ORIGINAL RESEARCH
Annals of Internal Medicine
Valganciclovir for the Prevention of Complications of Late Cytomegalovirus Infection After Allogeneic Hematopoietic Cell Transplantation A Randomized Trial Michael Boeckh, MD; W. Garrett Nichols, MD, MS; Roy F. Chemaly, MD, MPH; Genovefa A. Papanicolaou, MD; John R. Wingard, MD; Hu Xie, MS; Karen L. Syrjala, PhD; Mary E.D. Flowers, MD; Terry Stevens-Ayers, MS; Keith R. Jerome, MD, PhD; and Wendy Leisenring, ScD
Background: Optimal prevention of late cytomegalovirus (CMV) disease is poorly defined. Objective: To compare valganciclovir prophylaxis with polymerase chain reaction– guided preemptive therapy. Design: Randomized, double-blind trial. (ClinicalTrials.gov: NCT00016068) Setting: Multicenter trial. Patients: 184 recipients of hematopoietic cell transplantation (HCT) who were at high risk for late CMV disease (95 patients received valganciclovir and 89 received placebo). Intervention: 6 months of valganciclovir (900 mg/d) or placebo. Patients with polymerase chain reaction positivity at 1000 copies/mL or greater or a 5-fold increase over baseline were treated with ganciclovir or valganciclovir (5 mg/kg or 900 mg twice daily, respectively). Measurements: The composite primary end point was death, CMV disease, or other invasive infections by 270 days after HCT. Secondary end points were CMV disease, CMV DNAemia, death, other infections, resource utilization, ganciclovir resistance, quality of life, immune reconstitution, and safety.
G
anciclovir effectively prevents cytomegalovirus (CMV) disease during the first 3 months after hematopoietic cell transplantation (HCT) when given prophylactically at engraftment or preemptively for pp65 antigenemia or detection of CMV DNA by polymerase chain reaction (PCR). It improves survival in selected high-risk patients (1, 2). However, most cases of CMV disease now occur after withdrawal of ganciclovir (3–7), most frequently between 100 and 270 days after transplantation (3). In the absence of preventive strategies, both late CMV infection and disease are independent predictors for death after HCT (3). Although preemptive therapy based on virologic surveillance is the most commonly used strategy to prevent CMV disease during the first 3 months after HCT (8), maintaining surveillance is often difficult late after HCT because patients often return to remote locations and regular blood draws may be difficult to perform. The rationale for studying a prophylactic approach is supported by the observation that even asymptomatic CMV infection is associated with increased mortality rates, suggesting a role of indirect effects of CMV in the late period (3). However, the benefits of ganciclovir and valganciclovir prophylaxis are theoretically counterbalanced by their
Results: The primary composite outcome occurred in 20% of valganciclovir recipients versus 21% of placebo-preemptive therapy recipients (treatment difference, ⫺0.01 [95% CI, ⫺0.13 to 0.10]; P = 0.86). There was no difference in the primary end point or its components 640 days after HCT. The incidence of a CMV DNAemia level of 1000 copies/mL or greater or a 5-fold increase over baseline was reduced in the valganciclovir group (11% vs. 36%; P < 0.001). Neutropenia was not significantly different at the absolute neutrophil count of less than 0.5 × 109 cells/L (P = 0.57); however, more patients received hematopoietic growth factors in the valganciclovir group (25.3% vs. 12.4%; P = 0.026). No significant differences were seen in other secondary outcomes. Limitation: Some high-risk patients were not included. Conclusion: Valganciclovir prophylaxis was not superior in reducing the composite end point of CMV disease, invasive bacterial or fungal disease, or death when compared with polymerase chain reaction– guided preemptive therapy. Both strategies performed similarly with regard to most clinical outcomes. Primary Funding Source: Roche Laboratories. Ann Intern Med. 2015;162:1-10. doi:10.7326/M13-2729 For author affiliations, see end of text.
www.annals.org
most common toxicity (neutropenia), which is also independently associated with death early after HCT (9, 10).
METHODS Design This was an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The Fred Hutchinson Cancer Research Center (FHCRC) held the Investigational New Drug application and served as the coordinating center. Patients were randomly assigned to receive valganciclovir (900 mg once per day) or matching placebo (Appendix Figure 1, available at www.annals.org) between 1999 and 2008. Study patients, study personnel, and all clinical personnel were blinded. The study drug was withdrawn when CMV viral load was greater than 1000 copies/mL or greater than 5 times the baseline value, and preemptive therapy was started with intravenous ganciclovir (5 mg/kg twice daily) or valganciclovir (900 mg twice daily); foscarnet (90 mg/kg twice daily) was used instead if indicated due to neutropenia. All doses were adjusted to the creatinine clearance as per manufacturer recommendations. Weekly study samples were mailed to © 2015 American College of Physicians 1
Downloaded From: http://annals.org/ by a Tulane University User on 05/17/2015
ORIGINAL RESEARCH EDITORS' NOTES Context Cytomegalovirus (CMV) disease is a late complication of allogeneic hematopoietic cell transplantation (HCT). Contribution In a multicenter, randomized, double-blind trial of patients who had HCT and were at high risk for late CMV disease, continuous valganciclovir prophylaxis was compared with a strategy of CMV polymerase chain reaction–guided preemptive therapy with valganciclovir and ganciclovir. These 2 approaches did not differ in the occurrence of death, CMV disease, or other invasive fungal infections. Safety was similar. Caution More patients who received continuous valganciclovir required hematopoietic growth factors. Implication Both continuous valganciclovir prophylaxis and CMV polymerase chain reaction– guided preemptive therapy are viable alternatives to prevent late CMV disease after HCT.
Seattle, Washington, and tested at the University of Washington clinical laboratories. Cytomegalovirus and chemistry testing results were made available in real time to study sites to allow initiation of open-label preemptive treatment of CMV disease, dose adjustment, drug withdrawal, or start of hematopoietic growth factors as prespecified in the protocol. The study drug was held and growth factors were started if the absolute neutrophil count decreased to less than 1.0 × 109 cells/L. A CMV DNA level greater than 1000 copies/mL or consecutive positive results with increasing levels was used to withdraw the study drug and start preemptive treatment with open-label intravenous ganciclovir treatment. The protocol was amended halfway through the study to make valganciclovir open-label treatment available to patients for breakthrough preemptive therapy (instead of requiring intravenous treatment) and to formally include granulocyte colony-stimulating factor (G-CSF) treatment of neutropenia at an absolute neutrophil count of 1.0 × 109 cells/L. Setting and Patients Allogeneic HCT recipients aged 16 years or older who were seropositive for CMV before transplant or had a seropositive donor were eligible. Seropositive recipients had to have either CMV infection with appropriate treatment course before random assignment; a history of graft-versus-host disease (GVHD) after transplantation requiring treatment with systemic corticosteroids at doses greater than 0.5 mg/kg at any time before enrollment; chronic, clinically extensive GVHD requiring treatment with corticosteroids; or receipt of 2 Annals of Internal Medicine • Vol. 162 No. 1 • 6 January 2015
Downloaded From: http://annals.org/ by a Tulane University User on 05/17/2015
Late CMV Prevention After HCT
ganciclovir, valganciclovir, foscarnet, or cidofovir prophylaxis between engraftment and random assignment. Seronegative recipients with seropositive donors had to have a CMV infection with appropriate treatment course before random assignment. A complete listing of inclusion and exclusion criteria is shown in Appendix 1 (available at www.annals.org). Randomization and Interventions Randomization occurred once patients were identified as eligible for the study at a median of 97 and 98 days after HCT for the valganciclovir and placebo groups, respectively (Table 1). We used an adaptive randomization scheme implemented using a statistical program written by an FHCRC statistician and run by staff of the FHCRC protocol office. Randomization was stratified by study site, previous neutropenia (presence or absence of absolute neutrophil count 500 mg/day); limited treatment courses at higher doses for VZV infections are permissible 8. Ongoing prophylactic use of foscarnet, cidofovir, or ganciclovir (intravenous or oral); limited treatment courses of low-dose cidofovir (≤0.5 mg/kg per week) are permissible 9. Leukemic relapse; cytogenetic and molecular relapse are permissible 10. Pregnancy 11. Nursing mothers 12. Refusal to use birth control 13. Imminent demise (expected survival 1000 copies/mL)
CMV disease
0 358 154 5 Yes No No No Valganciclovir Valganciclovir Valganciclovir Placebo 6 7 8 9
Yes No No Yes
No No No No
No No No No
35 516 169 38
5 107 No No 49 290 Yes No No No Yes No Valganciclovir Valganciclovir 4 5
Patients, n (%) Valganciclovir (n ⴝ 95)
590 No CMV 100 100
7
No Yes, at 16 and 21 wk No Yes, at 23 wk No No 22 460 No CMV
Yes No Yes No Yes, at 21 wk No 322 42 8 150 190 95 334 137 17 Placebo Placebo Placebo 1 2 3
No No Yes
Yes No No
No No No
395 183 22
No No No
Study drug completed Study drug completed CMV disease, presenting with diarrhea AE: thrombocytopenia AE
Died
Annals of Internal Medicine
Valganciclovir for the Prevention of Complications of Late Cytomegalovirus Infection After Allogeneic Hematopoietic Cell Transplantation A Randomized Trial Michael Boeckh, MD; W. Garrett Nichols, MD, MS; Roy F. Chemaly, MD, MPH; Genovefa A. Papanicolaou, MD; John R. Wingard, MD; Hu Xie, MS; Karen L. Syrjala, PhD; Mary E.D. Flowers, MD; Terry Stevens-Ayers, MS; Keith R. Jerome, MD, PhD; and Wendy Leisenring, ScD
Background: Optimal prevention of late cytomegalovirus (CMV) disease is poorly defined. Objective: To compare valganciclovir prophylaxis with polymerase chain reaction– guided preemptive therapy. Design: Randomized, double-blind trial. (ClinicalTrials.gov: NCT00016068) Setting: Multicenter trial. Patients: 184 recipients of hematopoietic cell transplantation (HCT) who were at high risk for late CMV disease (95 patients received valganciclovir and 89 received placebo). Intervention: 6 months of valganciclovir (900 mg/d) or placebo. Patients with polymerase chain reaction positivity at 1000 copies/mL or greater or a 5-fold increase over baseline were treated with ganciclovir or valganciclovir (5 mg/kg or 900 mg twice daily, respectively). Measurements: The composite primary end point was death, CMV disease, or other invasive infections by 270 days after HCT. Secondary end points were CMV disease, CMV DNAemia, death, other infections, resource utilization, ganciclovir resistance, quality of life, immune reconstitution, and safety.
G
anciclovir effectively prevents cytomegalovirus (CMV) disease during the first 3 months after hematopoietic cell transplantation (HCT) when given prophylactically at engraftment or preemptively for pp65 antigenemia or detection of CMV DNA by polymerase chain reaction (PCR). It improves survival in selected high-risk patients (1, 2). However, most cases of CMV disease now occur after withdrawal of ganciclovir (3–7), most frequently between 100 and 270 days after transplantation (3). In the absence of preventive strategies, both late CMV infection and disease are independent predictors for death after HCT (3). Although preemptive therapy based on virologic surveillance is the most commonly used strategy to prevent CMV disease during the first 3 months after HCT (8), maintaining surveillance is often difficult late after HCT because patients often return to remote locations and regular blood draws may be difficult to perform. The rationale for studying a prophylactic approach is supported by the observation that even asymptomatic CMV infection is associated with increased mortality rates, suggesting a role of indirect effects of CMV in the late period (3). However, the benefits of ganciclovir and valganciclovir prophylaxis are theoretically counterbalanced by their
Results: The primary composite outcome occurred in 20% of valganciclovir recipients versus 21% of placebo-preemptive therapy recipients (treatment difference, ⫺0.01 [95% CI, ⫺0.13 to 0.10]; P = 0.86). There was no difference in the primary end point or its components 640 days after HCT. The incidence of a CMV DNAemia level of 1000 copies/mL or greater or a 5-fold increase over baseline was reduced in the valganciclovir group (11% vs. 36%; P < 0.001). Neutropenia was not significantly different at the absolute neutrophil count of less than 0.5 × 109 cells/L (P = 0.57); however, more patients received hematopoietic growth factors in the valganciclovir group (25.3% vs. 12.4%; P = 0.026). No significant differences were seen in other secondary outcomes. Limitation: Some high-risk patients were not included. Conclusion: Valganciclovir prophylaxis was not superior in reducing the composite end point of CMV disease, invasive bacterial or fungal disease, or death when compared with polymerase chain reaction– guided preemptive therapy. Both strategies performed similarly with regard to most clinical outcomes. Primary Funding Source: Roche Laboratories. Ann Intern Med. 2015;162:1-10. doi:10.7326/M13-2729 For author affiliations, see end of text.
www.annals.org
most common toxicity (neutropenia), which is also independently associated with death early after HCT (9, 10).
METHODS Design This was an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The Fred Hutchinson Cancer Research Center (FHCRC) held the Investigational New Drug application and served as the coordinating center. Patients were randomly assigned to receive valganciclovir (900 mg once per day) or matching placebo (Appendix Figure 1, available at www.annals.org) between 1999 and 2008. Study patients, study personnel, and all clinical personnel were blinded. The study drug was withdrawn when CMV viral load was greater than 1000 copies/mL or greater than 5 times the baseline value, and preemptive therapy was started with intravenous ganciclovir (5 mg/kg twice daily) or valganciclovir (900 mg twice daily); foscarnet (90 mg/kg twice daily) was used instead if indicated due to neutropenia. All doses were adjusted to the creatinine clearance as per manufacturer recommendations. Weekly study samples were mailed to © 2015 American College of Physicians 1
Downloaded From: http://annals.org/ by a Tulane University User on 05/17/2015
ORIGINAL RESEARCH EDITORS' NOTES Context Cytomegalovirus (CMV) disease is a late complication of allogeneic hematopoietic cell transplantation (HCT). Contribution In a multicenter, randomized, double-blind trial of patients who had HCT and were at high risk for late CMV disease, continuous valganciclovir prophylaxis was compared with a strategy of CMV polymerase chain reaction–guided preemptive therapy with valganciclovir and ganciclovir. These 2 approaches did not differ in the occurrence of death, CMV disease, or other invasive fungal infections. Safety was similar. Caution More patients who received continuous valganciclovir required hematopoietic growth factors. Implication Both continuous valganciclovir prophylaxis and CMV polymerase chain reaction– guided preemptive therapy are viable alternatives to prevent late CMV disease after HCT.
Seattle, Washington, and tested at the University of Washington clinical laboratories. Cytomegalovirus and chemistry testing results were made available in real time to study sites to allow initiation of open-label preemptive treatment of CMV disease, dose adjustment, drug withdrawal, or start of hematopoietic growth factors as prespecified in the protocol. The study drug was held and growth factors were started if the absolute neutrophil count decreased to less than 1.0 × 109 cells/L. A CMV DNA level greater than 1000 copies/mL or consecutive positive results with increasing levels was used to withdraw the study drug and start preemptive treatment with open-label intravenous ganciclovir treatment. The protocol was amended halfway through the study to make valganciclovir open-label treatment available to patients for breakthrough preemptive therapy (instead of requiring intravenous treatment) and to formally include granulocyte colony-stimulating factor (G-CSF) treatment of neutropenia at an absolute neutrophil count of 1.0 × 109 cells/L. Setting and Patients Allogeneic HCT recipients aged 16 years or older who were seropositive for CMV before transplant or had a seropositive donor were eligible. Seropositive recipients had to have either CMV infection with appropriate treatment course before random assignment; a history of graft-versus-host disease (GVHD) after transplantation requiring treatment with systemic corticosteroids at doses greater than 0.5 mg/kg at any time before enrollment; chronic, clinically extensive GVHD requiring treatment with corticosteroids; or receipt of 2 Annals of Internal Medicine • Vol. 162 No. 1 • 6 January 2015
Downloaded From: http://annals.org/ by a Tulane University User on 05/17/2015
Late CMV Prevention After HCT
ganciclovir, valganciclovir, foscarnet, or cidofovir prophylaxis between engraftment and random assignment. Seronegative recipients with seropositive donors had to have a CMV infection with appropriate treatment course before random assignment. A complete listing of inclusion and exclusion criteria is shown in Appendix 1 (available at www.annals.org). Randomization and Interventions Randomization occurred once patients were identified as eligible for the study at a median of 97 and 98 days after HCT for the valganciclovir and placebo groups, respectively (Table 1). We used an adaptive randomization scheme implemented using a statistical program written by an FHCRC statistician and run by staff of the FHCRC protocol office. Randomization was stratified by study site, previous neutropenia (presence or absence of absolute neutrophil count 500 mg/day); limited treatment courses at higher doses for VZV infections are permissible 8. Ongoing prophylactic use of foscarnet, cidofovir, or ganciclovir (intravenous or oral); limited treatment courses of low-dose cidofovir (≤0.5 mg/kg per week) are permissible 9. Leukemic relapse; cytogenetic and molecular relapse are permissible 10. Pregnancy 11. Nursing mothers 12. Refusal to use birth control 13. Imminent demise (expected survival 1000 copies/mL)
CMV disease
0 358 154 5 Yes No No No Valganciclovir Valganciclovir Valganciclovir Placebo 6 7 8 9
Yes No No Yes
No No No No
No No No No
35 516 169 38
5 107 No No 49 290 Yes No No No Yes No Valganciclovir Valganciclovir 4 5
Patients, n (%) Valganciclovir (n ⴝ 95)
590 No CMV 100 100
7
No Yes, at 16 and 21 wk No Yes, at 23 wk No No 22 460 No CMV
Yes No Yes No Yes, at 21 wk No 322 42 8 150 190 95 334 137 17 Placebo Placebo Placebo 1 2 3
No No Yes
Yes No No
No No No
395 183 22
No No No
Study drug completed Study drug completed CMV disease, presenting with diarrhea AE: thrombocytopenia AE
Died
