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Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors

Bone Marrow Transplantation volume 52, pages 627–629 (2017)Cite this article

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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 <20% 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 (60 mg/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

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Acknowledgements

We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance. This work was supported by NIH grant (9R01CA132197, PI: Anasetti) from the National Cancer Institute. This work has also been supported in part by the Translational Research Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292).

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Authors and Affiliations

  1. Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    L E Perez, H Fernandez, E Ayala, F Beato, J Pidala & C Anasetti

  2. Department of Oncologic Sciences, H. Lee Moffitt Cancer Center and Research Institute/University of South Florida College of Medicine, Tampa, FL, USA

    L E Perez, H Fernandez, E Ayala, J Pidala & C Anasetti

  3. Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    A Neuger

  4. Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    M J Schell

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Correspondence to L E Perez.

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Perez, L., Fernandez, H., Ayala, E. et al. Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors. Bone Marrow Transplant 52, 627–629 (2017). https://doi.org/10.1038/bmt.2016.330

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