Nonmyeloablative Stem Cell Transplant for Sickle Cell Anemia and Thalassemia

Recruiting at 1 trial location

Overseen By Matthew M Hsieh, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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: 6

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if using low dose radiation and certain drugs can help patients with beta-thalassemia or sickle cell disease better accept donor stem cells. The treatment aims to suppress the immune system to reduce rejection of the new cells.

Will I have to stop taking my current medications?

The trial information does not specify if 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 treatment Cyclophosphamide, Cytoxan, Neosar, Endoxan, Pentostatin, Radiotherapy, Radiation therapy, X-ray therapy, External beam radiation therapy, Sirolimus, Rapamune for sickle cell anemia and thalassemia?

Research shows that cyclophosphamide, when used with total body irradiation, has been effective in achieving lasting engraftment in bone marrow transplantation for conditions like preleukemia, suggesting potential benefits for similar blood disorders. ^{1 2 3 4 5}

Is the nonmyeloablative stem cell transplant treatment generally safe for humans?

Cyclophosphamide (also known as Cytoxan) has been used in various treatments, but high doses can cause severe side effects, including fatal toxicity, especially when combined with other treatments like total body irradiation. In some studies, it has been associated with significant risks, such as cardiac toxicity and severe gastrointestinal issues, although it has been successfully used in certain bone marrow transplant regimens with careful dosing. ^{1 6 7 8 9}

How is the nonmyeloablative stem cell transplant treatment for sickle cell anemia and thalassemia different from other treatments?

This treatment is unique because it uses a combination of drugs and radiotherapy to prepare the body for a stem cell transplant without completely destroying the bone marrow, which is different from traditional myeloablative (bone marrow destroying) regimens. Cyclophosphamide and pentostatin are used to suppress the immune system, while sirolimus helps prevent rejection of the transplanted cells, making it a less intense option compared to standard treatments. ^{4 7 8 10 11}

Research Team

Matthew M Hsieh, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for people aged 4 and older with severe sickle cell disease or beta-thalassemia, who are at high risk of complications not improved by other treatments. They must have a matched family donor willing to donate stem cells. Exclusions include serious infections within the last month, pregnancy, lactation, or any major illness that could interfere with transplant survival.

Inclusion Criteria

I am at least 4 years old.

I am eligible for hydroxyurea treatment or a stem cell transplant.

Negative beta-HCG, when applicable

Exclusion Criteria

I do not have any major illnesses or organ failures that would make a stem cell transplant impossible.

I need considerable assistance and am unable to carry out any work activities.

Evidence of uncontrolled bacterial, viral, or fungal infections within one month prior to starting the conditioning regimen

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Transplant Conditioning

Participants receive low dose radiation and immunosuppressive drugs to prepare for stem cell transplant

3 weeks

Multiple visits (in-person)

Transplantation

Participants receive donor stem cells via IV infusion

1 day

1 visit (in-patient)

Post-Transplant Recovery

Participants remain in the hospital for recovery and monitoring

30 days

In-patient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Weekly visits (outpatient clinic) for 4 months, then regular follow-ups

Treatment Details

Interventions

• Cyclophosphamide
• Pentostatin
• Radiotherapy
• Sirolimus

Trial Overview The study tests a new transplant method using low-dose radiation and immunosuppressive drugs (cyclophosphamide, pentostatin, sirolimus) to see if they help patients better accept donated stem cells. Participants will undergo various procedures including blood tests and bone marrow sampling before receiving the treatment in hospital.

Participant Groups

Group I: Participants with pre-existing antibodies and SCD or Beta-thalassemia receiving stem cell transplant Experimental Treatment 5 Interventions

Participants with pre-existing antibodies and Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

Group II: Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor Experimental Treatment 1 Intervention

Participants received filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling.

Group III: Female participants with SCD or Beta-thalassemia receiving stem cell transplant with male donor Experimental Treatment 5 Interventions

Female participants with Sickle Cell Disease (SCD) or Beta-thalassemia receiving stem cell transplant with male donor. Pentostatin given on days -21, -17, -13, -9 and oral cyclophosphamide from days -21 to -8, with the intention to be administered in the outpatient setting. Alemtuzumab on days 7 to 3, and 300 cGy TBI on day 2. Sirolimus started at a loading dose of 5mg PO every 4 hours for three doses on day -1 and adjusted to maintain trough levels between 10-15 ng/mL. The PBSC graft targeted to deliver .10 x 106 CD34+ cells/kg (minimum .5 x 106) and infused on day 0.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

National Institutes of Health Clinical Center (CC)

Collaborator

Trials

391

Recruited

30,880,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase I study involving 9 patients with advanced hematological malignancies, the combination of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) with total body irradiation (TBI) resulted in severe toxicity, with multiple patients experiencing fatal outcomes at higher doses.

The study concluded that the concurrent administration of Ara-C and CY may not be suitable for phase I trials due to the high risk of severe, dose-independent toxicity, highlighting the need for caution in developing such treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. Petersen, FB., Appelbaum, FR., Buckner, CD., et al.[2016]

High doses of cyclophosphamide (CY) can be toxic to bone marrow, but when combined with autologous marrow transplantation, it allows for recovery from severe side effects, as shown in dog studies where 100 mg/kg was lethal without support but manageable with marrow infusion.

In human patients, conditioning with CY (50 mg/kg) before allogeneic marrow transplantation for severe aplastic anemia has resulted in an 80% long-term survival rate, demonstrating the efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose therapy and bone marrow transplantation. Thomas, ED.[2018]

In a study of 58 patients with hematologic malignancies, a myeloablative regimen combining high-dose cytosine arabinoside (ara-C), cyclophosphamide, and total body irradiation (TBI) demonstrated a 1-year survival rate of 69% and a 5-year survival rate of 54%.

The regimen showed a low relapse rate of only 7% after a median follow-up of 28 months, suggesting that the combination of these treatments is both safe and effective, potentially due to the additional antileukemic effects of ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia. Jillella, AP., Doria, R., Khan, K., et al.[2013]

References

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

Relapse after allogeneic bone marrow transplantation for refractory anemia is increased by shielding lungs and liver during total body irradiation. [2013]

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

Busulfan and cyclophosphamide as a conditioning regimen for pediatric acute lymphoblastic leukemia patients undergoing bone marrow transplantation. [2019]

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

Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. [2021]

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

Marrow transplantation in preleukemia. [2016]

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

Radiopharmaceutical therapy of 5T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. [2016]

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

High-dose therapy and bone marrow transplantation. [2018]

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

Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia. [2013]

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

High-dose cytosine arabinoside in relapsed and refractory non-Hodgkin's lymphoma. Limited role as a single agent. [2019]

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

High-dose cyclophosphamide for aplastic anemia and autoimmunity. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Management of aplastic anemia after failure of frontline immunosuppression. [2020]