Hematopoietic Stem Cell Transplant for VEXAS

Division Of Basic Sciences - Nci

Investigators

Abstract

In our trial "A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS Syndrome" NCT05027945 in August 2021 our research objectives are: To determine whether allogeneic hematopoietic stem cell transplantation (HSCT) results in sustained donor engraftment at day 100 and one-year post-HSCT. To determine whether allogeneic HSCT results in reversal of the clinical phenotype of VEXAS at one year and two years post-HSCT without requiring interval prednisone at greater than 0.5 mg/kg per day for reasons other than graft-versus-host disease (GVHD). Eligibility: Recipients ages 18-75 year-old with or without a somatic mutation in UBA1 who have: 1) the clinical phenotype for VEXAS with refractory cutaneous, pulmonary, musculoskeletal, and/or other recurrent acute inflammatory manifestations, and 2) require greater than 0.5 mg/kg per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion dependent anemia, transfusion dependent thrombocytopenia/platelets less than 75,000, neutropenia less than 1,000/uL) or myeloid neoplasm (by WHO criteria) or being intolerant or refractory to use steroids. Have an 8/8 or 7/8 HLA-matched related or unrelated donor, or a haploidentical related donor. Design: For Recipients with 8/8 HLA Matched Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 40 mg/m2 IV once daily for four days on days -6, -5, -4, -3 and Busulfan IV for three days on days -6, -5, -and -4 followed by HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Recipients with 7/8 HLA Matched Donors or Haploidentical Related Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 30 mg/m2 IV once daily for five days on days -6, -5, -4, -3, and -2, cyclophosphamide 14.5 mg/kg for two days on days -6 and -5, 200 cGy total body irradiation (TBI) on day -1, busulfan IV once daily for two days on days -4 and -3, and HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Post-Transplant GVHD Prophylaxis: Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and sirolimus from day +5 to approximately day +180. We also published a review on VEXAS this year. Since its discovery four years ago, several groups have identified pleomorphic clinical phenotypes, but few effective medical therapies exist which include Janus Kinase (JAK) inhibitors, interleukin inhibitors (IL-1 and IL-6), and hypomethylating agents. Prospective trials are lacking at this time and most patients remain corticosteroid dependent. VEXAS has a high morbidity from frequent life threatening inflammatory symptoms and risk of progression to hematological malignancies and has an overall survival of 50% at 10 years. Allogeneic stem cell transplant (allo-HCT) is a curative option for this disease caused by somatic mutations in the UBA1 gene. We outline the role of allo-HCT in treating patients with VEXAS syndrome, highlighting the outcomes from several single-institution studies and case reports. Prospective trials will be required to precisely define the role of allo-HCT in the management of VEXAS syndrome.