Ph I/II Study of Allogeneic SCT for Clinically Aggressive Sickle Cell Disease (SCD)

Phase I/II Study of Allogeneic Stem Cell Transplantation to Treat Clinically Aggressive Sickle Cell Disease (SCD)

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.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Procedure: Allogeneic Non-Myeloablative Stem Cell Transplantation; Drug: Alemtuzumab; Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Damiano Rondelli, MD; Phone Number: 312-996-6179; Email: drond@uic.edu
• Study Contact Backup: Name: Lani Krauz, RN; Phone Number: 312-413-0242; Email: lignacio@uic.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois at Chicago
      • Contact: Lani Krauz, RN; Phone Number: 312-413-0242; Email: lignacio@uic.edu
      • Contact: Santosh Saraf, MD; Phone Number: 312-996-2187; Email: ssaraf@uic.edu
      • Principal Investigator: Damiano Rondelli, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 severe enough to interfere with the patient's normal daily function or require medical attention in the clinic, emergency room, acute care center, or hospital
  • 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 16-60 years
• Karnofsky performance status of 70 or higher
• Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%
• Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50%
• Estimated GFR ≥ 30mL/min as calculated by the modified MDRD equation
• ALT ≤ 3x upper limit of normal
• No evidence of chronic active hepatitis or cirrhosis
• HIV-negative
• Patient is not pregnant
• History of compliance with medications and medical care
• Patient is able and willing to sign informed consent
• Patient has an HLA-identical matched related donor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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; Campath-1H; MabCampath; 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: Rapamycin; Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the engraftment after non-myeloablative HSC transplant	Up to 30 days post-transplant.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the frequency of acute and chronic complications of sickle cell disease	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.	Up to 100 days post-transplant.
To evaluate the immune reconstitution after transplant.		Up to 12 months after transplant.
To determine the transplant related morbidity and mortality.	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.	Up to 365 days post-transplant.
To determine the long-term engraftment after non-myeloablative HSC transplant		Up to 10 years post-transplant.

Other Outcome Measures

Outcome Measure	Time Frame
To determine whether ocular findings from sickle cell disease are reversible in patients undergoing stem cell transplantation to treat their sickle cell disease.	Up to 5 years post-transplant

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago
• Investigators: Principal Investigator: Damiano Rondelli, MD, University of Illinois at Chicago

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2011
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: November 23, 2011
• First Submitted That Met QC Criteria: December 22, 2011
• First Posted (Estimated): December 26, 2011

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Stem Cell Transplantation; Allogeneic; Sickle Cell Disease; Sirolimus; Alemtuzumab; Total Body Irradiation; Subtype Hgb SS; Subtype Hgb SC; Subtype Hgb SB; Chronic Transfusion Therapy; Prior Stroke; Hydroxyurea Intolerant
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Alemtuzumab
• Other Study ID Numbers: 2011-0096

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No