Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease (SCD) and B-Thalassemia

People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults.

The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons.

To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused.

Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling.

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Study Overview

• Status: Active, not recruiting
• Conditions: Sickle Cell Disease; Congenital Hemolytic Anemia
• Intervention / Treatment: Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant; Drug: Alemtuzumab; Drug: Sirolimus; Procedure: Peripheral blood hematopoietic progenitor cell Apheresis

Detailed Description

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Preliminary data have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe graft versus host disease (GVHD) leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration.

In this protocol, we propose transplantation in patients with severe beta-globin disorders including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for complications from or ineligible for standard BMT, with allogeneic PBSCs from an HLA identical sibling using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of low dose radiation, Alemtuzumab (Campath) and Sirolimus (Rapamune) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony stimulating factor (filgrastim, G-CSF) mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with beta-thalassemia. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft-vs-host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Priscilla S Pollack, R.N.; Phone Number: (301) 496-1781; Email: priscilla.pollack@nih.gov
• Study Contact Backup: Name: John F Tisdale, M.D.; Phone Number: (301) 402-6497; Email: johntis@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

• INCLUSION CRITERIA:

RECIPIENTS:

Must fulfill one disease category from below:

DISEASE SPECIFIC:

Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end organ damage (A, B, C, D or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by and infarct on cerebral MRI

OR

an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);

OR

B. Sickle cell related renal insufficiency defined by a creatinine level greater than or equal to 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis

OR

Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl

Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl

Age is greater than 10 years and less than or equal to 15 years of age the the upper limit of normal serum creatinine 1.2mg/dl

Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl

C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso-occlusive crisis, OR

D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR

E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR

F. Any one of the below complications:

1. Vaso-occlusive crisis:

   • Eligible for hydroxyurea; at least 3 hospital admissions in the last year
   • Eligible for HSCT; More than 1 hospital admission per year while on therapeutic dose of hydroxyurea

2. Acute Chest Syndrome (ACS):

   • Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma
   • Eligible for HSCT: any ACS while on hydroxyurea*

3. Osteonecrosis of 2 or more joints:

   • Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60
   • Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level

4. Red cell alloimmunization:

   • Eligible for hydroxyurea: Transfusion dependent

   • Eligible for HSCT: Total hemoglobin increase less than 1 g/dL while on hydroxyurea*

     • hydroxyurea at therapeutic dose

   Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

   • portal fibrosis by liver biopsy
   • inadequate chelation history (defined as failure to maintain adequate compliance with chelation with desferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week)
   • Hepatomegaly of greater than 2 cm below the costochondral margin

   NON-DISEASE SPECIFIC:

   • Ages greater than or equal to 4 years
   • 6/6 HLA matched family donor available
   • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
   • Negative serum beta-HCG
   • Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation

   DONOR:

   Donor deemed suitable and eligible, and willing to donate per clinical evaluations, who are additionally willing to donate blood for research and undergo a neuropsychological test. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation under a separate NHLBI protocol. Note that participation in this study is offered to all donors, but is not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study.

   EXCLUSION CRITERIA:

   RECIPIENT:

   (Any of the following would exclude the subject from participating)

   ECOG performance status of 3 or more or Lansky performance status of less than 40.

   Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for hemoglobin and alveolar volume)

   Baseline oxygen saturation or less than 85 % or PaOa2 less than 70

   Left ventricular ejection fraction: less than 35% estimated by ECHO.

   Transaminases greater than 5 times the upper limit of normal for age

   Evidence of uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen

   Major anticipated illness or organ failure incompatible with survival from PBSC transplant.

   Pregnant or lactating

   Major ABO mismatch

   DONOR:

   None

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants; Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings.	Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant; Peripheral blood hematopoietic progenitor cell (PBPC) transplant; Drug: Alemtuzumab; Alemtuzumab; Other Names: Campath; Drug: Sirolimus; Sirolimus; Other Names: Rapamune
Experimental: Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor; Participants received Filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling.	Procedure: Peripheral blood hematopoietic progenitor cell Apheresis; Donor-Peripheral blood hematopoietic progenitor cell (PBPC) apheresis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants That Experience Treatment Success Following Stem Cell Transplant	Number of participants that experience treatment success at one year following stem cell transplant. Treatment success is defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with sickle cell disease and transfusion-independence for patients with beta-thalassemia.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Myeloid Chimerism Level	Mean Myeloid Chimerism Level in participants following stem cell transplant.	up to 2 years
Number of Participants Who Developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as Defined by CIMBTR Criteria for Organ Stages of Acute GVHD.	Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grades are defined as: Grade I: Skin = Maculopapular rash< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day. Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.	Up to 1 year
Number of Participants Who Developed Limited or Extensive Chronic GVHD	Number of participants who developed Limited or Extensive Chronic Graft vs Host Disease (GVHD). Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction. Limited disease is associated with a favorable outcome without systemic therapy, while extensive disease patients have an unfavorable outcome. Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD. Extensive disease presents either with generalized skin involvement, or with localized skin involvement or hepatic dysfunction plus at least one of the following: Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and classification of Sjögren's syndrome") Involvement of minor salivary glands or oral mucosa (as demonstrated on labial or mucosal biopsy specimen) Involvement of any other target organ	Day 100 up to 3 Years
Number of Participants With Regimen Failure	Number of participants with regimen failure. Regimen failure is defined as those participants that experienced graft verses host disease or relapse of sickle cell disease or beta-thalassemia.	Up to 1 year
Number of Participants With Disease-free Survival	Number of participants with disease-free survival, as defined by: alive and free of acute complications related to sickle cell disease or beta-thalassemia.	Up to 2 year
Number of Participants Overall Survival	Number of participants overall survival at year 1 and year 2. Overall survival is defined as participants alive at 1 and 2 years following stem cell transplant.	1 year and 2 year
Number of Participants That Experienced a Transplant-related Mortality	Number of participants that experienced a transplant related mortality, as defined as death from causes other than relapse (such as: GVHD, toxicity, infection, other and unknown causes).	Up to 2 year

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: John F Tisdale, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. doi: 10.1056/NEJM199406093302303.
• Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. doi: 10.1056/NEJM199505183322001.
• Wayne AS, Schoenike SE, Pegelow CH. Financial analysis of chronic transfusion for stroke prevention in sickle cell disease. Blood. 2000 Oct 1;96(7):2369-72.
• Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 Jul 2;312(1):48-56. doi: 10.1001/jama.2014.7192.
• Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD, Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale JF. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009 Dec 10;361(24):2309-17. doi: 10.1056/NEJMoa0904971.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2004
• Primary Completion (Actual): January 20, 2023
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: May 29, 2003
• First Submitted That Met QC Criteria: May 28, 2003
• First Posted (Estimated): May 29, 2003

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Stem Cell Transplant; Donor Apheresis; Beta-Thalassemia; Low Dose Radiation; Alemtuzumab (Campath); Sirolimus (Rapamune); Sickle Cell Anemia (SCA)
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Hemoglobinopathies; Anemia; Anemia, Sickle Cell; Anemia, Hemolytic; Anemia, Hemolytic, Congenital; 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: 030170; 03-H-0170

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Protocol is available to be shared upon request to PI.
• IPD Sharing Time Frame: Immediately
• IPD Sharing Access Criteria: Protocol is available to be shared upon request to PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No