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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether stem cell transplants from a donor (Allogeneic Hematopoietic Stem Cell Transplant, Allogeneic HSCT) can help treat VEXAS Syndrome, a condition causing serious health issues due to inflammation and low blood cell counts. Researchers aim to determine if this approach can improve symptoms and overall health in affected individuals. Those with VEXAS Syndrome experiencing major health issues, for whom standard treatments have failed or are unavailable, might be suitable candidates. Participants will undergo various medical tests and treatments, including drugs and possibly radiation, to prepare for and receive the transplant. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that allogeneic hematopoietic stem cell transplants (HSCT) are currently the only potential cure for VEXAS syndrome. Studies indicate that patients can have positive outcomes, but risks are involved. In one study, 81.8% of patients survived after receiving the treatment. However, complications like infections and graft-versus-host disease (GVHD), where donor cells attack the patient's body, were common. Specifically, 56.3% experienced some form of GVHD, and 37.5% faced infections.

Fludarabine, a drug used to prepare the body for transplants, has shown success in treating VEXAS syndrome in some cases, though detailed safety data remains limited.

Busulfan, another drug used in the process, has been linked to serious side effects like lung issues in some patients, but it remains an important part of the transplant procedure.

Cyclophosphamide is also part of this treatment. While specific safety data for VEXAS is limited, it is widely used in other transplants and carries known risks like infection and organ damage.

Total body irradiation (TBI) eliminates diseased cells before the transplant. While it aids transplant success, it can cause side effects like fatigue and increased risk of infection.

Researchers are currently studying this treatment to determine its effectiveness and safety. Some safety data is available, but ongoing research aims to better understand the risks and outcomes. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for VEXAS syndrome because they involve innovative uses of allogeneic hematopoietic stem cell transplantation (HSCT) combined with reduced intensity regimens. Unlike traditional treatments that focus on managing symptoms with corticosteroids and immunosuppressants, these regimens use a combination of drugs like fludarabine, busulfan, and cyclophosphamide, along with total body irradiation, to prepare the body for the transplant. This approach aims to offer a more durable and potentially curative solution by directly addressing the underlying hematopoietic disorders. By incorporating graft-versus-host disease (GVHD) prophylaxis, these treatments also work to minimize complications associated with stem cell transplants, making the procedure safer and more effective.

What evidence suggests that this trial's treatments could be effective for VEXAS Syndrome?

Research has shown that allogeneic hematopoietic stem cell transplantation (HSCT) offers promising results for treating VEXAS Syndrome. In this trial, participants will be assigned to different treatment arms. Arm A will receive a reduced intensity regimen with Fludarabine and Busulfan, followed by HSCT and GVHD prophylaxis. Arm B will receive a reduced intensity regimen with Fludarabine, low-dose Cyclophosphamide, 200cGY TBI, and Busulfan, followed by HSCT and GVHD prophylaxis. Studies have found that patients generally survive well, and the risk of graft-versus-host disease, where new cells attack the body, is manageable. These treatments aim to replace unhealthy cells with healthy donor cells, offering hope for improvement in VEXAS symptoms. ^{1 3 4 6 7}

Who Is on the Research Team?

Ajoy L Dias, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11489273/

Allogenic haematopoietic stem cell transplantation in VEXAS The purpose of this review is to provide clinicians with current data, raising awareness about the risks and benefits of allo-HSCT. This is of ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05027945

NCT05027945 | A Phase II Study of Allogeneic ... A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) Syndrome.

3. link.springer.com link.springer.com/article/10.1007/s00277-024-05942-2

Role of allogeneic hematopoietic cell transplantation in ... Here we outline the role of allo-HCT in treating patients with VEXAS syndrome, highlighting the outcomes from several single-institution studies and case ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1354/502722/Prevalence-and-Outcome-of-Vexas-Syndrome-in

Prevalence and Outcome of Vexas Syndrome in Unrelated ... Prevalence and outcome of vexas syndrome in unrelated hematopoietic stem cell transplantation available.

5. astctjournal.org astctjournal.org/article/S2666-6367(23)01926-7/fulltext

Outcomes of Allogeneic Hematopoietic Stem Cell ... Allogeneic HSCT has shown promising results in treating patients with VEXAS syndrome with good overall survival and acceptable incidence of graft versus host ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/708/504234/Allogeneic-Hematopoietic-Cell-Transplantation-for

Allogeneic Hematopoietic Cell Transplantation for Vexas ... As few literature reports have described the successful use of transplant, we here report the outcomes of patients with VEXAS in a multicenter ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123053120

Allogeneic Hematopoietic Cell Transplantation for Vexas ... Allo-HCT remains the only curative option for MDS and is used to treat rheumatologic conditions refractory to conventional treatments.