Bone Marrow Transplant for Sickle Cell Disease

Overseen By Paul Szabolcs, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Paul Szabolcs

Must be taking: Hydroxyurea

Disqualifiers: Pregnancy, CNS event, Infections, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

5 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how a bone marrow transplant from a mismatched donor might benefit individuals with severe sickle cell disease and other blood disorders requiring regular transfusions. Known as a T-Cell Depleted Alternative Donor Bone Marrow Transplant, this approach aims to increase transplant accessibility by using donors who are not a perfect match. The study also seeks to reduce complications such as graft-versus-host disease, where donor cells attack the recipient's body. Suitable candidates include those with sickle cell disease experiencing frequent pain episodes or chest problems, or those dependent on regular blood transfusions. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's function in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that hydroxyurea must have been tried and failed for patients with sickle cell disease, which might imply some changes in medication. It's best to discuss your specific medications with the trial team.

What prior data suggests that this T-Cell Depleted Alternative Donor Bone Marrow Transplant is safe for patients with severe sickle cell disease?

Previous studies have shown promise for bone marrow transplants from alternative donors, with certain immune cells (T-cells) removed, in patients with severe sickle cell disease. Research indicates that this method, which uses a specific type of donor stem cell, is generally well-tolerated. Removing T-cells reduces the risk of complications like graft-versus-host disease, where donor cells attack the recipient’s body.

One study found that this T-cell depleted approach led to successful engraftment, meaning the donor cells started to grow and produce new blood cells without severe complications in patients with sickle cell disease. Other studies have reported that patients did not experience serious issues like sinusoidal obstruction syndrome (a liver condition) or veno-occlusive disease (a type of blood vessel blockage in the liver).

While these findings are encouraging, it is important to remember that this treatment is still being tested. Participants in clinical trials help researchers learn more about its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for sickle cell disease?

Unlike the standard treatments for sickle cell disease, such as hydroxyurea or regular blood transfusions, this approach uses a T-cell depleted alternative donor bone marrow transplant. Researchers are excited because this method specifically targets and depletes CD3+/CD19+ cells, reducing the risk of graft-versus-host disease, which is a common complication of transplants. Additionally, by using HLA mismatched or haploidentical donors, it increases the availability of potential donors, making transplants more accessible for patients. This innovative technique aims to provide a more effective and safer option for those with sickle cell disease, offering hope for improved outcomes.

What evidence suggests that this T-Cell Depleted Alternative Donor Bone Marrow Transplant is effective for severe sickle cell disease?

Research has shown that using specially prepared stem cells from partially matched donors can help treat severe sickle cell disease. In this trial, participants will receive a T-Cell Depleted Alternative Donor Bone Marrow Transplant. Earlier studies demonstrated that patients who received these transplants successfully had the new stem cells start working in their bodies. This method reduces the risk of a common problem where the new stem cells attack the body. Early research indicates that this approach can work even for patients who typically have fewer donor options. ^{1 2 3 4 5}

Who Is on the Research Team?

Paul Szabolcs, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for people aged 5-40 with severe sickle cell disease or other anemias needing many blood transfusions and showing organ damage. They must have tried Hydroxyurea without success, not be pregnant, HIV negative, and agree to birth control post-transplant. A suitable donor match is also required.

Inclusion Criteria

I agree to use approved birth control methods for the required time.

I am between 5 and 40 years old.

Patient, parent, or legal guardian must have given written informed consent and/or assent according to FDA guidelines

Exclusion Criteria

I had a stem cell transplant less than 6 months ago.

I do not have any uncontrolled infections.

Patients with past or current medical problems that may pose additional risks, interfere with study requirements, or impact data quality

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo reduced-intensity, immune-ablative conditioning to prepare for stem cell transplant

2-3 weeks

Transplantation

Participants receive a CD3+/CD19+ depleted stem cell transplant from mismatched unrelated or haploidentical related donors

1 day

1 visit (in-patient)

Post-Transplant Monitoring

Participants are monitored for engraftment, immune reconstitution, and complications such as graft-versus-host disease

6 months

Regular visits (in-person and virtual)

Follow-up

Participants are monitored for long-term outcomes including chronic GVHD, organ toxicity, and quality of life

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• T-Cell Depleted Alternative Donor Bone Marrow Transplant

Trial Overview

The study tests if stem cell transplants from mismatched unrelated or related donors can help treat severe sickle cell disease and other anemias requiring frequent transfusions. It aims to reduce graft-versus-host disease using a T-cell depleted method in the transplant process.

How Is the Trial Designed?

Group I: Hematopoietic Stem Cell Transplantation Experimental Treatment 7 Interventions

All patients will receive a CD3+/CD19+ depleted stem cell transplant. In this study, the investigators will use HLA mismatched unrelated or haploidentical related donor peripheral blood stem cells. Prior to transplantation, the marrow (90-95%) will be negatively selected for CD3/CD19 using the ClinicMACs® depletion device. The remaining (5-10%) will undergo CD45+RA+ depletion and be frozen for future use as an immune boost. Subjects will undergo hematopoietic stem cell transplant utilizing CD3+/CD19+ depleted cells following conditioning therapy.

T-Cell Depleted Alternative Donor Bone Marrow Transplant is already approved in United States, European Union for the following indications:

Approved in United States as T-Cell Depleted Alternative Donor Bone Marrow Transplant for:

• Severe Sickle Cell Disease
• Transfusion Dependent Anemias

Approved in European Union as T-Cell Depleted Haploidentical Stem Cell Transplant for:

• Severe Sickle Cell Disease
• Acute Leukemias
• Other Hematological Disorders

Who Is Running the Clinical Trial?

Paul Szabolcs

Lead Sponsor

Trials

8

Recruited

230+

Published Research Related to This Trial

Matched sibling marrow, cord blood, or mobilized peripheral blood are the most effective sources for allogeneic hematopoietic stem cell transplantation in sickle cell disease, showing low rates of graft rejection and graft-versus-host disease (GVHD) along with high disease-free survival rates.

While fully matched unrelated donors are a viable option for patients without matched siblings, unrelated cord blood transplants have been associated with high GVHD and low engraftment rates, indicating that the choice of donor type should be guided by the expertise available at the treatment institution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. Fitzhugh, CD., Abraham, AA., Tisdale, JF., et al.[2022]

Haploidentical hematopoietic cell transplants offer a near-universal solution for patients with severe sickle cell disease, providing a potential cure when matched related donors are unavailable.

Both T-cell deplete and T-cell replete transplant approaches show comparable outcomes, allowing for individualized treatment decisions based on patient needs and institutional preferences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell deplete versus T-cell replete haploidentical hematopoietic stem cell transplantation for sickle cell disease: where are we? Patel, DA., Akinsete, AM., Connelly, JA., et al.[2020]

Hematopoietic stem cell transplantation remains the only curative treatment for sickle cell disease, but many patients lack an HLA-matched sibling donor, which limits their options.

Alternative donor options, including haploidentical, unrelated umbilical cord blood, and matched unrelated donor transplants, should be systematically considered for patients without a matched sibling to improve their chances of receiving potentially life-saving treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When there is no match, the game is not over: Alternative donor options for hematopoietic stem cell transplantation in sickle cell disease. Joseph, JJ., Abraham, AA., Fitzhugh, CD.[2019]

In a study of 870 leukemia patients who received T-cell-depleted transplants, those treated with narrow-specificity antibodies showed a higher leukemia-free survival (LFS) rate compared to other T-cell depletion techniques.

The 5-year LFS rate for transplants using narrow-specificity antibodies was similar to that of non-T-cell-depleted transplants, indicating that this method may effectively reduce treatment failure risk while maintaining comparable outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Champlin, RE., Passweg, JR., Zhang, MJ., et al.[2021]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for severe sickle cell disease and thalassemia, but its use has been limited by the availability of matched donors, with only 25%-30% of patients having suitable HLA-matched siblings.

Recent advancements in transplant technology, such as improved HLA typing and GVHD prevention strategies, are enhancing the feasibility of using alternative donors, showing promising early results that could make HSCT a preferred option for more patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative donor allogeneic hematopoietic cell transplantation for hemoglobinopathies. Alfraih, F., Aljurf, M., Fitzhugh, CD., et al.[2018]

T-cell depletion of donor bone marrow is the most effective method reported for preventing graft-versus-host disease (GVHD) and reducing mortality, particularly benefiting children with immunodeficiency.

However, applying T-cell depletion in bone marrow transplants for leukemia has been challenging, leading to higher rates of engraftment failure and leukemia relapse compared to unmodified transplants, indicating a need for improved preparative regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell depletion for bone marrow transplantation: effects on graft rejection, graft-versus-host disease, graft-versus-leukemia, and survival. Champlin, RE.[2019]

Blood and marrow transplantation can cure sickle cell disease, especially in children, with over 80% success rates when using HLA-matched sibling donors and specific conditioning regimens.

Emerging non-myeloablative conditioning methods and the use of alternative donors (like haploidentical or cord blood) show promising safety and efficacy, potentially making transplants more accessible for patients without matched donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood and marrow transplantation for sickle cell disease: is less more? Bolaños-Meade, J., Brodsky, RA.[2021]

Allogeneic bone marrow transplantation often requires alternative donors, such as haploidentical relatives or unrelated donors, due to the lack of HLA-identical siblings, which increases risks like graft failure and graft-versus-host disease compared to matched sibling donors.

Despite these risks, some studies suggest that alternative donor transplants may not lead to worse disease-free survival, potentially due to a beneficial graft-versus-leukemia effect, especially when performed earlier in the disease course.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mismatched bone marrow transplantation. Henslee-Downey, PJ.[2019]

A study of 144 patients undergoing alternative donor hematopoietic stem cell transplantation (HSCT) for sickle cell disease showed a promising 3-year overall survival rate of 86% and an event-free survival rate of 72%, indicating that this approach can be a viable treatment option.

However, the study also highlighted significant challenges, with 16% of patients experiencing graft failure and 24% developing chronic graft versus host disease (GVHD), suggesting that improving HLA matching and conditioning strategies is crucial for enhancing safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative donor hematopoietic stem cell transplantation for sickle cell disease in Europe. Gluckman, E., Cappelli, B., Scigliuolo, GM., et al.[2021]

Citations

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clinicaltrials.gov

clinicaltrials.gov/study/NCT03653338?cond=Sickle%20cell-beta-thalassemia%20disease%20syndrome%20OR%20%22Hb%20S-Beta%20thalassemia%22%20OR%20%22%20HbS-beta-thalassemia%20syndrome%22%20OR%20%22%20S-Beta%20thalassemia%22%20OR%20%22%20sickle%20cell-Beta%20thalassemia%22%20OR%20%22%20sickle%20cell-Beta-thalassemia%22&aggFilters=status:not%20rec&viewType=Table&rank=2

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Treosulfan-based T-cell depleted haplo-HSCT can achieve comparable OS and DFS even in young adult TDT patients with no SOS/VOD.

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