NCT05027945

A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 54 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Background: Allogeneic hematopoietic stem cell transplant involves taking blood stem cells from a donor and giving them to a recipient. The transplants are used to treat certain diseases and cancers. Researchers want to see if the transplant can treat VEXAS Syndrome. Objective: To see if stem cell transplants can be successfully performed in people with VEXAS and even improve the disease. Eligibility: People ages 18-75 who have VEXAS Syndrome that has caused significant health problems and standard treatment either has not worked or is not available. Design: Participants will be screened with: Physical exam Medical review Blood and urine tests Heart and lung function tests Bone marrow biopsy Participants will have a chest x-ray. They will have an imaging scan of the head, chest, abdomen, pelvis, and sinus. They will have a bone density scan. They will have a dental exam and eye exam. They will meet with specialists. They will repeat some screening tests. Participants will be admitted to the NIH hospital. They have a central venous catheter put into a vein in the chest or neck. They will receive drugs to prepare their bone marrow for the transplant. They may have total body irradiation. They will receive the donor stem cells through the catheter. They will get other drugs to prevent complications and infections. After discharge, they must stay in the DC area for 3 months for weekly study visits. Participants will have study visits 30, 60, 100, 180, 210, 240, 300, and 360 days later. After that, they will have yearly visits for 2 years and then be contacted yearly by phone....

Detailed description

Background: * In 2019, investigators at the National Institutes of Health defined a new disease syndrome named VEXAS: Vacuoles in bone marrow cells, E1 enzyme mutations, X-linked, Autoinflammatory, Somatic syndrome. This syndrome is characterized by inflammatory and hematologic features and is frequently accompanied by marrow dysplasia, progressive bone marrow failure, and in some cases, the development of overt myelodysplastic syndrome (MDS) or other myeloid neoplasms. Somatic mutations are present at methionine 41 in UBA1, an X-linked gene encoding the major E1 ubiquitin activating enzyme that initiates the majority of cellular ubiquitylation. * The inflammatory features of VEXAS include fever, pulmonary infiltrates, skin lesions, ear and nose chondritis, musculoskeletal involvement, and elevated inflammatory markers. The hematologic features include cytopenia, characteristic vacuoles in myeloid and erythroid precursors cells, and dysplastic bone marrow. Patients included in the initial description of the syndrome fulfill clinical or classification criteria for both inflammatory diseases (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis) and hematologic conditions (MDS, myeloid neoplasms or plasma cell dyscrasia). The inflammatory features of VEXAS are refractory to treatment other than high doses of glucocorticoids. Increased mortality and frequent morbidity are common in VEXAS secondary to the disease and treatment-related complications. The clinical manifestations of VEXAS are time-dependent. Systemic inflammation typically precedes progressive bone marrow failure with or without the development of hematologic malignancies leading to death. Escalating doses of glucocorticoids are typically administered to control the refractory, progressive features of systemic inflammation. Worsening cytopenias often require transfusion support. * The discovery of hematologic mosaicism as the genetic driver of rheumatologic/hematologic syndromes defines a novel class of diseases, termed hematoinflammatory diseases (HINDS), and it raises the possibility that therapies aimed at eradicating these clones may be efficacious in this patient population. Objectives: Primary Objectives: * 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 \>= 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 \>= 0.5 mg/kg per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion dependent anemia, transfusion dependent thrombocytopenia/platelets \<75,000, neutropenia \<1,000/microL) 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/m\^2 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 and/or real time PKs and will be targeted to AUC of 2500-3500 microMol\*min/L (31-43 mg\*h/L) (2.5 - 2.8 mg/kg IV may be used on D-6 with real time PK for D-5 and D-4). -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/m\^2 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 and/or real time PKs and will be targeted to an AUC of 2500-3500 microMol\*min/L (21-29 mg\*h/L) (2.5 -2.8 mg/kg IV per day may be used on D-4 with real time PK for D-3). -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 +45 and tacrolimus from day +5 to approximately day +180.

Conditions

• Immunodeficiency
• Hematopoietic Stem Cell Transplantation

Interventions

Type	Name	Description
PROCEDURE	Allogeneic HSCT	stem cell transplant on day 0
DRUG	Busulfan test dose	0.8 mg/kg IV over 2 hours. May be skipped if real-time PKs are done during conditioning.
DRUG	Mycophenolate mofetil (MMF)	Mycophenolate mofetil (MMF): 15 mg/kg IV over 2 hours BID starting on day +5 until approximately day +35 (+/-2 days)
DRUG	Tacrolimus	Starting on day +5, start at 0.02 mg/kg IV continuous infusion over 24 hours until day +180 and titrated to trough levels of 5-15 mg/ml.
DRUG	Busulfan	AUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 8/8 Matched Related or Unrelated Donor Busulfan dose will be on days -6, -5, and -4 For 7/8 Matched Related or Unrelated or Haploidentical Donor Busulfan dose will be on days -4 and -3
RADIATION	Total Body Irradiation (TBI)	For 7/8 Matched Related or Unrelated or Haploidentical Donor, 200cGy on day -1
DRUG	Fludarabine	40 mg/m2 IV over 30 mins daily For 8/8 Matched Related or Unrelated Donor Fludarabine dose will be on days -6, -5, -4, and -3 For 7/8 Matched Related or Unrelated or Haploidentical Donor Fludarabine dose will be on days -6, -5, -4, -3, and -2
DRUG	Cyclophosphamide (CY)	For 7/8 Matched Related or Unrelated or Haploidentical Donor, prior to transplant 14.5 mg/kg IV daily on days -6 and -5
DRUG	Post-Transplant Cyclophosphamide (PTCY)	Post-Transplant Cyclophosphamide: 50 mg/kg IV daily over 2 hours on days +3 and +4, dosed according to ideal body weight

Timeline

• Start date: 2023-02-23
• Primary completion: 2026-07-01
• Completion: 2026-07-01
• First posted: 2021-08-31
• Last updated: 2026-04-02

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study