Tehran University of Medical Sciences International Journal of Hematology-Oncology and Stem Cell Research 2008-2207 19 4 2025 10 16 310 319 EN Maryam Barkhordar Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Amirabbas Rashidi Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Mohammad Vaezi Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Neda Alijani Department of Infectious Diseases, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran Seied Asadollah Mousavi Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Sahar Tavakoli Shiraji Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Mehrdad Abbaszadeh Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Hossein Kamranzadeh Fumani Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran Tanaz Bahri Hematologic Malignancies Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran 2025 05 31 2025 10 16 Background: Cytomegalovirus (CMV) reactivation remains a critical concern following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in CMV-seropositive patients undergoing allo-HSCT from alternative donors. This study explored whether a hybrid CMV prophylaxis regimen would be more effective than the standard preemptive regimen in resource-limited settings where Letermovir is unavailable or cost-prohibitive. Materials and Methods: This prospective single-center cohort study included adult patients with acute leukemia who received allo-HSCT from alternative donors between November 2018 and May 2022. The primary outcome was the evaluation of the CMV reactivation incidence in allo-HSCT patients receiving the hybrid CMV prophylaxis regimen comprising pretransplant ganciclovir followed by high-dose valacyclovir compared with the control patients who received the preemptive regimen. Secondary outcomes included overall survival (OS), disease-free survival (DFS), GVHD-free relapse-free survival (GRFS), and non-relapse mortality (NRM) between the two groups.      Results: A total of 80 patients, 34 received hybrid CMV prophylaxis, and 46 received the preemptive protocol. The hybrid prophylaxis group exhibited a significantly lower incidence of CMV reactivation at 90 days post-transplantation (34% vs. 82%, P = 0.000). However, no statistically significant differences were observed in overall survival, disease-free survival, or non-relapse mortality rates. Conclusion: The hybrid regimen reduced CMV reactivation in high-risk HSCT recipients but did not improve survival outcomes, offering a practical alternative in settings with limited access to Letermovir. https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/view/2465 https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/download/2465/1113