Defibrotide Prophylaxis + Stem Cell Transplant for Sickle Cell Disease

(NYMC-571 Trial)

Recruiting at 3 trial locations

Overseen By Erin Morris, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Must not be taking: Anticoagulants, Fibrinolytics

Disqualifiers: Pregnancy, Uncontrolled infection, Liver cirrhosis, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if Defibrotide can safely and effectively prevent liver damage in high-risk sickle cell or beta thalassemia patients undergoing a special stem cell transplant. The medication works by improving blood flow in the liver to prevent blockages.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking systemic anticoagulants or fibrinolytic therapies.

What data supports the effectiveness of the drug Defibrotide in combination with stem cell transplant for sickle cell disease?

Research shows that Defibrotide can protect cells from damage and inflammation caused by other drugs used in stem cell transplants, suggesting it might help reduce complications during the transplant process. ^{1 2 3 4 5}

Is defibrotide safe for use in humans?

Defibrotide has been used safely in humans, particularly for treating a liver condition called sinusoidal obstruction syndrome (SOS) after stem cell transplants. It is generally well tolerated, with common side effects including bleeding and low blood pressure, but it has not been linked to a higher risk of serious bleeding events. ^{6 7 8 9 10}

How is the drug Defibrotide unique in treating sickle cell disease with stem cell transplant?

Defibrotide is unique because it is primarily used to prevent and treat veno-occlusive disease (a liver condition) in patients undergoing stem cell transplants, and it works by protecting blood vessel cells and restoring balance in blood clotting and breakdown. Its use in sickle cell disease with stem cell transplant is novel, as it is not a standard treatment for this condition. ^{6 7 8 11 12}

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

This trial is for high-risk sickle cell or beta thalassemia patients who have had severe complications like acute chest syndrome, stroke, or organ damage. It's open to those with specific genetic forms of the disease and certain health indicators like elevated NT-proBNP levels. Adults up to age 34.99 can join if they meet additional criteria such as a history of frequent blood transfusions or leg ulcers.

Inclusion Criteria

I have a specific type of blood disorder related to hemoglobin.

I have complications from Sickle Cell Disease.

I am between 18 and 34 years old and meet at least two specified criteria.

Exclusion Criteria

I cannot take defibrotide due to health reasons.

Demonstrated lack of compliance with medical care

Patients with a previously known hypersensitivity reaction to defibrotide

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Prophylactic Treatment

Defibrotide prophylaxis is administered starting 10 days before stem cell infusion and continues through Day +21

31 days

Daily visits (in-patient)

Stem Cell Transplantation

Familial haploidentical allogeneic stem cell transplantation with CD34 enrichment and T-cell addback

1 day

1 visit (in-patient)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for the development of SOS

1 year

Regular visits as needed

Treatment Details

Interventions

• Defibrotide

Trial Overview The study tests Defibrotide prophylaxis in patients undergoing haploidentical allogeneic stem cell transplantation (a type of bone marrow transplant). The goal is to prevent sinusoidal obstructive syndrome (SOS), a serious complication that can occur after transplants in these patients.

Participant Groups

Group I: Defibrotide prophylaxis Experimental Treatment 1 Intervention

defibrotide will be given prior to and during myeloablative immunotherapy conditioning (MAIC) followed by familial haploidentical (FHI) allogeneic stem cell transplantation (AlloSCT) with CD34 enrichment and t-cell addback in patients with high-risk sickle cell disease or beta thalassemia to reduced the risk and rate of the development of sinusoidal obstructive syndrome (SOS).

Defibrotide is already approved in United States, European Union for the following indications:

Approved in United States as Defitelio for:

• Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Approved in European Union as Defitelio for:

• Severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Medical College of Wisconsin

Collaborator

Trials

645

Recruited

1,180,000+

Tufts Medical Center

Collaborator

Trials

264

Recruited

264,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Findings from Research

Fludarabine, while effective as an immunosuppressant in stem cell transplantation, can cause damage to human microvascular endothelial cells, but the compound Defibrotide (DF) protects against this damage without reducing fludarabine's effectiveness against leukemia.

A new derivative of Defibrotide, called Oligotide, also protects endothelial cells from fludarabine-induced damage and prevents harmful immune cell migration, suggesting both DF and Oligotide could be beneficial in pre-transplant conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oligotide, a defibrotide derivative, protects human microvascular endothelial cells against fludarabine-induced activation, damage and allogenicity. Eissner, G., Iacobelli, M., Blüml, S., et al.[2013]

A reduced-toxicity conditioning regimen (BFA) before HLA-matched sibling donor transplantation in children with sickle cell disease resulted in a 100% event-free survival (EFS) and overall survival (OS) over two years, indicating high efficacy.

The study, involving 18 pediatric patients, showed a low incidence of grade II-IV acute graft-versus-host disease (GVHD) at 17%, along with stable or improved organ function, highlighting the safety of the BFA regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. Bhatia, M., Jin, Z., Baker, C., et al.[2021]

In a study involving 13 high-risk adult patients with sickle cell disease, a chemotherapy-free stem cell transplantation regimen resulted in successful engraftment in all patients, with 92% maintaining stable mixed donor/recipient chimerism after a median follow-up of 22 months.

The treatment showed no mortality or graft-versus-host disease, and patients experienced significant improvements in hemoglobin levels and quality of life, including aspects like bodily pain and vitality, highlighting the efficacy and safety of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. Saraf, SL., Oh, AL., Patel, PR., et al.[2017]

In a study of 20 adult patients with sickle cell disease who underwent stem cell transplantation, a conditioning regimen combining fludarabine, busulfan, anti-T-cell lymphocyte globulin, and low-dose total body irradiation resulted in successful donor cell engraftment without any cases of graft rejection or severe graft-versus-host disease (GVHD).

The treatment showed promising outcomes with no non-relapse mortality and a low incidence of major complications, suggesting that this transplantation approach could be a safe and effective option for adults with sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogenic peripheral stem cell transplantation from HLA-matched related donors for adult sickle cell disease: remarkable outcomes from a single-center trial. Ozdogu, H., Boga, C., Yeral, M., et al.[2019]

Fludarabine, while used to reduce toxicity in bone marrow transplantation, can actually damage human endothelial and epithelial cells and provoke a proinflammatory response, which may complicate transplantation outcomes.

Defibrotide has been identified as a protective agent against the harmful effects of fludarabine, potentially allowing for safer pretransplant conditioning without compromising its antileukemic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Eissner, G., Multhoff, G., Gerbitz, A., et al.[2021]

In a study of 23 patients undergoing hematopoietic stem cell transplantation, defibrotide was effective in treating sinusoidal obstruction syndrome (SOS/VOD), with 14 patients showing a positive response to the therapy.

Patients treated with defibrotide experienced significant improvements in symptoms and biochemical markers, including a decrease in bilirubin levels and weight, and a 70% survival rate at 100 days post-transplant, indicating its potential as a key treatment option for SOS/VOD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes. Coutsouvelis, J., Avery, S., Dooley, M., et al.[2021]

Defibrotide has shown effectiveness in managing sinusoidal obstruction syndrome (VOD/SOS) in patients undergoing stem cell transplantation, with a recommended safe dose of 25 mg/kg/day for at least 14 days or until a complete response is achieved.

Despite its efficacy, defibrotide faces barriers to routine use due to high costs and lack of licensing in many countries, highlighting the need for further studies to optimize dosing and treatment duration, especially in both pediatric and adult populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide for the management of sinusoidal obstruction syndrome in patients who undergo haemopoietic stem cell transplantation. Coutsouvelis, J., Avery, S., Dooley, M., et al.[2017]

Defibrotide has been approved in the EU for treating severe hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem cell transplantation (HSCT), showing a significantly higher complete response rate and lower mortality at day +100 compared to historical controls.

The treatment was generally well tolerated, with no increased risk of hemorrhagic adverse events, making it a safe option for patients with severe hepatic VOD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide: a review of its use in severe hepatic veno-occlusive disease following haematopoietic stem cell transplantation. Keating, GM.[2021]

Defibrotide is effective in treating severe sinusoidal obstruction syndrome (SOS) after hematopoietic stem cell transplantation (HSCT), showing improved overall survival rates, especially in pediatric patients, with 62% survival at day +100 for severe cases.

The study suggests that using defibrotide for SOS prophylaxis can significantly enhance the prognosis for high-risk patients, with an 89% survival rate at day +100 for those receiving prophylactic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide in hematopoietic stem cell transplantation: A multicenter survey study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH). González Vicent, M., Díaz de Heredia, C., González de Pablo, J., et al.[2021]

Defibrotide significantly improves the survival rate at day +100 post-hematopoietic stem cell transplantation (HSCT) for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), with a pooled survival rate of 58% based on a meta-analysis of 16 studies involving 3,002 participants.

While defibrotide shows promise in enhancing treatment outcomes, the analysis indicates a high incidence of adverse events, particularly hemorrhage and hypotension, and highlights the need for more rigorous randomized control trials to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. Yang, L., Qi, J., Pan, T., et al.[2020]

In a study of 44 pediatric patients undergoing hematopoietic stem cell transplantation, the use of defibrotide (DFT) prophylaxis was associated with a statistically significant delay in the engraftment of neutrophils and white blood cells.

The findings suggest that while DFT is a promising therapy for veno-occlusive disease, its prophylactic use may negatively impact the speed of neutrophil engraftment in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does defibrotide induce a delay to polymorphonuclear neutrophil engraftment after hematopoietic stem cell transplantation? Observation in a pediatric population. Maximova, N., Pizzol, A., Giurici, N., et al.[2018]

In a study of 52 patients undergoing stem cell transplantation, the use of defibrotide as a prophylactic treatment significantly reduced the incidence of veno-occlusive disease (VOD) compared to historical controls, with none of the patients in the defibrotide group developing VOD.

Defibrotide treatment also led to lower maximum bilirubin levels and improved event-free survival at day 100, indicating its potential efficacy and safety as a preventive measure against VOD in patients with hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. Chalandon, Y., Roosnek, E., Mermillod, B., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Oligotide, a defibrotide derivative, protects human microvascular endothelial cells against fludarabine-induced activation, damage and allogenicity. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. [2021]

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

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease. [2017]

4. England pubmed.ncbi.nlm.nih.gov

Allogenic peripheral stem cell transplantation from HLA-matched related donors for adult sickle cell disease: remarkable outcomes from a single-center trial. [2019]

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

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Defibrotide for the management of sinusoidal obstruction syndrome in patients who undergo haemopoietic stem cell transplantation. [2017]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Defibrotide: a review of its use in severe hepatic veno-occlusive disease following haematopoietic stem cell transplantation. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Defibrotide in hematopoietic stem cell transplantation: A multicenter survey study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH). [2021]

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

Efficacy and Safety of Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. [2020]

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

Does defibrotide induce a delay to polymorphonuclear neutrophil engraftment after hematopoietic stem cell transplantation? Observation in a pediatric population. [2018]

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

Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. [2013]