Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof‐of‐concept study

Abstract

It is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV‐specific T‐cell responses. Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real‐time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV‐specific interferon‐γ (IFN‐γ)‐producing CD8+ and CD4+ T‐cells in whole blood was performed by flow cytometry. Median TTV DNA load in ibrutinib‐treated patients increased significantly (p = 0.025) from baseline (median: 5.76 log10 copies/mL) to day +120 (median: 7.83 log10 copies/mL). A moderate inverse correlation (Rho = −0.46; p < 0.001) was found between TTV DNA load and absolute lymphocyte count. In ruxolitinib‐treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception (p ≥ 0.12). TTV DNA load was not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV‐specific IFN‐γ‐producing CD8+ and CD4+ T‐cell counts in either patient group. The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV‐specific T‐cell reconstitution; nevertheless, due to the small sample size, further studies involving larger cohorts are warranted to elucidate this issue.

TTV and CMV viral load dynamics: Which emerges first during immunosuppression?

“…This can, at least in part, justify the possibility that TTV load may vary depending on the harbored number of specific hematopoietic cells in a specific patient. 6,15 However, the study does not provide conclusive data regarding the latter aspect. Nevertheless, in our opinion it has the merit of confirming the complexity of the phenomenon and offers interesting insights for the choice of approaches and conditions to continue experimental studies on the topic.…”

“…On the other hand, TTV replication has been demonstrated in hematopoietic cells such as granulocytes, 14 and blood disorders such as chronic and acute myeloid leukemias disrupt the cellular precursors of granulocytes. This can, at least in part, justify the possibility that TTV load may vary depending on the harbored number of specific hematopoietic cells in a specific patient 6,15 . However, the study does not provide conclusive data regarding the latter aspect.…”

Torque Teno Virus DNA Load in Blood as an Immune Status Biomarker in Adult Hematological Patients: The State of the Art and Future Prospects

“…These drugs have a profound effect on B- and T-cell homeostasis, which largely explains the increased incidence of opportunistic infections in patients treated with these compounds [ 57 ]. Solano de la Asunción et al [ 58 ] characterized the kinetics of TTV DNA load in plasma (at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment administration) in patients treated with ibrutinib or ruxolitinib, and investigated whether TTV DNAemia dynamics could anticipate CMV DNAemia, a common event in these patients [ 59 , 60 ]. TTV DNA load increased over time in ibrutinib-treated patients, reaching the peak by day +120.…”

“…A total of 121 patients. AML (58), ALL (15), MDS (12), NHL (10), MPS (6), MM (9), HL (5), CML (3), CLL…”

“…A total of 123 patients. AML (58), ALL (9), MDS (33), NHL (11), and others (12) Days + 0-15, +16-30, +31-45, +46-60, +61-80, +81-99, +100-119, +120-140, +141-160, +161-180, +181-200, +201-219, +221-239, +240-260, +261-280, +281-300, +301-320, +321-345…”