Myeloablative Conditioning, Prophylactic Defibrotide and Haplo AlloSCT for Patients With Sickle Cell Disease

Official title

The Safety and Efficacy of Prophylactic Defibrotide Administration in Children, Adolescents, and Young Adults With Sickle Cell Disease or Beta Thalassemia Following Myeloablative Conditioning (MAC) and Haploidentical or Matched Unrelated Donor (MUD) Stem Cell Transplantation Utilizing CD34 Enrichment and T-Cell (CD3) Addback

Overview

This is a follow-up trial to NYMC 526 (NCT01461837) to assess the safety, efficacy and toxicity of administering Defibrotide prophylaxis for high-risk sickle cell or beta thalassemia patients undergoing a familial haploidentical or MUD allogeneic stem cell transplantation with CD34 enrichment and T-cell addback. This patient population historically has a risk of developing sinusoidal obstructive syndrome (SOS) and Defibrotide has demonstrated efficacy in treatment of SOS. The Funding Source is FDA OOPD.

Interventions

• Drug Defibrotide
  defibrotide will be given prophylactically prior to AlloSCT to determine if it decreases the incidence of SOS in this high risk population, and determine that it is safe and feasible to give along with myeloimmunoablative therapy and allogeneic transplant.

Primary outcome measures

• All patients will be monitored for known and unknown side effects of defibrotide with daily physical exams while in the hospital and then as needed in addition to daily laboratory values including chemistries, hematology labs as needed [Time frame: 100 days]
• All patients will be monitored for the development of SOS. [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Disease: Homozygous Hemoglobin S Disease, or Hemoglobin S B0/+ thalassemia, or Hemoglobin SC Disease, or Beta thalassemia intermedia/majora
• Patients must demonstrate one or more of the following Sickle Cell Disease Complications
• Clinically significant neurologic event (stroke) or any neurologic deficit lasting >24 hours that is accompanied by an infarct on cerebral MRI
• Acute chest syndrome in the preceding two year period prior to enrollment that have failed, been non-compliant or declined hydroxyurea treatment, or prior to chronic RBC transfusion therapy, exchange transfusion or erythrocyte pheresis.
• Recurrent painful events (at least 3 in the 2 years prior to enrollment or prior to chronic RBC transfusion therapy, exchange transfusion or erythrocyte pheresis).
• Abnormal TCD study requiring starting on chronic transfusion therapy and/or exchange transfusions.
• At least one silent infarct lesion on a MRI scan of the head. Or (directly or probably related to SCD)
• Sickle Cell nephropathy;
• Splenic sequestration requiring RBC transfusion;
• Aplastic crisis requiring RBC transfusion;
• Avascular necrosis of the hip diagnosed by MRI;
• Two episodes or more of leg ulcerations;
• Recurrent priapism .
• Infant dactylitis.
• all patients must meet disease, age, organ function and donor criteria;

Exclusion criteria

• Patients who are receiving concomitant systemic anticoagulants and/or fibrinolytic therapies.
• Patients with a previously known hypersensitivity reaction to defibrotide.
• Females who are pregnant or breast-feeding are not eligible
• Patients with documented uncontrolled infection at the time of study entry are not eligible.
• Patients who have an unaffected HLA matched sibling donor willing to proceed to donation will not be eligible for this study.
• Karnofsky or Lansky (age appropriate) Performance Score <50% (hemiplegia alone secondary to a previous stroke is not an exclusion)
• Demonstrated lack of compliance with medical care.
• Patients with clinically significant fibrosis or cirrhosis of the liver will not be eligible.
• Patients who have previously received a HSCT will not be eligible.
• Patients with contraindications to the use of defibrotide

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• University of California Los Angeles — Los Angeles
• University of Florida — Gainesville
• New York Medical College — Valhalla
• Medical College of Wisconsin — Milwaukee

Publications

• Chu Y, Talano JA, Baxter-Lowe LA, Verbsky JW, Morris E, Mahanti H, Ayello J, Keever-Taylor C, Johnson B, Weinberg RS, Shi Q, Moore TB, Fabricatore S, Grossman B, van de Ven C, Shenoy S, Cairo MS. Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease. Front Immunol. 2022 Dec 9;13:1055497. doi: 10.3389/fimmu.2022.1055497. eCollection 2022. PMID 36569951

Identifiers

NCT: NCT02675959 · NYMC 571 · 7837

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗