Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation

Brief Title

Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation

Official Title

PEDS024, Phase I/II Feasibility Study of Busulfan Fludarabine and Thiotepa Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation (HSCT) for Children With Non-Malignant Disorders

Brief Summary

      In this study, the investigators test 2 dose levels of thiotepa (5 mg/kg and 10 mg/kg) added
      to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte
      globulin (rATG) to determine the minimum effective dose required for reliable engraftment for
      subjects undergoing hematopoietic stem cell transplantation for non-malignant disease.

Detailed Description

      Hematopoietic stem cell transplantation is the only curative choice for a number of inherited
      bone marrow failure syndromes, hemoglobinopathies, metabolic disorders and primary immune
      deficiencies. While survival of these patients is typically better than survival of patients
      with malignancies, toxicities of conditioning regimens and failure of engraftment remain
      challenges. Most children with non-malignant disorders present with normocellular or even
      hypercellular bone marrow, posing a barrier to engraftment and requiring intensive
      conditioning. Commonly used backbone of busulfan and fludarabine, although well tolerated,
      results in variable engraftment, in particular with mismatched unrelated donors and cord
      blood recipients. In this study, the investigators test 2 dose levels of thiotepa (5 mg/kg
      and 10 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and
      rabbit anti-thymocyte globulin (rATG) in order to determine the minimum effective dose
      required for reliable engraftment. Subjects are stratified in groups A and B based the risk
      of graft failure.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Assessment of minimum effective dose (MED) of Thiotepa

Secondary Outcome

 Evaluation of risk of graft rejection/failure.


Bone Marrow Failure Syndrome


Thiotepa--single daily dose

Study Arms / Comparison Groups

 Group A--Thiotepa single dose
Description:  Fully matched 10/10 subjects with lower risk of graft failure. Subjects will undergo 10/10 HLA (human leukocyte antigen) matched bone marrow and peripheral blood transplant. Subjects receive combination of single daily dose thiotepa (5 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG).


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

June 15, 2018

Completion Date

February 2022

Primary Completion Date

February 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnoses:

               -  Hemoglobinopathies (e.g. thalassemia or sickle cell disease),

               -  Cytopenias (e.g.Diamond-Blackfan anemia, congenital or acquired neutropenia,
                  congenital or acquired thrombocytopenia, congenital or acquired anemia, and
                  others, regardless clonality),

               -  Hemophagocytic lymphohistiocytosis,

               -  Primary immunodeficiencies (e.g. Wiscott Aldrich Syndrome, chronic granulomatous
                  disease, common variable immune deficiency, X-linked lymphoproliferative disease,
                  NK+ severe combined immune deficiencies),

               -  Metabolic disorders (Hurler's syndrome, mannosidosis, adrenal leuko-dystrophy)

               -  Other non-malignant disorders for which there is published evidence that HSCT
                  (hematopoietic stem cell transplant) is a curative therapy.

          -  Donor Requirements

               -  Related or unrelated donor who is suitable and willing to donate bone marrow or
                  peripheral blood stem cells. HLA typing should be done by high-resolution typing
                  at A, B, C, DrB1 and DQ loci and the donor should be at a minimum ≥8/10 match
                  (with one antigen/allele mismatch allowed at A, B, or C-loci and other at DQ

               -  Cord blood units must be matched at a minimum of 6/8 antigens/alleles at A, B, C
                  and DrB1 loci. High resolution typing at all loci is required. The minimum TNC
                  dose pre-cryopreservation must be ≥3.7 x10^7/kg of recipient's weight, if a
                  single cord blood unit is used, or at least 2x10^7/kg per unit, if two cord blood
                  units are used. The mismatches cannot be at the same loci (e.g. double A

               -  Haploidentical related stem cell donor who is suitable and willing to donate
                  peripheral blood stem cells. T-cell depletion is required if haploidentical
                  donors are used. Pharmacologic GVHD prophylaxis will not be used for T-cell
                  depleted transplant recipients.

          -  Adequate organ function defined as:

               -  Cardiac: ejection fraction ≥55% or shortening fraction ≥30%

               -  creatinine clearance ≥70 ml/min/1.73m2

               -  Pulse oximetry >95% on room air or FEV1/DLCO >60%

               -  LFTs < 3 x ULN, Total bilirubin <3 mg/dl (unless due to non-hepatic cause (e.g.
                  Gilbert's syndrome or hemolysis)

          -  Lansky/Karnofsky score ≥60%

          -  Written informed consent obtained from the subject or parental/guardian permission ±
             child's assent per institutional guidelines

          -  Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy for at least 1 month after completion of
             conditioning. WOCBP include any woman who has experienced menarche and who has not
             undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
             or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined

               -  Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or

               -  For women with irregular menstrual periods who are taking hormone replacement
                  therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of
                  greater than 35 mIU/mL.

               -  Males with female partners of childbearing potential must agree to use
                  physician-approved contraceptive methods (e.g., abstinence, condoms, or
                  vasectomy) for at least one month after completion of conditioning.

        Exclusion Criteria:

          -  Diagnoses that do not require myeloablative transplant for cure (e.g. NK- SCID
             patients), unless the subject previously did not engraft with non-myeloablative or
             reduced intensity conditioning transplant.

          -  Known or suspected sensitivity to chemotherapy or radiation (e.g Fanconi's anemia,
             Dyskeratosis congenita, Ligase IV deficiency, etc).

          -  Subjects with fast-progressing neurodegenerative disorders (e.g. Krabbe disease or
             adrenal leukodystrophy with Loes score of ≥10)

          -  Cytopenias with increased blasts (>5%)

          -  Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as
             a positive cross-match test of any titer (by complement-dependent cytotoxicity or flow
             cytometric testing) or the presence of anti-donor HLA antibody to the high expression
             loci HLA-A, B, C, DRB1 with mean fluorescence intensity (MFI)>3000 by solid phase

          -  Prior allogeneic stem cell transplant, except for patients with immune deficiencies
             who underwent previous non-myeloablative or reduced intensity transplants.

          -  Haploidentical donor using in vivo T-cell depletion (e.g. post-transplant

          -  Uncontrolled bacterial, viral, or fungal infection at the time of enrollment.
             Uncontrolled is defined as currently taking medication and with progression or no
             clinical improvement on adequate medical treatment.

          -  Seropositive for HIV

          -  Active Hepatitis B or C determined by a detectable viral load of HBV or HCV by PCR

          -  Bridging fibrosis or liver cirrhosis

          -  Females or males of childbearing potential who are unwilling or unable to use an
             acceptable method to avoid pregnancy for the entire study period and for at least 1
             months after the end of conditioning

          -  Females who are pregnant or breastfeeding

          -  History of any other disease, metabolic dysfunction, physical examination finding, or
             clinical laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of protocol therapy or that might affect the interpretation of
             the results of the study or that puts the subject at high risk for treatment
             complications, in the opinion of the treating physician.

          -  Subjects demonstrating an inability to understand the study and comply with the study
             and/or follow-up procedures




3 Months - 39 Years

Accepts Healthy Volunteers



Biljana Horn, MD, 3522739050, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

University of Florida


 Live Like Bella Pediatric Cancer Research

Study Sponsor

Biljana Horn, MD, Principal Investigator, University of Florida

Verification Date

July 2021