Abstract
Background: Consolidative high-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC)-conditioning results in highly favorable outcomes in patients with central nervous system lymphoma (CNSL), but it is met with regimen-related toxicity. In a recent analysis, we noted a higher than expected incidence of DNA virus reactivations and several cases of serious viral organ disease (Scordo et al., BBMT 2017). We aimed to compare the incidence of DNA virus infections between patients with CNSL undergoing TBC-conditioned ASCT and those with systemic non-Hodgkin lymphoma (NHL) undergoing carmustine, etoposide, cytarabine, and melphalan (BEAM)-conditioned ASCT. We hypothesized that patients receiving TBC are at a higher risk for viral infections, and may require unique post-ASCT surveillance and follow-up.
Methods: We retrospectively evaluated adults with chemosensitive CNSL undergoing TBC-conditioned ASCT and those with systemic, chemosensitive diffuse large B-cell lymphoma undergoing BEAM-conditioned ASCT between 2013 and 2016. We recorded all positive DNA virus reactivations infections by serum polymerase chain reaction (PCR) from the start of conditioning until 6 months post-ASCT, and then assessed for evidence of clinically relevant viral infection. We used a combined viral infection endpoint that included: cytomegalovirus (CMV), adenovirus (ADV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6). The cumulative incidences (CI) of combined viral PCR reactivation and clinically relevant viral infection were compared by the log rank test. Cox proportional hazard analysis was used to compare the risk of viral infection between both groups. Variables with p-values of < 0.2 in the univariate analysis were included in the multivariate analysis.
Results: We evaluated 67 patients that underwent BEAM-conditioned and 54 patients that underwent TBC-conditioned ASCT. Baseline patient characteristics including age, gender, disease status, pre-ASCT absolute lymphocyte count (ALC), day +30 ALC, and steroid use during the first 30 days post-ASCT (prednisone 40 mg equivalent or higher) were similar between groups, and are shown in Table 1. There were 6 viral reactivations (5 HHV-6 and 1 CMV) among the BEAM patients (CI 9.1%), and 19 (1 ADV, 5 CMV, 13 HHV-6) among TBC patients (CI 35.2%), p=0.0003, as shown in Figure 1. No BEAM patients had a clinically significant viral infection, while there were 7 clinically significant viral infections (2 CMV, 1 ADV, 4 HHV-6) among TBC patients, p=0.0003, as shown in Figure 2. Among all patients in the univariate analysis, receiving TBC conditioning was the only characteristic that was associated with a higher risk of viral reactivation/infection, hazard-ratio (HR) 4.78 (1.91-12.0), p<0.001. In the multivariate analysis, receiving TBC conditioning was associated with an increased risk of viral reactivation [HR 5.43 (2.1-13.8), p<0.001], and advanced age [HR 0.97, (0.94-0.99), p=0.03] was associated with a slightly reduced risk of viral reactivation as shown in Table 2.
Conclusions: Patients with CNSL undergoing TBC-conditioned ASCT are at an increased risk for DNA virus reactivation and clinically relevant DNA virus infections when compared to patients receiving BEAM. This may reflect the higher myeloablative intensity of TBC compared to BEAM, and possibly inherent differences in immune function in patients with CNSL compared to systemic NHL. These data highlight the need to implement early post-ASCT viral serum PCR monitoring for patients undergoing TBC-conditioned ASCT, with the goal of pre-emptive treatment of clinically relevant infections.
No relevant conflicts of interest to declare.
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