Background: Post-transplantation cyclophosphamide (PTCy) is widely used for graft-versus-host-disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). However, the standard PTCy dose (50 mg/kg/day) and timing (given on days +3 and +4) were largely extrapolated from murine skin allografting models, and these have never been rigorously tested to determine if they are optimal. We have shown in murine HCT models that an intermediate PTCy dose of 25 mg/kg/day on days +3/+4 is superior at preventing severe GVHD compared with 50 mg/kg/day on days +3/+4 (Wachsmuth et al., JCI. 2019). Furthermore, PTCy 25 mg/kg/day given on day +4 alone is equivalent to 25 mg/kg/day given on days +3/+4 at preventing severe GVHD (Wachsmuth et al. BBMT. 2019). Thus, the standard clinical dosing may be higher than necessary and potentially come at the cost of increased toxicity, delayed engraftment, and impaired immune reconstitution. Methods: This is a single institutional prospective phase I/II study (NCT03983850) to de-escalate PTCy exposure for adult patients with hematologic malignancies. All patients received myeloablative conditioning with IV daily busulfan/fludarabine, HLA-haploidentical bone marrow, and GVHD prophylaxis with PTCy (dose and timing based on Dose Level (DL)), mycophenolate mofetil (days +5 to +35), and sirolimus (days +5 to +80). The first 5 patients received PTCy 50 mg/kg/day on days +3/+4 (standard dosing, Dose Level 1) for comparative data. This was followed by a 3+3 dose de-escalation design testing 25 mg/kg/day on days +3/+4 (experimental, Dose Level 2) and 25 mg/kg on day +4 only (experimental, Dose Level 3), followed by a phase II expansion cohort at the better experimental dose level. The primary endpoint and dose limiting toxicity for the dose de-escalation was grade III-IV acute GVHD. Results: Phase I enrolled 19 patients, and the phase II expansion has enrolled 13 of 14 patients, 9 of whom have sufficient follow-up (60 days) to be considered evaluable for the primary endpoint; median follow-up of survivors evaluable for the primary endpoint is 288 (range 60-676) days. Patient and disease characteristics and outcomes for these patients are summarized in Table 1. No grade III-IV acute GVHD was seen at either experimental DL, and there have been no cases of grade II-IV acute GVHD at DL2 (Figure 1). Based on more reliable early engraftment (see below) but less intense and shorter duration of engraftment fevers, DL2 was taken to phase II. Engraftment was faster at the experimental DLs but was most consistent with DL2. Median neutrophil engraftment was at day 14 at DL2 compared with day 19 at the standard dosing (p=0.0004) (Figure 2A). Median platelet engraftment was at day 23 at DL2 compared with day 33 at the standard dosing (p=0.026) (Figure 2B). Correspondingly, transfusional requirements were lessened with DL2 (Figure 2C-D). Engraftment syndrome, manifesting as fever, rash, and mild transaminitis, occurred in 1 patient at DL2 and 2 patients at DL3, but resolved rapidly without intervention in all cases. Primary graft failure was seen in 1 patient at DL2, and relapse prior to engraftment was seen in 1 patient at DL3. Mucositis was less severe and shorter in duration for both experimental DLs when compared with standard PTCy dosing (Figure 2E). CMV reactivation requiring pre-emptive therapy was less frequently seen after lower PTCy dosing (Figure 3A). Symptomatic BK virus-associated cystitis in at-risk patients was shorter in duration for patients receiving lower PTCy; median duration was 74 days for the standard DL versus 26 days at DL2 and 7 days at DL3 (Figure 3B). At DL2, there have been 3 cases to date of chronic GVHD requiring systemic immunosuppression among the 13 engrafting patients with at least 100 days of follow-up. Conclusions: De-escalating PTCy exposure is feasible and effective in maintaining protection against severe acute GVHD while promoting more rapid engraftment and less early post-transplant toxicity. Two-day dosing of 25 mg/kg/day PTCy appears to allow for more consistent early engraftment and protection against protracted engraftment fevers compared with day +4 only. Longer follow-up and comparative studies are needed to understand if de-escalated PTCy is superior to the standard dosing schedule. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: The use of cyclophosphamide as graft-versus-host disease prophylaxis
A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.
The cultivation area and use of genetically modified (GM) crops have been increased continuously over the world. Concerns about the potential risks of GM crops are also increasing. Safe management for the development and production of GM crops is required according to Living Modified Organism Act in Korea. Planning about the methods, duration, and frequency of environmental monitoring is also required for commercial use of GM crops. GM Zoysia japonica Steud. (event name: JG21) expressing resistance to glufosinate-ammonium has been generated previously. By using gamma ray treatment to JG21 we also developed male sterility and dwarf Z. japonica (event name: JG21-MS). The objective of this study was to establish the monitoring system for environment release of JG21-MS. In this study we extracted RNA from JG21 and JG21-MS and conducted RAPD (random amplified polymorphic DNA) method to distinguish JG21 and JG21-MS.
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