Study of Allogeneic Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Illinois at Chicago
Sponsor:
Information provided by (Responsible Party):
Damiano Rondelli, MD, University of Illinois at Chicago
ClinicalTrials.gov Identifier:
NCT01499888
First received: November 23, 2011
Last updated: May 9, 2014
Last verified: May 2014
  Purpose

The investigators propose to determine the engraftment and transplant related morbidity and mortality after a non-myeloablative allogeneic hematopoietic stem cell transplant protocol using immune- suppressive agents and low-dose total body irradiation (TBI) without standard chemotherapy in patients with aggressive sickle cell disease who are not candidates for or experienced complications from hydroxyurea therapy.

Fully HLA matched siblings will be used as donors for hematopoietic stem cells to reduce the risk of morbidity and mortality in this cohort of patients.


Condition Intervention Phase
Sickle Cell Disease
Procedure: Allogeneic Non-Myeloablative Stem Cell Transplantation
Drug: Alemtuzumab
Drug: Sirolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of Allogeneic Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by University of Illinois at Chicago:

Primary Outcome Measures:
  • To determine the engraftment after non-myeloablative HSC transplant [ Time Frame: Up to 30 days post-transplant. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the frequency of acute and chronic complications of sickle cell disease [ Time Frame: Up to 100 days post-transplant. ] [ Designated as safety issue: Yes ]
    To assess for the frequency of acute and chronic complications of sickle cell disease after allogeneic hematopoietic stem cell transplantation using a protocol of immunosuppressive agents and low-dose TBI without standard chemotherapy. The acute complications include vaso-occlusive pain episodes, acute chest syndrome, stroke, and priapism. The chronic complications include nephropathy, retinopathy, osteonecrosis, pulmonary artery pressures, and chronic lung disease.

  • To evaluate the immune reconstitution after transplant. [ Time Frame: Up to 12 months after transplant. ] [ Designated as safety issue: Yes ]
  • To determine the transplant related morbidity and mortality. [ Time Frame: Up to 365 days post-transplant. ] [ Designated as safety issue: Yes ]
    Transplant related mortality will be evaluated at day 100 and day 365. If mortality is greater than 25% at day 100 or 35% at day 365, then the trial will be closed.

  • To determine the long-term engraftment after non-myeloablative HSC transplant [ Time Frame: Up to 10 years post-transplant. ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • To determine whether ocular findings from sickle cell disease are reversible in patients undergoing stem cell transplantation to treat their sickle cell disease. [ Time Frame: Up to 5 years post-transplant ] [ Designated as safety issue: No ]

Estimated Enrollment: 15
Study Start Date: May 2011
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Allogeneic Non-Myeloablative Stem Cell Transplantation
The transplant regimen will consist of alemtuzumab 1mg/kg divided over five days, 300 cGy TBI, followed by sirolimus dosed for a target serum trough level of 10- 15 ng/mL.
Procedure: Allogeneic Non-Myeloablative Stem Cell Transplantation

Alemtuzumab-based non-myeloablative allogeneic hematopoietic stem cell transplantation using immune-suppressive agents and low-dose total body irradiation (TBI) without standard chemotherapy.

Transplant regimen Day -7 to -3: Alemtuzumab (1mg/kg, total dose) divided over the 5 days, IVPB over 2 hours daily Day -3 until 100% chimerism obtained: Sirolimus dosed for target trough level of 10-15 ng/mL Day -2: Total body irradiation with 300cGy Day 0: Stem cell infusion

Drug: Alemtuzumab
In this protocol, patients will be given alemtuzumab 1mg/kg divided equally over five days with the maximum dose of 20mg per day.
Other Names:
  • Campath
  • MabCampath
  • Campath-1H
Drug: Sirolimus
On day -1, patients will receive a loading dose of 12 mg followed by 4 mg per day. Subsequent dosing will be based on clinical toxicity, GVHD concurrent medications, medical conditions, prior drug levels, drug-drug interactions, and blood levels with target of 3 to 12 ng/mL.
Other Names:
  • Rapamune
  • Rapamycin

Detailed Description:

Sickle cell disease is an inherited defect caused by a mutation in the Beta globin gene affecting red blood cells. Symptoms begin at 6 months of life and often lead to debilitating vaso-occlusive pain crises, acute insults to vital organ systems,chronic organ injury, and decreased survival with median survival estimated at 42 years for men and 48 years for women. Several cohort studies have identified clinical and laboratory predictors for decreased survival which include acute complications, and chronic complications of sickle cell disease.

Hydroxyurea is the only FDA approved drug to help ameliorate symptoms associated with sickle cell disease. Two nonrandomized studies have suggested a reduction in mortality after 17 years of long term hydroxyurea treatment. However, the mortality rate is still high in the hydroxyurea cohort at 43.1% and only 38.1% of patients have a rise in fetal hemoglobin indicating that a significant percentage of patients still have aggressive disease despite hydroxyurea treatment. Hydroxyurea therapy also does not seem to prevent the development of pulmonary hypertension.

In the pediatric population, patients that have not clinically improved despite optimized hydroxyurea management are offered allogeneic stem cell transplantation. Until recently, the options were more limited in adults with sickle cell disease that had aggressive disease despite hydroxyurea therapy. Most rely on chronic red blood cell transfusions which carry significant risks of infection, iron overload, and alloimmunization. Up to 50% of patients with sickle cell disease who are on chronic transfusion therapy will develop allo-antibodies making further transfusions difficult with a high potential for hemolytic transfusion reactions.

Patients with sickle cell disease often have chronic underlying organ disease and so the effects of chemotherapy may be unpredictable and potentially more harmful, making low dose TBI more attractive as a safer modality for conditioning.

The investigators propose to determine the engraftment and transplant related morbidity and mortality after a non-myeloablative allogeneic hematopoietic stem cell transplant protocol using immune- suppressive agents and low-dose total body irradiation (TBI) without standard chemotherapy in patients with aggressive sickle cell disease who are not candidates for or experienced complications from hydroxyurea therapy.

Fully HLA matched siblings will be used as donors for hematopoietic stem cells to reduce the risk of morbidity and mortality in this cohort of patients.

An optional correlative trial will be conducted to compare ocular findings after stem cell transplantation with those findings before stem cell transplantation. Anterior and posterior ocular examination as well as objective tests will be performed on subjects.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with sickle cell disease, subtype Hgb SS, SC, or SB disease who are on chronic transfusion therapy for a prior stroke or those patients who were intolerant of hydroxyurea therapy or were being treated with hydroxyurea therapy and were complicated by at least one of the following:

    • Stroke or central nervous system event lasting longer than 24 hours
    • Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring emergency room visits or hospital admissions
    • Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room visits
    • Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime events
    • Red-cell alloimmunization (≥ 2 antibodies) during longterm transfusion therapy
    • Bilateral proliferative retinopathy with major visual impairment in at least one eye
    • Osteonecrosis of 2 or more joints
    • Sickle cell nephropathy
    • Stage I or II sickle lung disease
    • Symptoms of pulmonary hypertension and mean pulmonary artery pressure > 25mmHg
  • Age 18-60 years
  • Karnofsky performance status of 70 or higher (Appendix A)
  • Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%
  • Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50%
  • Estimated GFR ≥ 50mL/min as calculated by the modified MDRD equation
  • ALT ≤ 3x upper limit of normal
  • Patient is able and willing to sign informed consent
  • Patient has an HLA-identical matched related donor

Exclusion Criteria:

  • Evidence of chronic active hepatitis or cirrhosis
  • HIV-positive
  • Current pregnancy
  • History of non-compliance with medications and medical care
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01499888

Contacts
Contact: Damiano Rondelli, MD 312-996-6179 drond@uic.edu
Contact: Lani Krauz, RN 312-413-0242 lignacio@uic.edu

Locations
United States, Illinois
University of Illinois at Chicago Recruiting
Chicago, Illinois, United States, 60612
Contact: Lani Krauz, RN    312-413-0242    lignacio@uic.edu   
Contact: Santosh Saraf, MD    312-996-2187    ssaraf@uic.edu   
Principal Investigator: Damiano Rondelli, MD         
Sponsors and Collaborators
University of Illinois at Chicago
Investigators
Principal Investigator: Damiano Rondelli, MD University of Illinois at Chicago
  More Information

No publications provided

Responsible Party: Damiano Rondelli, MD, Professor, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT01499888     History of Changes
Other Study ID Numbers: 2011-0096
Study First Received: November 23, 2011
Last Updated: May 9, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Illinois at Chicago:
Stem Cell Transplantation
Sickle Cell Disease
Subtype Hgb SS
Subtype Hgb SC
Subtype Hgb SB
Chronic Transfusion Therapy
Prior Stroke
Allogeneic
Alemtuzumab
Sirolimus
Total Body Irradiation
Hydroxyurea Intolerant

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Sirolimus
Everolimus
Alemtuzumab
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 01, 2014