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....
Age >= 18-year-old and <= 75-year-old
Availability of an 8/8 or 7/8 HLA-matched related or unrelated donor, or a haploidentical related donor
Karnofsky performance status of >= 40%
Left ventricular ejection fraction > 35%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to treatment initiation.
HCT Comorbidity Index >= 5. Note: Comorbidities that are specifically addressed in the inclusion criteria will not be included in the calculation of HCT-CI score.
Participants with multiple myeloma. Note: participants with low risk smoldering multiple myeloma or monoclonal gammopathy of unknown significance will not be excluded)
Participants who are receiving any other investigational agents within the last 30 days before treatment initiation.
HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
Parallel
Allogeneic HSCT
Procedure/Surgerystem cell transplant on day 0
Busulfan test dose
Drug0.8 mg/kg IV over 2 hours. May be skipped if real-time PKs are done during conditioning.
Mycophenolate mofetil (MMF)
DrugMycophenolate mofetil (MMF): 15 mg/kg IV over 2 hours BID starting on day +5 until approximately day +35 (+/-2 days)
Tacrolimus
DrugStarting 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.
Busulfan
DrugAUC 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
Total Body Irradiation (TBI)
RadiationFor 7/8 Matched Related or Unrelated or Haploidentical Donor, 200cGy on day -1
Fludarabine
Drug40 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
Cyclophosphamide (CY)
DrugFor 7/8 Matched Related or Unrelated or Haploidentical Donor, prior to transplant 14.5 mg/kg IV daily on days -6 and -5
Post-Transplant Cyclophosphamide (PTCY)
DrugPost-Transplant Cyclophosphamide: 50 mg/kg IV daily over 2 hours on days +3 and +4, dosed according to ideal body weight
Reversal of clinical phenotype of VEXAS
fraction of subjects who achieve complete clinical response without use of additional glucocorticoid therapy and without steroid-sparing therapy
Sustained donor engraftment
defined as neutrophil recovery with ANC = 500/mm\^3 for 3 consecutive days associated with \> 50% T-cell and myeloid cell donor chimerism at day 100 and one year post-HSCT
Safety of allo HSCT
Transplant-related toxicity will include if allogeneic HSCT in participants with VEXAS results in the absence of secondary graft failure. The fraction of participants who have secondary graft failure will be reported along with a 95% two-sided confidence interval, separately by cohort.
incidence of grade III-IV acute GVHD and moderate to severe chronic GVHD
group comparison of participants with an 8/8 HLA matched related or unrelated donor compared to group of participants with 7/8 HLA matched related or unrelated donor or haploidentical donor. Reported with 95% two-sided confidence intervals. The fractions will also be reported separately by cohort using simple estimates along with 95% two-sided confidence intervals. In addition cumulative incidence curves along with a 95% two-sided confidence interval.
Overall survival and event free survival
Overall and event free survival will be determined using Using the Kaplan-Meier method, along with the median value and the 95% confidence interval at the median, separately by cohort.
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