Background: Hematopoietic stem cell (HSC) transplantation (HSCT) is used in the treatment of hematologic malignancies, bone marrow failure and immunodeficiencies and is often associated with cytomegalovirus (CMV) reactivation/infection. Ganciclovir or its prodrug valganciclovir (herein GCV) are guanine analogs that compete with dGTP for DNA incorporation, thereby inhibiting viral DNA replication. A recent study by de Kanter et al. (Cell Stem Cell. 2021) demonstrated that GCV induces mutagenesis in human cells, including HSC. In particular, GCV induces C > A changes at CpA dinucleotides. In contrast, the antiviral foscarnet was not associated with mutations in HSCs. The authors found the GCV mutational signature in relapses and second neoplasias in transplantation recipients, raising the possibility of increased incidence of secondary cancers in patients (pts) receiving GCV treatment.
Aims: To evaluate the incidence of secondary neoplasia in HSCT recipients treated with GCV.
Methods: Unicentric retrospective analysis of HSCT recipients receiving GCV between 2007 and 2021. HSCT pts not receiving GCV were also included as controls (C). Pts who had documented CMV reactivation but no complete information about antiviral exposure were excluded. Statistical analysis was performed in SPSS.
Results: A total of 930 pts were included, 522 (56.1%) receiving GCV and 408 (43.9%) control pts not exposed to GCV (C). Median follow-up was 23 months (0-170) (20 for GCV and 30 for C, p=0.124). CMV reactivation was detected in 68% of pts (96.9% for GCV and 19.8% for C, p<0.001). Median age was 42 years old (0-69) (43 for GCV and 39 for C, p=0.001) and 59% were man (56.7% for GCV and 59.3% for C, p=0.517). Myeloablative conditioning was used in 32.9% of pts (34.5% in GCV and 30.6% in C, p=0.208). HSC sources were similar between groups (p=0.133) and peripheral blood was the most common (86% in GCV and 81.6% in C). Donor kinship was also similar (p=0.056) and donors were HLA-identical in 69.5% of the cases (66.3% in GCV and 73.3% in C, p=0.062). Within the GCV group, 411 (44.2%) pts were exposed to ganciclovir alone, 276 (29.7%) pts to valganciclovir alone and 159 (17.1%) pts to both drugs.
We detected a total of 228 (24.5%) relapses, 115 (22.0%) in GCV and 113 (27.7%) in C (p=0.048). We also detected a total of 43 (4.6%) secondary malignancies, 28 (5.4%) in GCV and 15 (3.7%) in C (p=0.222). Subtypes of secondary malignancies were similar (p=0.205) and included basocellular carcinoma and post-transplant lymphoproliferative disorders. No donor-cell leukemias were detected in our cohort. Combined incidence of relapse and secondary cancers was similar between groups (26.1% vs 30.6%, p=0.127). We next scored relapses and secondary cancers as events. The median event-free survival was 133 months in GCV and not reached in C (p=0.339; HR 1.126). Global overall survival (OS) was 48 months, with median OS of 33 months for GCV vs 97 months for C (p=0,025, HR 1,238).
Summary/Conclusion: In our study, GCV exposure in HSCT was not associated with combined incidence of relapse and secondary cancers. In contrast, an excess of relapses was detected in HSCT pts not exposed to GCV. Shorter OS in GCV-treated pts likely translates other HSCT complications not related with relapse/cancer. Our study is limited by its retrospective and unicentric nature. A longer follow-up might be required to detect more subtle differences. In conclusion, we suggest that although GCV induces in vivo mutagenesis of human cells, it does not translate in increased risk of cancer in HSCT.