Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors.
Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors.
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Visilizumab 与他克莫司和甲氨蝶呤联合用于预防来自不匹配的无关供体的同种异体造血细胞移植后的 GvHD。
DOI：
10.1038/bmt.2016.330
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发表时间：
2017
影响因子：
4.8
通讯作者：
Anasetti,C
中科院分区：
文献类型：
--
作者：
Perez,LE;Fernandez,H;Ayala,E;Beato,F;Neuger,A;Pidala,J;Schell,MJ;Anasetti,C
Effective GvHD prevention after T-cell-replete, HLA-mismatched transplant is needed and has incentivized alternative approach development. 1 CD3-specific antibodies induce immunotolerance by rapidly clearing pathogenic T cells and promoting tolerance by sparing regulators. 2 Their success in experimental GvHD prevention, human autoimmune disease treatment and post-transplant rejection has established the basis to test visilizumab for GvHD prophylaxis in humans. 3, 4 Visilizumab (Abbott), an anti-CD3 monoclonal Ab with T-cell-receptor partial agonist ligand function, enhances activation-induced cell death (AICD), leading to T-cell apoptosis. 5, 6 We reasoned that visiluzimab, with safety and biological activity previously described in clinical studies of glucocorticoid-resistant GvHD treatment, 3, 4 could prevent GvHD by depleting activated T cells, yet allow immune reconstitution. Here, we report results from our prospective pilot trial using visilizumab for GvHD prevention in combination with tacrolimus (from day+ 4 at 0.02 mg/kg per day) and methotrexate (day+ 1 at 15 mg/m2 and then at 10 mg/m2 on days+ 3,+ 6 and+ 11) after unrelated donor allogeneic hematopoietic cell transplant (HCT) mismatched for 1 or 2 HLA-A,-B,-C or DRB1 loci. We used a Simon two-stage clinical trial design planned for 15 patients in stage 1. If serious toxicities were> 2%(defined as grade 4/5 reaction to visiluzimab, HHV6 encephalitis, or PTLD within 100 days or any grade 4/5 adverse event unexpected with HCT) and o20% had GvHD grade 3/4, patients would proceed to stage 2, with groups randomized 1: 1 with ATG or visiluzimab (30 per group). A G-CSF-mobilized peripheral blood CD34+ cell dose per kg of 5–10× 106 was used to minimize high-risk rejection compared with bone marrow. Conditioning regimen included fludarabine (40 mg/m2 over 4 days) and busulfan (145 mg/m2 IV over 4 days) to a steady-state concentration of 900±100 ng/mL (AUC of 5300±500 μmol/min). Prophylaxis with foscarnet (60mg/kg per day on day+ 1 until ANC> 500) followed by ganciclovir (5 mg/kg per day from ANC> 500 to day+ 100 if CMV-positive or to day+ 42 if CMV-negative) or valganciclovir (900 mg/day orally from ANC> 500 if able to tolerate oral administration) days+ 2 to+ 42 was used. 7 Eight patients (six women, two men) were enrolled (median age 46 years; range, 23–50). Three patients had AML, two had ALL, one had MDS, one had follicular NHL and one had severe aplastic anemia, with HLA-mismatched 6/8 (n= 2) or 7/8 (n= 6). We hypothesized that visilizumab⩾ 2000 ng/mL might be optimal to prevent GvHD. A single 3 mg/m2 visilizumab dose immediately resulted in goal levels 3 in the first 7 patients. Visilizumab depleted blood T cells for o14 days. Using a non-compartmental ELISA with a murine anti-M291 monoclonal Ab (PDL, Fremont, CA, USA), we determined mean maximal concentration (±sd) at 1–2 h of 1564±428 ng/mL and terminal half-life of 157±48 h (Figure 1a). We surmised that repeated Ab administration was necessary to produce T lymphopenia for> 14 days. Patient-8 received four 3 mg/m2 doses on days 0, 3, 10 and 17 before premature study closure due to lack of efficacy, 8 and a two-compartment model was used to analyze that patient’s pharmacokinetics (Figure 1b). All 8 patients had similar maximal concentration and alpha half-life parameter estimates; however, patient-8 showed a prolonged beta half-life (335 vs 187 h for multiple vs single dose) and a significantly slower clearance rate (0.02 vs 0.05 L/h for multiple vs single dose).Visiluzimab infusion toxicity was CTC grade 1–2 in six patients and grade 3 in two patients. Median time to …
