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.
