Stem Cell Transplant Conditioning for SCID

(CSIDE Trial)

Not currently recruiting at 58 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if lower doses of chemotherapy can help babies with Severe Combined Immunodeficiency (SCID) develop strong immune systems after a stem cell transplant, with fewer risks. The study tests two different doses of busulfan (also known as Busulfex or Myleran) to identify which dose better supports immune recovery, focusing on T and B cells, which are crucial for fighting infections. Babies with certain types of SCID and no matched sibling donors may be suitable candidates, particularly if they haven't had serious infections or if their infections are under control. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant findings in SCID treatment.

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.

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

Research has shown that busulfan, a chemotherapy drug used in stem cell transplants, has been studied at various dosage levels. One study used a low dose of busulfan to prepare children with severe combined immunodeficiency (SCID) for a transplant. The results indicated that this method helped their immune systems recover without causing serious problems.

Another study found that the amount of busulfan patients received affected their outcomes after the transplant. Although patients experienced different effects based on their dosage, the drug was generally well-tolerated. The most common side effects were manageable and included nausea and temporary drops in blood cell counts, which are typical with chemotherapy.

Overall, busulfan has been safely used in many patients, and its side effects are well-known and usually controllable. This suggests that the treatment is generally safe for use in clinical trials like the one under consideration. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the use of Busulfan in stem cell transplant conditioning for Severe Combined Immunodeficiency (SCID) because it offers a targeted approach to preparing patients for transplants. Unlike standard treatments that might use higher doses of chemotherapy indiscriminately, this trial explores the benefits of precisely calibrated doses of Busulfan, tailored to the patient’s genetic profile (RAG1/RAG2 and IL2RG/JAK3). The use of low and medium doses aims to minimize the side effects of conditioning therapy while optimizing transplant success. By focusing on specific area-under-the-curve (cAUC) exposure levels, this approach promises a more personalized and potentially safer preparative regimen for SCID patients.

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

This trial will compare low and medium doses of busulfan as part of the conditioning regimen for stem cell transplants in patients with severe combined immunodeficiency (SCID). Research has shown that busulfan can improve outcomes by preparing the body for a stem cell transplant. Studies have found that different doses of busulfan can lead to good recovery of the immune system. Specifically, busulfan use is linked to better chances of living without complications and more successful integration of donor cells. Previous patients experienced low rates of graft-versus-host disease (GVHD), a common issue after transplants. These findings suggest that busulfan can help develop a working immune system in babies with SCID, making it a promising treatment option. ^{1 6 7 8 9}

Who Is on the Research Team?

Michael Pulsipher, MD

Principal Investigator

Children's Hospital Los Angeles

Sung-Yun Pai, MD

Principal Investigator

National Institutes of Health (NIH)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11470247/

Association of busulfan exposure and outcomes after HCT ... Key Points. •. In patients with IEI, improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUC of 80 mg × h/L.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666636720300506

The Relationship Between Busulfan Exposure and ... The rates of both acute and chronic GVHD were very low, with three patients (5%) experiencing grade 2 aGVHD and two patients (5%) experiencing moderate cGVHD ( ...

3. nationwidechildrens.org nationwidechildrens.org/research/clinical-research/cell-therapy/pbmtc-nmd1801

Infants with Severe Combined Immunodeficiency (SCID) CSIDE: A Phase II Trial Comparing Low and Moderate Busulfan Doses in Infants with Severe Combined Immunodeficiency (SCID) Undergoing TCRαβ+/CD19+ Depleted ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7384257/

Low Exposure Busulfan Conditioning to Achieve Sufficient ... However, other factors beyond busulfan exposure may also play critical roles in determining long-term myeloid chimerism and full T and B cell reconstitution.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1815408

Lentiviral Gene Therapy Combined with Low-Dose ... The primary objectives of the trial were to assess the safety, feasibility, and efficacy of lentiviral gene transfer in infants with newly ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03619551

NCT03619551 | Conditioning SCID Infants Diagnosed Early These data will be used to measure the outcomes ... A Randomized Trial of Low Versus Moderate Exposure Busulfan for Infants With Severe Combined Immunodeficiency ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7529956/

Busulfan Pharmacokinetics in ADA SCID Gene Therapy The pharmacokinetics of low dose busulfan (BU) were investigated as a non-myeloablative conditioning regimen for autologous gene therapy (GT) in pediatric ...

8. ashpublications.org ashpublications.org/blood/article/140/7/685/485484/Outcomes-following-treatment-for-ADA-deficient

Outcomes following treatment for ADA-deficient severe ... Infection was the most common reason to suspect ADA deficiency (57.5%), followed by a positive SCID NBS result (23.6%) and family history (18.9%).

9. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT03619551

Conditioning SCID Infants Diagnosed Early The study will test if patients receiving transplant using either a low dose busulfan or a medium dose busulfan will have immune recovery of ...