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

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

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.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Mycophenolate mofetil; Drug: Sirolimus; Procedure: Allogeneic bone marrow transplant; Radiation: Total body irradiation - 200; Drug: Levetiracetam; Biological: Anti-thymocyte globulin; Radiation: Total body irradiation - 400

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.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Transplant - 200 cGy; 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.	Drug: Cyclophosphamide; 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.; Other Names: Cytoxan; CTX; Cy; Drug: Fludarabine; Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.; Other Names: Fludara; Drug: Mycophenolate mofetil; Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.; Other Names: CellCept; MMF; Drug: Sirolimus; 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.; Other Names: Rapamune; Procedure: Allogeneic bone marrow transplant; An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.; Other Names: Allo BMT; Radiation: Total body irradiation - 200; 200 centigray (cGy) in one fraction on Day -1.; Other Names: TBI; Drug: Levetiracetam; Given at 500 mg PO twice daily from Day -6 to Day +365.; Other Names: Keppra; Biological: Anti-thymocyte globulin; Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.; Other Names: ATG; Thymoglobulin
Experimental: Transplant - 400 cGy; 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.	Drug: Cyclophosphamide; 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.; Other Names: Cytoxan; CTX; Cy; Drug: Fludarabine; Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.; Other Names: Fludara; Drug: Mycophenolate mofetil; Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.; Other Names: CellCept; MMF; Drug: Sirolimus; 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.; Other Names: Rapamune; Procedure: Allogeneic bone marrow transplant; An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.; Other Names: Allo BMT; Drug: Levetiracetam; Given at 500 mg PO twice daily from Day -6 to Day +365.; Other Names: Keppra; Biological: Anti-thymocyte globulin; Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.; Other Names: ATG; Thymoglobulin; Radiation: Total body irradiation - 400; 400 centigray (cGy) in one fraction on Day -1.; Other Names: TBI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant-related Mortality	Number of participants who died for reasons related to bone marrow transplant.	Up to one year
Progression-free Survival	Percentage of participants who are alive without relapse.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 days
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.	1 year

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Javier Bolanos-Meade, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2008
• Primary Completion (Actual): December 29, 2018
• Study Completion (Actual): December 29, 2018

Study Registration Dates

• First Submitted: June 20, 2007
• First Submitted That Met QC Criteria: June 20, 2007
• First Posted (Estimate): June 21, 2007

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: sickle cell disease
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Anticonvulsants; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Nootropic Agents; Antibiotics, Antitubercular; Cyclophosphamide; Fludarabine; Mycophenolic Acid; Sirolimus; Thymoglobulin; Antilymphocyte Serum; Levetiracetam
• Other Study ID Numbers: J0676; P30CA006973 (U.S. NIH Grant/Contract); P01CA015396 (U.S. NIH Grant/Contract); NA_00002479 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No