Valganciclovir to Prevent Cytomegalovirus Infection in Patients Following Donor Stem Cell Transplantation

A Phase III Multicenter Study Of Valganciclovir For The Prevention Of Late Cytomegalovirus Infection After Allogeneic Hematopoietic Stem Cell Transplantation

RATIONALE: Antivirals such as valganciclovir act against viruses and may be effective in preventing cytomegalovirus. It is not yet known if valganciclovir is effective in preventing cytomegalovirus.

PURPOSE: This randomized phase III trial is studying valganciclovir to see how well it works in preventing cytomegalovirus in patients who have undergone donor stem cell transplantation.

OBJECTIVES:

Primary

• Compare cytomegalovirus (CMV) disease and non-CMV invasive infection-free survival in patients undergoing allogeneic hematopoietic stem cell transplantation treated with valganciclovir vs placebo.
• Compare the incidence of CMV disease in patients treated with these drugs.
• Compare the incidence of other severe invasive bacterial and fungal infections and overall survival in patients treated with these drugs.

Secondary

• Compare the incidence of CMV infection or disease at baseline and at days 270 and 640 after allogeneic hematopoietic stem cell transplantation in patients treated with these drugs.
• Compare the incidence of herpes simplex virus and varicella-zoster virus infections at baseline and day 270 in patients treated with these drugs.
• Determine the safety of valganciclovir in these patients.
• Compare the quality of life of patients treated with these drugs.
• Compare CMV-specific immune reconstitution in patients treated with these drugs.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to participating center, prior neutropenia (yes vs no), and presence of refractory graft-versus-host disease requiring secondary therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral valganciclovir daily.
• Arm II: Patients receive oral placebo daily. Treatment begins around day 80-120 post-transplantation and continues until day 270 post-transplantation in the absence of active infection or unacceptable toxicity. Patients developing active cytomegalovirus (CMV) infection receive induction doses of ganciclovir IV or open-label oral valganciclovir for 1 week followed by open-label oral valganciclovir maintenance dosing until CMV can no longer be detected.

Quality of life is assessed at baseline and days 180 and 270 post-transplantation.

Patients are followed at days 400, 520, and 640 post-transplantation.

PROJECTED ACCRUAL: A total of 184 patients (92 per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Have undergone allogeneic peripheral blood stem cell, cord blood, or marrow transplantation (related or unrelated, T-cell depleted or non-T-cell depleted, CD34-selected or non-selected, or myeloablative or non-myeloablative) within the past 80-120 days

• Positive pre-transplantation cytomegalovirus (CMV) serology of recipient and/or donor

  • Seropositive recipients with one of the following:

    • CMV infection before day 80, as determined by:

      • pp65 antigenemia
      • CMV DNA in plasma
      • Peripheral blood leukocytes (PBL) or whole blood at any level detected by polymerase chain reaction or hybrid capture
      • CMV pp67 mRNA
      • CMV viremia by blood culture
      • Surveillance bronchoalveolar lavage (culture or cytology)

    • CMV disease more than 6 weeks prior to enrollment

    • Presence of graft-versus-host disease (GVHD) at enrollment

      • Acute GVHD that requires treatment with systemic corticosteroids of doses greater than 0.5 mg/kg OR
      • Chronic clinically extensive GVHD requiring treatment with corticosteroids

    • Continuous prophylaxis with ganciclovir, foscarnet, or cidofovir between engraftment and day 80 OR

  • Seronegative recipient with seropositive donor who has CMV infection before day 80

• No rising or uncontrolled CMV load (pp65 antigenemia levels no greater than 1/slide or no greater than 100 copies of CMV DNA per mL of plasma or per million PBL allowed)

• No CMV disease within 6 weeks prior to randomization

• No leukemic relapse

  • Cytogenetic or molecular relapse allowed

PATIENT CHARACTERISTICS:

Age:

• 16 and over

Performance status:

• Not specified

Life expectancy:

• At least 2 weeks

Hematopoietic:

• Absolute neutrophil count at least 1,000/mm^3 for at least 1 week prior to enrollment

Hepatic:

• Not specified

Renal:

• Creatinine no greater than 2.5 mg/mL

Other:

• No hypersensitivity to ganciclovir or valganciclovir
• No uncontrolled diarrhea or severe gastrointestinal disease that would preclude oral medication
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 90 days after study participation
• HIV negative
• Proficient in English

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics

Chemotherapy:

• Not specified

Endocrine therapy:

• See Disease Characteristics

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• Prior ganciclovir, foscarnet, cidofovir, high-dose acyclovir, or valacyclovir as prophylaxis or preemptive therapy allowed

• No concurrent prophylactic foscarnet, cidofovir, or ganciclovir (IV or oral)

• No concurrent prophylactic high-dose acyclovir (more than 800 mg twice daily), valacyclovir (more than 500 mg twice daily), cidofovir (more than 0.5 mg/kg per week), or famciclovir (more than 500 mg/day) except for limited treatment courses at higher doses for varicella-zoster virus infections

  • Concurrent low-dose (≤ 0.5 mg/kg per week) cidofovir allowed for limited treatment courses