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Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders

Primary Purpose

Sickle Cell Disease

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
Mycophenolate mofetil
Sirolimus
Allogeneic bone marrow transplant
Total body irradiation - 200
Levetiracetam
Anti-thymocyte globulin
Total body irradiation - 400
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring sickle cell disease

Eligibility Criteria

2 Years - 70 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following sickle cell anemias (Hb SS):

    • Hb S/β° thalassemia
    • Hb S/β+ thalassemia
    • Hb SC disease
    • Hb SE disease
    • Hb SD disease
    • Hemoglobin SO-Arab disease
    • Hb S/hereditary persistence of fetal hemoglobin

  • Meets 1 of the following criteria:

    • History of invasive pneumococcal disease
    • Stroke or CNS event lasting > 24 hours
    • MRI changes indicative of brain parenchymal damage
    • Evidence of cerebrovascular disease by magnetic resonance angiography
    • Acute chest syndrome requiring exchange transfusion or hospitalization
    • Recurrent vaso-occlusive pain crisis (> 2 per year for the last 2 years)
    • Stage I or II sickle lung disease
    • Sickle retinopathy
    • Osteonecrosis
    • Red cell alloimmunization (> 2 antibodies) during long-term transfusion
    • Constellation of dactylitis in the first year of life AND a baseline hemoglobin < 7 g/dL and leukocytosis (WBC > 13.4/mm^3) in the absence of infection during the second year of life
    • Pitted RBC count > 3.5% during the first year of life
  • Ineligible for or refused bone marrow transplantation from an HLA-matched sibling donor

  • Partially mismatched (at least haploidentical) first-degree relative donor available

    • No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100%
  • LVEF ≥ 35%
  • FEV_1 and forced vital capacity ≥ 40% predicted
  • Direct bilirubin < 3.1 mg/dL
  • No moderate to severe pulmonary hypertension by ECHO
  • No debilitating medical or psychiatric illness that would preclude study participation
  • No HIV positivity
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • No prior transfusions from donor
  • No immunosuppressive agents, including steroids as antiemetics, within 24 hours after the last dose of post-transplantation cyclophosphamide

Sites / Locations

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Transplant - 200 cGy

Transplant - 400 cGy

Arm Description

Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 200. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.

Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 400. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.

Outcomes

Primary Outcome Measures

Transplant-related Mortality
Number of participants who died for reasons related to bone marrow transplant.
Progression-free Survival
Percentage of participants who are alive without relapse.

Secondary Outcome Measures

Donor Chimerism at 30 Days
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Donor Chimerism at 1 Year
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.

Full Information

First Posted
June 20, 2007
Last Updated
March 25, 2019
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00489281
Brief Title
Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders
Official Title
A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Anemia and Other Hemoglobinopathies
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Terminated
Why Stopped
Initiation of CMS BMT study for sickle-cell disease operating under NCT01166009 made further accrual to this study impossible.
Study Start Date
June 23, 2008 (Actual)
Primary Completion Date
December 29, 2018 (Actual)
Study Completion Date
December 29, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by a donor bone marrow transplant works in treating patients with sickle cell anemia and other blood disorders.
Detailed Description
OBJECTIVES: Determine the transplant-related mortality and progression-free survival of patients with severe hemoglobinopathies receiving nonmyeloablative conditioning comprising fludarabine phosphate, cyclophosphamide, and total-body irradiation followed by partially HLA-mismatched bone marrow transplantation from first-degree relatives or HLA-matched donors. Characterize donor hematopoietic chimerism at 30, 60, and 180 days after transplantation in these patients. Determine the hematologic and non-hematologic toxicity of this regimen in these patients. OUTLINE: Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients also undergo total-body irradiation on day -1. Bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Graft-versus-host disease prophylaxis: Patients receive sirolimus orally daily on days 5-365 and oral mycophenolate mofetil 3 times a day on days 5-35. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
sickle cell disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Transplant - 200 cGy
Arm Type
Experimental
Arm Description
Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 200. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.
Arm Title
Transplant - 400 cGy
Arm Type
Experimental
Arm Description
Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 400. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, Cy, CTX
Intervention Description
Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
MMF, CellCept
Intervention Description
Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic bone marrow transplant
Other Intervention Name(s)
Allo BMT
Intervention Description
An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation - 200
Other Intervention Name(s)
TBI
Intervention Description
200 centigray (cGy) in one fraction on Day -1.
Intervention Type
Drug
Intervention Name(s)
Levetiracetam
Other Intervention Name(s)
Keppra
Intervention Description
Given at 500 mg PO twice daily from Day -6 to Day +365.
Intervention Type
Biological
Intervention Name(s)
Anti-thymocyte globulin
Other Intervention Name(s)
ATG, Thymoglobulin
Intervention Description
Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.
Intervention Type
Radiation
Intervention Name(s)
Total body irradiation - 400
Other Intervention Name(s)
TBI
Intervention Description
400 centigray (cGy) in one fraction on Day -1.
Primary Outcome Measure Information:
Title
Transplant-related Mortality
Description
Number of participants who died for reasons related to bone marrow transplant.
Time Frame
Up to one year
Title
Progression-free Survival
Description
Percentage of participants who are alive without relapse.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Donor Chimerism at 30 Days
Description
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Time Frame
30 days
Title
Donor Chimerism at 1 Year
Description
Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
DISEASE CHARACTERISTICS: Diagnosis of 1 of the following sickle cell anemias (Hb SS): Hb S/β° thalassemia Hb S/β+ thalassemia Hb SC disease Hb SE disease Hb SD disease Hemoglobin SO-Arab disease Hb S/hereditary persistence of fetal hemoglobin Meets 1 of the following criteria: History of invasive pneumococcal disease Stroke or CNS event lasting > 24 hours MRI changes indicative of brain parenchymal damage Evidence of cerebrovascular disease by magnetic resonance angiography Acute chest syndrome requiring exchange transfusion or hospitalization Recurrent vaso-occlusive pain crisis (> 2 per year for the last 2 years) Stage I or II sickle lung disease Sickle retinopathy Osteonecrosis Red cell alloimmunization (> 2 antibodies) during long-term transfusion Constellation of dactylitis in the first year of life AND a baseline hemoglobin < 7 g/dL and leukocytosis (WBC > 13.4/mm^3) in the absence of infection during the second year of life Pitted RBC count > 3.5% during the first year of life Ineligible for or refused bone marrow transplantation from an HLA-matched sibling donor Partially mismatched (at least haploidentical) first-degree relative donor available No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100% LVEF ≥ 35% FEV_1 and forced vital capacity ≥ 40% predicted Direct bilirubin < 3.1 mg/dL No moderate to severe pulmonary hypertension by ECHO No debilitating medical or psychiatric illness that would preclude study participation No HIV positivity Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: No prior transfusions from donor No immunosuppressive agents, including steroids as antiemetics, within 24 hours after the last dose of post-transplantation cyclophosphamide
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Javier Bolanos-Meade, MD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Study Chair
Facility Information:
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231-2410
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30878319
Citation
Bolanos-Meade J, Cooke KR, Gamper CJ, Ali SA, Ambinder RF, Borrello IM, Fuchs EJ, Gladstone DE, Gocke CB, Huff CA, Luznik L, Swinnen LJ, Symons HJ, Terezakis SA, Wagner-Johnston N, Jones RJ, Brodsky RA. Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial. Lancet Haematol. 2019 Apr;6(4):e183-e193. doi: 10.1016/S2352-3026(19)30031-6. Epub 2019 Mar 14. Erratum In: Lancet Haematol. 2019 May;6(5):e238.
Results Reference
derived

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Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders

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