduction in CMV disease. However, the use of GCV is associated with two major side effects, myelosuppression and late CMV disease. When GCV is given at engraftment, it prevents CMV disease but often leads to myelosuppression and a delay in the reconstitution of CMV-specific T-cell immunity, resulting in recurrent CMV disease occurs after discontinuation of GCV treatment. Pioneering work at the FHCRC has shown that adoptive T-cell transfer for CMV can provide CMV-specific immune-reconstitution in some patients. However, there are still clinical situations where antiviral chemotherapy is required, specifically in recipients who lack the CMV-positive donor necessary for generation of T-cells for adoptive transfer and in patients with severe graft vs. host disease (GvHD) who require immunosuppressive therapy. Consequently, improved antiviral therapy remains essential for reducing morbidity and mortality of CMV disease. The overall goal of these studies is to develop a strategy for reduction of CMV disease among CMV-seropositive marrow/stem cell recipients that is less toxic than current GCV regimens and reduces the incidence of late CMV disease.

In the first component of the project, the investigators have hypothesized that a high rate of GCV-related neutropenia is due to toxic serum levels of GCV as a result of limited excretion of the drug in transplant recipients with subclinical renal tubular defects. The investigators are developing a dosing scheme to minimize toxicity without compromising the GCV antiviral effect. The GCV treatment regimen can then be adjustable per individual patient after analysis of renal clearance. These studies will be crucial in defining those antiviral strategies that provide safe, long-term protection against CMV required by patients who can't receive donor-derived CMV-specific T-cells because of an HLA-mismatched donor or because there is no CMV-seropositive donor to provide these cells, or in those patients with severe GvHD. The specific aims of the first component of this project are to:

1. Optimize GCV preemptive therapy using targeted pharmacologic dosing to reduce GCV-related neutropenia in the early posttransplant period.
2. Evaluate new anti-CMV agents that can be administered orally as prophylaxis for late CMV disease.

The purpose of the second component of this project is to compare the reconstitution of CMV, HSV and VZV T-cell immunity of bone marrow transplant (BMT) and peripheral blood stem cell transplant (PBSCT) patients and to define mechanisms of transmission of CMV via marrow and PBSC. Reconstitution of virus-specific T-cell immunity protects against the complications of herpesvirus infections after transplantation. The long term immunity of allograft recipients depends on the reconstitution of lymphocytes, and this process is prolonged as de novo production of lymphocytes is limited. Allogeneic PBSCT patients receive more than ten times as many lymphocytes than do BMT recipients. Consequently, PBSCT recipients might have better virus-specific T-cell immunity. However, suppressive effects on T-cell function have also been described after granulocyte-colony stimulating factor (GCSF)-mobilized PBSCT. The major objective of this study is to investigate whether the time course and persistence of herpesvirus-specific immunologic recovery differs between BMT and PBSCT recipients. The reconstitution of T-cell immunity in BMT and PBSCT recipients will be analyzed by functional assays and transmission of CMV will be studied to:

1. Determine CMV, HSV and VZV-specific Th responses and CMV-specific CTL responses, including analysis of CMV-specific Th and CTL precursor frequencies (by limiting dilution) in recipients seropositive before transplant,
2. Determine the incidence of CMV, HSV and VZV infection at days 100 and 365 after transplant,
3. Determine if G-CSF stem cell mobilization suppresses herpesvirus-specific donor T-cell function, and
4. Determine whether patterns of transmission and immune reconstitution in primary CMV infection from seropositive donors via marrow and PBSC are different.

This study will define if there are earlier and longer lasting herpesvirus-specific immune recoveries after PBSCT. If so, this finding could have major implications for posttransplant prophylaxis strategies, including the use of antiviral chemoprophylaxis and development of donor and recipient immunization strategies.

The investigators have recently described clinical studies of strategies for designing ganciclovir treatment regimens including using CMV antigenemia as a guide for treatment. They have identified risk factors for neutropenia in GCV recipients after marrow transplantation and found an association of specific CMV genotypes with death due to myelosuppression.

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Recent Publications

Boeckh M, Gooley TA, Bowden R. Effect of High-Dose Acyclovir on Survival in Allogeneic Marrow Transplant Recipients Who Received Ganciclovir at Engraftment or for Cytomegalovirus pp65 Antigenemia. J Infect Dis 1998; 178:1153-7.

Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88:4063-71.

Salzberger B, Bowden RA, Hackman R, Davis C, Boeckh M. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 1997; 90:2502-8.

Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Myerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood 1997; 90:2097-102.

Boeckh M, Hoy C, Torok-Storb B. Occult Cytomegalovirus Infection of Marrow Stroma. Clin Infect Dis 1998; 26:209-10.

Boeckh M, Zaia JA, Jung D, Skettino S, Chauncey TR, Bowden RA. A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation. Biol of Blood and Marrow Trans 1998; 4:13-9.