Stem Cell Transplant for VEXAS Syndrome

Overseen By Ajoy L Dias, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Multiple myeloma, HIV, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 33

54 Participants Needed

Trial Summary

What is the purpose of this trial?

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....

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, participants who are receiving any other investigational agents within the last 30 days before treatment initiation are excluded, which might imply some restrictions on concurrent medications.

What data supports the effectiveness of the treatment for VEXAS Syndrome?

The treatment involves allogeneic hematopoietic stem cell transplantation (Allo-HSCT), which has been shown to be effective in treating other blood-related conditions like acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) when combined with conditioning regimens such as busulfan and cyclophosphamide or total body irradiation and cyclophosphamide. These regimens help prepare the body for the transplant and have been associated with improved survival outcomes in these conditions. ^{1 2 3 4 5}

Is stem cell transplant generally safe for humans?

Stem cell transplants, including those using busulfan and cyclophosphamide, have been studied in various conditions like leukemia. While they can be effective, they may also cause side effects such as pulmonary toxicity (lung damage) and other adverse reactions, which vary depending on the specific treatment regimen used. ^{1 3 5 6 7}

How is the treatment for VEXAS Syndrome different from other treatments?

The treatment for VEXAS Syndrome using allogeneic hematopoietic stem cell transplant (Allo-HSCT) combined with busulfan, cyclophosphamide, and total body irradiation (TBI) is unique because it involves replacing the patient's diseased bone marrow with healthy stem cells from a donor, which is not a standard approach for this condition. This method is typically used for blood cancers and involves a rigorous pre-treatment regimen to prepare the body for the transplant. ^{1 2 3 4 8}

Research Team

Ajoy L Dias, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-75 with VEXAS Syndrome, significant health issues from the disease, and no success with standard treatments can join. They need a compatible stem cell donor, meet specific health criteria like good heart function and kidney clearance, agree to contraception use for one year post-transplant, and stay near NIH for at least 3 months after.

Inclusion Criteria

You have a condition or characteristic that is not related to the disease being studied.

- Serum conjugated bilirubin < 3.0 mg/dl; serum ALT and AST <= 5 times upper limit of normal.

I have lung symptoms like fluid in lungs or chest due to VEXAS.

Exclusion Criteria

Uncontrolled intercurrent illness or social situations (as determined by a licensed master social worker) that would limit compliance with study requirements.

I do not have any active infections that would make a transplant unsafe.

Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for exams and tests

Pre-Transplant Conditioning

Participants receive reduced intensity conditioning with fludarabine, busulfan, and possibly cyclophosphamide and total body irradiation, depending on donor match

6 days

Inpatient stay for conditioning regimen

Transplantation

Participants receive allogeneic hematopoietic stem cell transplant

1 day

Inpatient procedure

Post-Transplant Monitoring

Participants receive GVHD prophylaxis and are monitored for engraftment and complications

6 months

Weekly visits for 3 months, then regular follow-ups

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Visits at 30, 60, 100, 180, 210, 240, 300, and 360 days, then yearly

Treatment Details

Interventions

• Allogeneic HSCT
• Busulfan
• Busulfan test dose
• Cyclophosphamide
• Fludarabine
• Mycophenolate mofetil (MMF)
• Post-Transplant Cyclophosphamide (PTCY)
• Sirolimus
• Total Body Irradiation (TBI)

Trial Overview The trial is testing if blood stem cells from a donor can treat VEXAS Syndrome. Participants will undergo physical exams, imaging scans, bone marrow biopsy; receive chemotherapy drugs like Cyclophosphamide and Busulfan; possibly total body irradiation; then get the donor's stem cells through a catheter.

Participant Groups

Group I: Arm B Experimental Treatment 9 Interventions

Reduced intensity regimen (Fludarabine, low dose cyclophosphamide, 200cGY TBI, busulfan)+HSCT+GVHD prophylaxis

Group II: Arm A Experimental Treatment 7 Interventions

Reduced intensity regimen (Fludarabine, busulfan)+HSCT+GVHD prophylaxis

Allogeneic HSCT is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

Approved in United States as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia
• Hodgkin Lymphoma
• Non-Hodgkin Lymphoma

Approved in Canada as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

Approved in Japan as Allogeneic Hematopoietic Stem Cell Transplant for:

• Acute Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Myeloid Leukemia
• Myelodysplastic Syndromes
• Primary Immunodeficiency Diseases
• Severe Combined Immunodeficiency
• Sickle Cell Disease
• Thalassemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 119 adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation, the TBI/Cy conditioning regimen resulted in a median overall survival of 11 months, compared to 6.2 months for the Bu/Cy regimen.

Although both conditioning regimens showed no statistically significant differences in overall survival and disease-free survival, the Bu/Cy regimen was associated with a higher risk of relapse, indicating a potential disadvantage in using this non-TBI approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation. Abdelaty, MM., Gawaly, A., Fathy, GM., et al.[2021]

In a study of 631 pediatric patients with acute myeloid leukemia undergoing hematopoietic stem cell transplantation, the conditioning regimen of busulfan, cyclophosphamide, and melphalan (BuCyMel) resulted in significantly lower relapse rates and improved overall survival compared to total body irradiation and cyclophosphamide (TBI-Cy) and busulfan with cyclophosphamide (BuCy).

Patients receiving BuCyMel had a 5-year relapse rate of 14.7% and an overall survival rate of 76.6%, while those receiving BuCy and TBI-Cy had higher relapse rates (31.5% and 30%, respectively) and similar overall survival rates (64% for both), indicating that BuCyMel is a more effective conditioning regimen for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation. Lucchini, G., Labopin, M., Beohou, E., et al.[2018]

In a meta-analysis of 15 randomized controlled trials involving 10,160 pediatric patients, total body irradiation plus cyclophosphamide (TBI/CY) was found to be more effective than busulfan plus cyclophosphamide (BU/CY) in reducing transplant failure rates and improving long-term disease-free survival rates.

The TBI/CY regimen also demonstrated a lower incidence of adverse reactions compared to the BU/CY regimen, indicating it may be a safer option for pediatric hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. Wang, X., Mu, D., Geng, A., et al.[2023]

In a study of 77 patients undergoing haploidentical stem cell transplantation for hematologic malignancies, the conditioning regimen with busulfan plus cyclophosphamide (BU+CY) resulted in a significantly better 3-year overall survival rate of 56.4% compared to 31.6% for total body irradiation plus cyclophosphamide (TBI+CY).

The BU+CY regimen also demonstrated a lower short-term relapse rate (2.56% at 1 year) compared to TBI+CY (26.67%), while both regimens had similar rates of acute graft-versus-host disease (GVHD), but TBI+CY was associated with a higher incidence of chronic GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of BU and CY versus TBI and CY as conditioning regimens on the efficacy of haploidentical stem cell transplantation in patients with hematologic malignancy]. Shao, Q., Han, D., Liu, D., et al.[2014]

In a randomized phase III trial involving 550 adult patients with standard-risk B-cell acute lymphoblastic leukemia (ALL), the busulfan plus cyclophosphamide (BuCy) regimen demonstrated noninferior overall survival compared to total body irradiation plus cyclophosphamide (TBI-Cy), with 2-year survival rates of 76.6% and 79.4%, respectively.

Both treatment regimens showed similar rates of relapse (20.2% for BuCy vs. 18.4% for TBI-Cy) and nonrelapse mortality (11.0% for both), indicating that BuCy is as safe and effective as TBI-Cy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial. Zhang, H., Fan, Z., Huang, F., et al.[2023]

Nonmyeloablative doses of parenteral busulfan demonstrated significant hematologic toxicity, particularly during the second to third week after administration, but were less toxic than myeloablative total body irradiation (TBI).

Busulfan facilitated over 70% donor leukocyte engraftment with a dose of just 20 mg/kg, and this level of engraftment was achievable even when hematopoietic stem cells were infused up to 20 days after busulfan treatment, indicating a flexible time window for HSC infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose parenteral busulfan provides an extended window for the infusion of hematopoietic stem cells in murine hosts. Hsieh, MM., Langemeijer, S., Wynter, A., et al.[2019]

In a study of 311 pediatric patients who underwent allogeneic hematopoietic stem cell transplantation, the incidence of severe pulmonary toxicity (grade ≥3) was similar between those receiving total body irradiation (TBI) and those receiving busulfan-based conditioning, with rates of 29.2% and 34.7% respectively at 2 years.

Factors such as older age, preexisting pulmonary conditions, and the development of acute or chronic graft-versus-host disease (GVHD) were linked to higher rates of severe pulmonary toxicity, which in turn was associated with lower overall survival rates (81.1% vs. 61.5% at 2 years).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients. Liu, KX., Poux, N., Shin, KY., et al.[2022]

In a study of 50 patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) undergoing allogeneic bone marrow transplantation, the conditioning regimen of busulfan, cyclophosphamide, and total body irradiation resulted in a 5-year leukemia-free survival rate of 85% for patients in first remission (group I) compared to 50% for those with advanced disease (group II).

Severe regimen-related toxicities occurred in 16% of patients, primarily affecting the lungs, liver, and heart, indicating that while the treatment is effective, there are significant risks associated with the conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia. Hirabayashi, N., Goto, S., Ishii, M., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Effect of BU and CY versus TBI and CY as conditioning regimens on the efficacy of haploidentical stem cell transplantation in patients with hematologic malignancy]. [2014]

5. United States pubmed.ncbi.nlm.nih.gov

Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Low-dose parenteral busulfan provides an extended window for the infusion of hematopoietic stem cells in murine hosts. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Busulfan, cyclophosphamide and total body irradiation as conditioning for allogeneic bone marrow transplantation for acute and chronic myeloid leukemia. [2013]