Stem Cell Transplant Conditioning for SCID

(CSIDE Trial)

Recruiting at 55 trial locations

Overseen By CSIDE Study Team

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Center for International Blood and Marrow Transplant Research

Disqualifiers: Serious infections, HIV, HTLV, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

56 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Busulfan in the treatment of SCID?

Research shows that low-exposure busulfan can be effective in achieving sufficient immune system recovery in over half of SCID patients undergoing stem cell transplants, with most patients surviving long-term. Additionally, intravenous busulfan has been shown to result in high rates of successful engraftment and promising survival outcomes in pediatric patients undergoing stem cell transplants. ^{1 2 3 4 5}

Is busulfan safe for use in stem cell transplant conditioning for SCID and other conditions?

Busulfan, used in stem cell transplant conditioning, is generally well tolerated in humans, with studies showing it can be safely used in both children and adults for various conditions. While some mild to moderate side effects like elevated liver enzymes and veno-occlusive disease (a liver condition) have been reported, these are usually manageable and resolve over time. Overall, busulfan has been associated with good survival outcomes and low transplant-related mortality. ^{1 2 4 6 7}

How does the drug Busulfan differ from other treatments for SCID?

Busulfan is unique in its use as a conditioning agent before stem cell transplantation for SCID, as it helps prepare the body by eradicating diseased cells and suppressing immune reactions. Unlike traditional irradiation methods, Busulfan can be administered intravenously, which avoids issues with absorption and may reduce toxicity, making it potentially safer for young patients with SCID. ^{4 7 8 9 10}

What is the purpose of this trial?

The investigators want to study if lower doses of chemotherapy will help babies with SCID to achieve good immunity with less short and long-term risks of complications after transplantation. This trial identifies babies with types of immune deficiencies that are most likely to succeed with this approach and offers them transplant early in life before they get severe infections or later if their infections are under control. It includes only patients receiving unrelated or mismatched related donor transplants. The study will test if patients receiving transplant using either a low dose busulfan or a medium dose busulfan will have immune recovery of both T and B cells, measured by the ability to respond to immunizations after transplant. The exact regimen depends on the subtype of SCID the patient has. Donors used for transplant must be unrelated or half-matched related (haploidentical) donors, and peripheral blood stem cells must be used. To minimize the chance of graft-versus-host disease (GVHD), the stem cells will have most, but not all, of the T cells removed, using a newer, experimental approach of a well-established technology. Once the stem cell transplant is completed, patients will be followed for 3 years. Approximately 9-18 months after the transplant, vaccinations will be administered, and a blood test measuring whether your child's body has responded to the vaccine will be collected.

Research Team

Michael Pulsipher, MD

Principal Investigator

Children's Hospital Los Angeles

Sung-Yun Pai, MD

Principal Investigator

National Institutes of Health (NIH)

Eligibility Criteria

This trial is for babies aged 0-2 years with Severe Combined Immunodeficiency (SCID), including typical SCID, leaky SCID, or Omenn syndrome. They should have specific immune cell counts and gene mutations related to SCID. Babies must not have serious infections at enrollment and need a suitable unrelated or half-matched related donor for stem cell transplant.

Inclusion Criteria

My condition is diagnosed as typical SCID.

My body does not have any T cells from my mother.

My kidney function is good, based on tests.

Exclusion Criteria

I had a fungal infection confirmed by a test but have completed at least 14 days of treatment.

I do not have any serious or life-threatening infections.

My skin infection has fully healed after finishing at least 10 days of antibiotics.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a busulfan-based preparative regimen targeted at specific exposure levels, followed by TCRαβ+/CD19+ depleted stem cell transplantation.

6 weeks

Multiple visits for treatment and monitoring

Follow-up

Participants are monitored for immune reconstitution, engraftment, and post-transplant complications.

3 years

Regular visits at defined intervals for clinical and laboratory assessments

Vaccination and Immune Response Assessment

Vaccinations are administered approximately 9-18 months post-transplant, and immune response is assessed.

18 months

Treatment Details

Interventions

• Busulfan
• Cell processing for TCRαβ+/CD19+ depletion

Trial Overview The study tests whether low or medium doses of busulfan chemotherapy can help infants with SCID develop immunity after a stem cell transplant from an unrelated or half-matched donor. The transplanted cells undergo special processing to reduce the risk of graft-versus-host disease.

Participant Groups

Group I: Medium Dose Busulfan Experimental Treatment 2 Interventions

Busulfan based preparative regimen targeted at area-under-the-curve (cAUC) exposure of 55-65 mg\*h/L. Randomization between the two dose levels will be done separately in each genotype stratum (RAG1/RAG2 and IL2RG/JAK3), using permuted blocks.

Group II: Low Dose Busulfan Experimental Treatment 2 Interventions

Busulfan based preparative regimen targeted at area-under-the-curve (cAUC) exposure of 25-35 mg\*h/L . Randomization between the two dose levels will be done separately in each genotype stratum (RAG1/RAG2 and IL2RG/JAK3), using permuted blocks.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

Center for International Blood and Marrow Transplant Research

Lead Sponsor

Trials

40

Recruited

200,190,000+

Michael Pulsipher

Lead Sponsor

Trials

1

Recruited

60+

Michael Pulsipher, MD

Lead Sponsor

Trials

5

Recruited

240+

Findings from Research

In a study of 10 patients with severe combined immunodeficiency (SCID) undergoing hematopoietic cell transplantation (HCT) with low-exposure busulfan, all patients survived, and over 50% achieved full T and B cell reconstitution despite varying levels of myeloid chimerism.

The study found that while low-exposure busulfan was well tolerated and led to high initial myeloid chimerism, factors beyond busulfan exposure influenced long-term chimerism and immune recovery, indicating a complex interplay in achieving successful outcomes post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency. Dvorak, CC., Long-Boyle, J., Dara, J., et al.[2020]

Intravenous busulfan, used as a conditioning treatment before hematopoietic stem cell transplantation in pediatric patients, effectively achieves targeted therapeutic plasma levels, leading to high rates of sustained engraftment and low transplant-related mortality.

This formulation is well tolerated, with fewer severe adverse effects compared to oral busulfan, particularly showing a lower incidence of severe hepatic veno-occlusive disease (HVOD) and organ toxicity, making it a safer option for young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. Hoy, SM., Lyseng-Williamson, KA.[2018]

In a study of 101 pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, treosulfan-based conditioning regimens were associated with significantly lower rates of grade II-IV acute graft-versus-host disease (GvHD) compared to busulfan-based regimens (15% vs 39%).

Despite busulfan being the more commonly used conditioning agent, treosulfan is gaining popularity, particularly for younger patients, and both regimens showed no significant differences in overall survival or transplant-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of treosulfan versus busulfan-based conditioning in pediatric patients. Olivas-Mazón, R., Bueno, D., Sisinni, L., et al.[2022]

Combining busulfan with stem-cell niche-directed agents like G-CSF or plerixafor may improve the efficacy of conditioning regimens for hematopoietic stem cell transplantation, potentially leading to better immune recovery in patients, especially those with severe combined immunodeficiency (SCID).

The study found that busulfan conditioning resulted in comparable immune recovery to total body irradiation, with better T cell reconstitution observed in both humanized NSG mice and SCID models, suggesting a safer alternative to traditional conditioning methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation. Garcia-Perez, L., van Roon, L., Schilham, MW., et al.[2021]

High dosage busulfan is commonly used in preparative regimens for hematopoietic stem cell transplantation (HSCT), but its effectiveness and safety can vary significantly based on individual patient factors, particularly age and disease type.

Therapeutic drug monitoring of busulfan is crucial, as achieving specific plasma concentration targets (Css) can improve engraftment rates and reduce the risk of complications like hepatic veno-occlusive disease, especially in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma concentration monitoring of busulfan: does it improve clinical outcome? McCune, JS., Gibbs, JP., Slattery, JT.[2018]

In a study of 97 children with Hurler syndrome who underwent cord blood transplantation (CBT) between 2004 and 2016, the five-year overall survival rate was 88%, indicating a high efficacy of the treatment.

The study found that different conditioning regimens affected survival outcomes, with the best overall survival (95%) observed in patients receiving a combination of busulfan, fludarabine, and antithymocyte globulin, highlighting the importance of conditioning strategy in improving graft success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome. Lum, SH., Orchard, PJ., Lund, TC., et al.[2021]

In a study of 27 patients with sickle cell disease undergoing matched sibling donor hematopoietic stem cell transplantation, targeted busulfan therapy led to successful engraftment in all cases, with 84% achieving full donor chimerism.

Targeting a higher busulfan area under the curve (AUC) was associated with better engraftment outcomes, as lower AUC levels correlated with partial donor chimerism, while the incidence of hepatic veno-occlusive disease was not linked to busulfan AUC levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease. McPherson, ME., Hutcherson, D., Olson, E., et al.[2013]

This study identified that different strains of genetically diverse mice exhibit varying susceptibilities to busulfan (BU)-induced injury in hematopoietic stem cells (HSCs), which is crucial for the effectiveness of BU as a conditioning agent before stem cell transplantation.

Urinary protein analysis revealed that angiotensin-converting enzyme may serve as a potential biomarker for predicting HSC susceptibility to BU, suggesting that urine protein levels can reflect the risk of HSC injury from BU treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Screening for urinary markers predicting hematopoietic stem cell injury induced by busulfan using genetically diverse mice. Sun, Y., Guan, B., Liu, X., et al.[2023]

A single dose of Busilvex (busulfan) at 35 mg/kg can achieve similar levels of human hematopoietic stem cell engraftment in NOD/SCID mice as traditional sublethal irradiation (3.5 Gy).

Using two doses of 25 mg/kg of busulfan reduced toxicity and increased chimerism, suggesting that busulfan can be a safer alternative to irradiation for conditioning in stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human cell engraftment after busulfan or irradiation conditioning of NOD/SCID mice. Robert-Richard, E., Ged, C., Ortet, J., et al.[2013]

Intravenous busulfan and cyclophosphamide conditioning before allogeneic peripheral blood stem cell transplantation resulted in successful hematopoietic engraftment in all 15 leukemia patients, with a median engraftment time of 12 days for neutrophils and 15 days for platelets.

The intravenous method significantly reduced the rates of hepatic damage and oral mucositis compared to oral administration, indicating a safer profile while maintaining similar efficacy in hematopoietic reconstruction and acute graft-versus-host disease rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and toxicity of intravenous busulfan-based conditioning before allogeneic peripheral blood stem cell transplantation for leukemia]. Tong, XZ., Xu, DR., Zou, WY., et al.[2015]

References

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

Low Exposure Busulfan Conditioning to Achieve Sufficient Multilineage Chimerism in Patients with Severe Combined Immunodeficiency. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. [2018]

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

A retrospective study of treosulfan versus busulfan-based conditioning in pediatric patients. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Plasma concentration monitoring of busulfan: does it improve clinical outcome? [2018]

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

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease. [2013]

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

Screening for urinary markers predicting hematopoietic stem cell injury induced by busulfan using genetically diverse mice. [2023]

9. Italy pubmed.ncbi.nlm.nih.gov

Human cell engraftment after busulfan or irradiation conditioning of NOD/SCID mice. [2013]

10. China pubmed.ncbi.nlm.nih.gov

[Efficacy and toxicity of intravenous busulfan-based conditioning before allogeneic peripheral blood stem cell transplantation for leukemia]. [2015]