Haplocompatible Transplant for Severe Combined Immunodeficiency

Overseen By Ewelina Mamcarz, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: HIV, Active malignancy, Organ failure, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to help infants with severe combined immunodeficiency (SCID) develop a healthy immune system. SCID is a serious condition where babies lack enough functioning immune cells to fight infections, posing life-threatening risks. The study tests a special type of cell transplant (haplocompatible transplant) that could quickly restore a baby's immune defenses without harmful side effects. Infants with SCID who lack a matched sibling donor might be suitable for this trial. As a Phase 1/Phase 2 trial, the research focuses on understanding how the treatment works and measuring its effectiveness in an initial, smaller group of infants.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their 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 shows that each treatment in this trial presents different safety concerns. Here is a breakdown:

1. **Busulfan**: Studies with patients who have blood cancers have shown that busulfan can reduce bone marrow activity, leading to fewer blood cells. This condition, called myelosuppression, can take from a month to two years to recover from. During this time, patients might be at risk for infections or bleeding.

2. **Fludarabine**: High doses of fludarabine can cause serious nerve damage, potentially affecting mental functions and, in severe cases, leading to blindness. Careful use is important, especially in individuals who are not in optimal health.

3. **Thiotepa**: Thiotepa may increase the risk of cancer. In studies, high doses were harmful to rabbit fetuses, suggesting potential risks for unborn children.

4. **Donor Lymphocyte Infusion (DLI)**: The main risk with DLI is graft-versus-host disease (GVHD), where the donor's immune cells attack the patient's body. This underscores the need for careful monitoring.

Overall, these treatments have been used in other situations, providing insight into their risks. However, close monitoring is crucial to managing potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Severe Combined Immunodeficiency (SCID) because they offer innovative approaches compared to traditional bone marrow transplants. The TCRα/β/CD19-depleted Stem Cell Transplant (SCT) uses a specialized cell preparation method, CliniMACS, to remove specific immune cells that could lead to complications, potentially improving transplant success rates and patient outcomes. Additionally, the Donor Lymphocyte Infusions (DLI) are being fine-tuned to find the maximum tolerated dose, which could enhance immune recovery by boosting the patient's immune system with carefully adjusted doses of donor lymphocytes. These unique strategies aim to provide safer and more effective treatment options for SCID patients.

What evidence suggests that this trial's treatments could be effective for severe combined immunodeficiency?

Research has shown that a special type of stem cell transplant, called TCRα/β/CD19-depleted SCT, is one of the treatment options in this trial for infants with severe combined immunodeficiency (SCID) who lack a matching sibling donor. This transplant can help rebuild the immune system, enabling the body to fight infections more effectively. Patients who have received this type of transplant have experienced positive results, and it has also succeeded in treating other non-cancerous conditions.

Donor Lymphocyte Infusions (DLI) are another treatment option under study in this trial. Some studies have found that DLI can be very effective when used after stem cell transplants, although success can vary depending on the specific situation. DLI is believed to help strengthen the immune system. ^{6 7 8 9 10}

Who Is on the Research Team?

Ewelina Mamcarz, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

This trial is for infants over 2 months old with severe combined immunodeficiency (SCID) who have a genetic mutation confirmed by DNA sequencing. They need to have a suitable sibling or unrelated donor, or a family member donor that's at least half-matched. Their heart and kidneys must function well, they should be able to breathe without assistance, and their liver enzymes should not be too high.

Inclusion Criteria

Inclusion Criteria - Transplant Recipient

My liver enzymes are within 5 times the normal limit.

My DNA test shows a specific genetic mutation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants undergo a preparative regimen based on the type of SCID they have, including ATG, Fludarabine, Busulfan, and Thiotepa administration

9 days

Transplantation

Infusion of TCRα/β/CD19-depleted donor cells followed by CD45RA-depleted DLI

1 day

Follow-up

Participants are monitored for safety and effectiveness, including evaluation of engraftment and immune reconstitution

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Donor Lymphocyte Infusion
• Fludarabine
• Thiotepa

Trial Overview The study tests a transplant method using TCRα/β depletion followed by CD45RA-depleted donor lymphocyte infusions in SCID patients lacking sibling donors. The goal is to establish rapid immune recovery with tolerable conditioning and reduce the risk of Graft-Versus-Host-Disease while monitoring survival rates after one year.

How Is the Trial Designed?

Group I: Donor Lymphocyte Infusions Experimental Treatment 2 Interventions

Phase I: On the Phase I portion of the study, up to 4 different dose levels will be evaluated: Dose level -1, Dose ≥0.1 to ≤0.3; Dose level 1, Dose \>0.3 to ≤0.56; Dose level 2, Dose \>0.56 to ≤1.8; Dose level 3, Dose \>1.80 to ≤3.0 Dosing is determined based on the number of CD3+CD45RA-cells/kg and the patient weight in kilograms. Phase II: Participants will receive the Phase I determined maximum tolerated dose (MTD) of DLI. Cells for infusion are prepared using the CliniMACS System.

Group II: TCRα/β/CD19-depleted SCT Active Control 5 Interventions

A preparative regimen based on the type of SCID will be given followed by infusion of donor cells. Cells for infusion are prepared using the CliniMACS System Regimen 1 - IL2RG, JAK 3 (Haplocompatible) and all MSD ATG (rabbit) IV Days -9 -8 and -7, Rest Days -6 and -5, Busulfan IV Days -4, -3, and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0 Regimen 2 - RAG1, RAG2 (Haplocompatible) ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan IV Days -5, -4 and -3, Thiotepa IV twice daily, Day -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0 Regimen 3 - ADA, IL7R, CD45 deficiency, CD3 subunits (Haplocompatible) ATG (rabbit) IV Days -9 -8 and -7, Fludarabine IV Days -7, -6, -5 and -4, Busulfan: IV Days -4, -3 and -2, Rest Day -1, TCRα/β/CD19-depleted SCT, Day 0

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Published Research Related to This Trial

In a study of 30 patients undergoing matched sibling or alternative donor transplantation with a conditioning regimen of fludarabine, thiotepa, and total body irradiation, most patients achieved prompt engraftment, but there were significant complications, including regimen-related toxicity leading to 18 deaths.

The 12-month progression-free survival rates were 47% for HLA-identical sibling transplants and 30% for all patients, but due to high rates of complications and relapses, the researchers decided to discontinue this conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. van Besien, K., Devine, S., Wickrema, A., et al.[2013]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8357755/

Donor lymphocyte infusions after first allogeneic ... Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1473050216300301

Donor lymphocyte infusion after allogeneic stem cell ... In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use. Introduction.

3. nature.com nature.com/articles/s41409-024-02312-4

Safety but limited efficacy of donor lymphocyte infusion for ... DLIs given to PTCy-treated patients had low toxicity but limited efficacy, although pre-HCT serotherapy may modulate both toxicity and response.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1401177

Transplantation Outcomes for Severe Combined ... Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection.

5. astctjournal.org astctjournal.org/article/S1083-8791(07)00461-2/fulltext

High Response Rate to Donor Lymphocyte Infusion after ... The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood. 2002; 100 ...

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Safety Data Sheet If this product is combined with other materials, deteriorates, or becomes contaminated, it may pose hazards not mentioned in this SDS.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2016/020954s016lbl.pdf

MYELOSUPPRESSION BUSULFEX® (busulfan) Injection ... The safety outcomes reported in those trials are summarized in Table 2 below for a mixed population of hematological malignancies (AML, CML, and ALL). Table 2: ...

8. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Busulfan

Busulfan | C6H14O6S2 | CID 2478 - PubChem - NIH Busulfan-induced pancytopenia may be more prolonged than that induced by other alkylating agents; although recovery may take 1 month to 2 years, the toxicity is ...

9. echemi.com echemi.com/sds/busulfan-pid_Seven40958.html

Busulfan SDS, 55-98-1 Safety Data Sheets Avoid dust formation. Avoid breathing mist, gas or vapours.Avoid contacting with skin and eye. Use personal protective equipment.Wear chemical impermeable ...

10. aspenpharmausa.com aspenpharmausa.com/wp-content/uploads/2020/11/Myleran-Labeling_USPI-and-cartoon.pdf

MYLERAN R (busulfan) Tablets - Aspen USA WARNING. MYLERAN is a potent drug. It should not be used unless a diagnosis of chronic myelogenous leukemia has been adequately established and the responsible ...