1730. Outcomes of Patients With Detectable Cytomegalovirus (CMV) DNA at Randomization in the Double-blind, Placebo-Controlled Phase 3 Trial of Letermovir (LET) Prophylaxis for CMV-Seropositive Allogeneic Hematopoietic-Cell Transplantation (HCT) Recipients
Authors: Marty Francisco M , Ljungman Per , Chemaly Roy F , Wan Hong , Teal Valerie L , Butterton Joan , Yeh Wendy W , Leavitt Randi Y , Badshah Cyrus 
Published: November 2018

Background

LET prophylaxis through HCT Week 14 was highly effective in preventing clinically significant CMV infection (CS-CMVi), had a good safety profile, and was associated with lower all-cause mortality by HCT Week 24 compared with placebo (PBO). Patients with detectable CMV DNA at randomization were excluded from the trial’s efficacy analyses (NCT02137772). Here we report the outcomes of these patients.

Methods

We compared patients randomized 2:1 and treated with LET or PBO who had detectable CMV DNA at randomization (n = 70) to those with undetectable CMV DNA (n = 495; primary efficacy population, PEP). CS-CMVi was defined as CMV viremia requiring antiviral preemptive therapy (PET) or CMV disease; patients with missing data were imputed as events. PET was prescribed blinded to study drug. We analyzed CS-CMVi incidence, CMV viral load (VL) kinetics, and mortality using post study vital status. Detectable, nonquantifiable CMV VL (&lt;151 c/mL) was imputed as 150 c/mL.

Results

Of 70 patients with detectable CMV DNA at randomization (48 LET, 22 PBO), CMV VL was 150 c/mL in 63 patients (range, 150–716). All patients had undetectable CMV VL ≤5 days before randomization. Baseline characteristics were similar to the PEP, except for more patients with myeloablative conditioning (62.9% vs. 48.3%) and longer median days post-HCT to start of study drug (15 days vs. 8 days). Median study drug exposure was 70 days (range, 1–113) in LET group and 14 days (range, 7–99) in PBO group. By HCT Week 14, CS-CMVi occurred in 15 (31.3%) LET-treated patients and 17 (77.3%) PBO patients; CS-CMVi with imputed events were 22 (45.8%) in LET group and 20 (90.9%) in PBO group (difference –44.8%; 95% CI, –64.7% to –24.8%; P &lt; 0.0001). Median CMV VL at time of PET was 413 c/mL (range, 150–31,847) and was similar between groups. Eight patients had quantifiable CMV VL (range, 171–1,728 c/mL) 1 week after starting study drug: 6 did not receive PET (5 LET [10.4%], 1 PBO [4.5%]). CMV VL was undetectable subsequently; other 2 withdrew from study. One (2.1%) LET-treated patient developed breakthrough CMV viremia with a UL56 C325W mutation. HCT Week 48 all-cause mortality was 26.5% in LET and 40.9% in PBO (figure).

Conclusion

LET prevented CS-CMVi compared with PBO among patients with detectable CMV DNA at randomization.

Disclosures

F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium. Astellas: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Fate Therapeutics: Consultant, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee. LFB: Consultant, Consulting fee. Roche Molecular Diagnostics: Consultant, Consulting fee. Shire: Consultant and Investigator, Consulting fee and Research support. Cidara: Investigator, Research support. Ansun: Investigator, Research support. Gilead: Investigator, Research support. WHISCON: Investigator, Research support. P. Ljungman, Merck: Investigator, Research support. AiCuris: Consultant, Consulting fee. Astellas: Investigator, Research support. Oxford Immunotec: Consultant and Investigator, Consulting fee and Research support. R. F. Chemaly, Merck: Consultant and Investigator, Consulting fee and Research support. Chimerix: Consultant and Investigator, Consulting fee and Research support. Astellas: Consultant, Consulting fee. Novartis: Investigator, Research support. Oxford Immunotec: Consultant, Consulting fee. H. Wan, Merck: Employee and Shareholder, Salary. V. L. Teal, Merck: Employee and Shareholder, Salary. J. Butterton, Merck: Employee and Shareholder, Salary. W. W. Yeh, Merck: Employee and Shareholder, Salary. R. Y. Leavitt, Merck: Employee and Shareholder, Salary. C. Badshah, Merck: Employee and Shareholder, Salary.