Treatment of Sickle Cell Anemia With Stem Cell Transplant

NCT01350232 | Terminated Results DMC

• 4 other identifiers: 09F.3271-RC2HL101496-0JT 15261RC2HL101496
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

This is a clinical research trial in which a novel preparatory regimen was developed for bone marrow transplant (BMT) which eliminates the primary obstacle to transplant, the lack of a matched sibling donor. It is believed this regimen is sufficiently efficacious and sufficiently gentle to apply to patients with sickle cell anemia and related disorders. It is proposed to characterize the efficacy and toxicity of this regimen in high risk patients with sickle cell anemia using criteria for patient selection that have been accepted in prior BMT trials in patients with sickle cell disease, specifically only the subset of patients whose prior clinical behavior indicates that they are at high risk for serious morbidity and early mortality. In addition, it is proposed to characterize the pathophysiology of a consistent febrile response seen in the haploidentical BMT regimen the investigators have developed at Thomas Jefferson University (TJU). The primary goal of this study is to determine the response rate to a reduced intensity conditioning regimen which consists of fludarabine, cytarabine, low dose total body irradiation and cyclophosphamide in patients with severe sickle cell anemia.

Conditions

Sickle Cell Anemia; Sickle Cell-hemoglobin C Disease; Sickle Cell-β0-thalassemia

Keywords

sickle cell; SS disease; SC disease; S-thalassemia; transplant; bone marrow transplant; stem cell transplant; matched sibling; haploidentical; hemoglobinopathy; anemia; desensitization

Outcome Measures

Primary Outcomes (1)

• Stable Engraftment

  To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia.

  180 days post-infusion

Secondary Outcomes (7)

• Organ Toxicity

  30 days post infusion

• Overall Survival

  6 months post infusion

• Acute Graft Versus Host Disease

  100 days post infusion

• Correction of Hemoglobinopathy

  100 days post infusion through 5 years post infusion

• Immune Recovery

  100 days post infusion through 5 years post infusion

Study Arms (1)

HSCT

EXPERIMENTAL

Subjects receive the preparative regimen in 2 steps. The "first step" will be with fludarabine and cytarabine and a low dose of total body irradiation. This will be followed by the "first step" of the transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two doses of cyclophosphamide. This will then be followed by the "second step" of the transplant graft - the stem cells. Only subjects with prior alloimmunization against donor will receive desensitization. Subjects who demonstrate alloimmunization against the HLA of the donor will receive bortezomib and rituximab in combination with plasmapheresis prior to the admission for transplant.

Drug: Fludarabine; Drug: Cytarabine; Device: Cellular Infusions; Radiation: Total Body Irradiation; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Rituximab; Procedure: Plasmapheresis

Interventions

Fludarabine DRUG

Subjects will receive fludarabine at a dose of 30 mg/m2 daily for 4 days as part of the preparative regimen

Also known as: Fludara

HSCT

Cytarabine DRUG

Subjects will receive cytarabine at a dose of 2 g/m2 daily for 4 days, approximately 4 hours after the fludarabine

Also known as: Ara-C, Cytosar, Cytosine arabinoside

HSCT

Cellular Infusions DEVICE

Subjects will receive the cellular product in 2 steps. The first is a lymphocyte infusion of 2 X 10e8 lymphocytes/kg on the day they receive total body irradiation. The second is a CD34 enriched stem cell product approximately 48 hours after the cyclophosphamide. The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.

Also known as: Stem Cells, DLI, HPCT

HSCT

Total Body Irradiation RADIATION

All subjects will receive 200cGy TBI in a single fraction on the AM they receive the lymphocyte infusion

Also known as: TBI

HSCT

Cyclophosphamide DRUG

All subjects will receive cyclophosphamide at a dose of 60 mg/kg at approximately 72 and 96 hours after the lymphocyte infusion

Also known as: Cytoxan

HSCT

Bortezomib DRUG

Subjects will receive bortezomib 1.3 mg/kg on Day 1,4,8, and 11 of a 21 day cycle. This will be repeated for 2 cycles.

Also known as: Velcade

HSCT

Rituximab DRUG

Subjects will receive rituximab 375 mg/m2 on day 1 and day 8 of a 21 day cycle, on days they will also be receiving rituximab. This will be repeated for 2 cycles.

Also known as: Rituxan

HSCT

Plasmapheresis PROCEDURE

Subjects who continue to have detectable anti-donor antibody will receive plasmapheresis to reduce the antibody further

Also known as: Plasma exchange

HSCT

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patient Selection:
• i) Patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, or sickle cell-β0-thalassemia) confirmed by hemoglobin electrophoresis.
• ii) Patients should have one or more of the following:
• History of acute chest syndrome requiring recurrent hospitalization or exchange transfusion (Acute chest syndrome is defined as pulmonary infiltrate involving at least one complete lung segment, consistent with alveolar consolidation but not atelectasis, accompanied by chest pain, fever, cough, tachypnea or wheezing)
• History of nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours
• Recurrent vaso-occlusive pain (≥5 episodes during the past two years) or recurrent priapism requiring hospitalization or visits to the emergency room or sickle cell day unit
• Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of normal predicted value) with progression on ACE inhibitor therapy iii) Patient must have failed therapy with hydroxyurea, as HU as evidenced by at least 6 months of maximum HU dosage for sickle cell disease, i.e. dose escalation to a level which caused some minimal hematologic toxicity in terms of CBC values. Failure to respond must also be documented by no significant increase in subjects HbF levels at this maximally tolerated dosage.AND development/ persistence of items listed in (ii) Patients who are deemed not eligible for hydroxyurea by the primary hematologist will be considered eligible without having failed hydroxyurea. Non-eligibility for hydroxyurea therapy is based on:
• (1) the diagnoses of SC disease and sickle cell-β0-thalassemia in which no clear evidence supports the use of hydroxyurea therapy and thus treatment with hydroxyurea is not considered the standard of care in these entities (2) the presence of high hemoglobin F levels in patients with sickle cell anemia and documented Hereditary Persistence of Fetal Hemoglobin (HPFH) in which hydroxyurea is not considered the standard of care (3) severe adverse reactions to hydroxyurea in patients with sickle cell anemia based on, but not limited to, count suppression, GI intolerance, and dermatomyositis Patient unwillingness to be compliant with hydroxyurea therapy is not an acceptable reason for non-eligibility iv) Patients must have an acceptable related donor
• who is matched at the HLA-A;B; C; DR loci (8 of 8 match) or mismatched for at most one locus (7 of 8 match) (well matched related donor
• who is mismatched at 2-4 alleles (haplo-identical) v) Patient age greater than 18 - 45 years vi) ECOG performance status 0-2/ Karnofsky 70-100% vii) Written informed consent obtained from the patient. viii) Transaminases \<3X ULN; patients with transaminases greater than the ULN but less than 3XULN will be evaluated by the hepatology service and will undergo further imaging and biopsy as deemed necessary by hepatology. They will not be considered eligible unless cleared by hepatology.

You may not qualify if:

• Patient Selection:
• i) Pregnancy/ unwillingness to use adequate contraception during study period ii) Liver disease including
• Acute hepatitis (transaminases \>3x normal value)
• Chronic hepatitis C
• Chronic hepatitis B or history of exposure to hepatitis B iii) Cardiac ejection fraction \< 50% iv) Pulmonary hypertension - as evidenced by findings on resting echocardiogram of pulmonary artery systolic pressure ≥ 40 mmHg or any evidence of right ventricular dysfunction (hypokinesis or RV dilation) v) Severe renal impairment (GFR \<30% of predicted normal value) vi) Severe residual functional neurologic impairment (other than hemiplegia alone) vii) DLCO ≤50 viii) Any evidence of infection by the human immunodeficiency virus ix) Psychiatric disorder that would preclude patients from signing an informed consent x) Severe neuro-cognitive or executive function making informed consent possible

Sponsors & Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

Related Links

• Thomas Jefferson University Hospitals
• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center

MeSH Terms

Conditions

Anemia, Sickle Cell; Hemoglobin SC Disease; Hemoglobinopathies; Anemia

Interventions

fludarabine; fludarabine phosphate; Cytarabine; Whole-Body Irradiation; Cyclophosphamide; Bortezomib; Rituximab; Plasmapheresis; Plasma Exchange

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Radiotherapy; Therapeutics; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Blood Component Removal; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative; Blood Transfusion; Biological Therapy

Limitations and Caveats

Study was terminated due to poor accrual. No reportable data has been collected.

Results Point of Contact

• Title: Joanne Filicko-O'Hara, MD
• Organization: Thomas Jefferson University

jef001@jefferson.edu

215-955-8874

Study Officials

• Joanne Filicko-O'Hara, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 4, 2011
• First Posted: May 9, 2011
• Study Start: September 1, 2009
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: May 16, 2025
• Results First Posted: November 20, 2014

Record last verified: 2025-05

Locations

US (1)