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Adding Azathioprine/Hydroxyurea Preconditioning to Alemtuzumab/TBI to Reduce Risk of Graft Failure in MSD HSCT in Adult SCD Patients

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ClinicalTrials.gov Identifier: NCT05249452
Recruitment Status : Recruiting
First Posted : February 21, 2022
Last Update Posted : February 21, 2022
Sponsor:
Information provided by (Responsible Party):
Erfan Nur, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description
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Brief Summary:
In this study the investigators will prospectively investigate whether the addition of a 3-months long preconditioning with azathioprine to the alemtuzumab/TBI non-myeloablative conditioning results in improved disease-free survival and donor chimerism after allo-SCT in SCD patients. Furthermore, the investigators will evaluate whether azathioprine/hydroxyurea preconditioning leads to more patients being able to taper and discontinue sirolimus at 12 months post-transplantation.

Condition or disease Intervention/treatment
Sickle Cell Disease Other: Preconditioning with azathiprine and hydroxyurea (3 months)

Detailed Description:

Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (1 mg/kg alemtuzumab and 300 cGy total body irradiation (TBI)) using peripheral blood derived stem cells has shown promising results in adult SCD patients. However, a large part of these patients did not reach complete donor chimerism (especially relatively low T-cell chimerism) with graft failure rates of approximately 13%. Furthermore a significant proportion of sickle cell patients need to continuously use the immunosuppressive medication sirolimus to prevent graft failure due to poor donor T-cell chimerism. Graft failure is more common in sickle cell patients than in patients who are transplanted for hematological malignancies. Due to the continuously active erythropoiesis, patients with hemoglobinopathies, such as thalassemia and SCD, have expanded bone marrow, which negatively affects engraftment. Another reason for graft failure in these patients is a continuously triggered immune system due to chronic hemolysis and inflammation in hemoglobinopathies. To improve engraftment and donor chimerism, a preconditioning with azathioprine (immunosuppressive) and hydroxyurea (suppressing bone marrow expansion) during three months has been added to the actual conditioning with alemtuzumab/TBI. Azathioprine/hydroxyurea preconditioning has been proven effective in allo-SCT in thalassemia.

In this study the investigators will prospectively investigate whether the addition of a 3-months long preconditioning with azathioprine to the alemtuzumab/TBI non-myeloablative conditioning results in improved disease-free survival and donor chimerism after allo-SCT in SCD patients. A secondary objective is to evaluate whether azathioprine/hydroxyurea preconditioning leads to more patients being able to taper and discontinue sirolimus at 12 months post-transplantation.

Study Design
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Study Type : Observational
Estimated Enrollment : 20 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Adding Azathioprine/Hydroxyurea Preconditioning to Alemtuzumab/TBI to Reduce Risk of Graft Failure in Matched Sibling Donor Allogeneic HSCT in Adult Sickle Cell Patients
Actual Study Start Date : March 8, 2018
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : December 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Organ Donation

Groups and Cohorts
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Group/Cohort Intervention/treatment
Adult transplant-eligible SCD patients with a MSD
Sickle cell disease patients aged 16 years and older with an available matched sibling donor.
 Other: Preconditioning with azathiprine and hydroxyurea (3 months)
Preconditioning with azathiprine and hydroxyurea (3 months) before alemtuzumab/TBI conditioning and matched sibling donor allogeneic stem cell transplantation.


Outcome Measures
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Primary Outcome Measures :
  1. Disease-free survival [ Time Frame: 1 year post-transplantation ]

Secondary Outcome Measures :
  1. Transplantation-related complications [ Time Frame: Day 100 post-transplantation ]
  2. Transplantation-related complications [ Time Frame: 1 year post-transplantation ]
  3. Attenuation of SCD-related organ complications [ Time Frame: 1 year post-transplantation ]
  4. Percentage of donor myeloid chimerism [ Time Frame: 2 years post-transplantation ]
    Using genetic profiles of both the patient and the donor, percentages of myeloid (isolated granulocytes) chimerism will be measured periodically to evaluate the level of engraftment.

  5. Percentage of donor T-cell chimerism [ Time Frame: 2 years post-transplantation ]
    Using genetic profiles of both the patient and the donor, percentages of T-cell (CD3 cells) chimerism will be measured periodically to evaluate the level of engraftment.

  6. Primary graft failure [ Time Frame: day 42 post-transplantation ]
    Defined as never achieving >5% donor whole blood or myeloid chimerism (myeloid is preferable) assessed by bone marrow or peripheral blood chimerism assays by day +42 post-transplant. Second infusion of stem cells is also considered indicative of primary graft failure by day +42 post-transplant.

  7. Secondary graft failure [ Time Frame: 2-years post-transplantation ]
    Defined as < 5% donor whole blood or myeloid chimerism (myeloid is preferable) in peripheral blood or bone marrow beyond day +42 post-transplant in patients with prior documentation of hematopoietic recovery with >5% donor cells by day +42 post-transplant. Second infusion of stem cells is also considered indicative of secondary graft failure.


Eligibility Criteria
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Ages Eligible for Study:   16 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Sickle cell disease patients, 16 years and older, with an available matched sibling donor.
Criteria

Inclusion Criteria:

  • SCD patients with an HLA-identical matched sibling donor eligible for allogeneic stem cell transplantation.
  • Age 16 - 60 years
  • Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
  • Patients and donors (MSD) must be able to sign consent forms for receiving and donating hematopoietic stem cells respectively. The sibling donor should be willing to donate.
  • Patients must be geographically accessible and willing to participate in all stages of treatment.
  • Eligible diagnoses: Patients with sickle cell disease such as sickle cell anemia (Hb SS), Hb/Sβ0-thalassemia, Hb/Sβ+-thalassemia, HbSC disease, HbSE disease, HbSD disease and Hemoglobin SO- Arab disease.

Exclusion Criteria:

  • Poor performance status (ECOG>1).
  • Poor cardiac function: left ventricular ejection fraction<35%.
  • Poor pulmonary function: FEV1 and FVC<40% predicted.
  • Poor liver function: direct bilirubin >3.1 mg/dl
  • HIV-positive
  • Women of childbearing potential who currently are pregnant (Beta-HCG+) or who are not practicing adequate contraception.
  • Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up. However, patients with history of stroke and significant cognitive deficit, that would preclude giving informed consent or assent will not be excluded, if they have a family member or significant other with Power of Attorney to also consent of their behalf.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05249452


Contacts
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Contact: Erfan Nur, MD, PhD 0031-20 - 4442604 e.nur@amsterdamumc.nl
Contact: Management hematology 0031-20 - 4442604 hematology@amsterdamumc.nl

Locations
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Netherlands
Amsterdam Medical Centre Recruiting
Amsterdam, Netherlands
Contact: Erfan Nur, MD, PhD    0031-20-4442604    e.nur@amsterdamumc.nl   
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
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Principal Investigator: Erfan Nur, MD, PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
More Information
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Responsible Party: Erfan Nur, Principal Investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT05249452    
Other Study ID Numbers: W21_160
First Posted: February 21, 2022    Key Record Dates
Last Update Posted: February 21, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Erfan Nur, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Sickle Cell Disease
Allogeneic stem cell transplantation
Mixed chimerism
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
 Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors