Have you or your loved ones been diagnosed with acquired anemia hemolytic?
You may be eligible to participate in a acquired anemia hemolytic clinical trial.
Have you or your loved ones been diagnosed with acquired anemia hemolytic? You may be eligible to participate in a acquired anemia hemolytic clinical trial.
What is a clinical trial? Is participating in a clinical trial right for you? Learn more
Acquired Anemia Hemolytic Clinical Trial in Gainesville FL
Have you or your loved ones been diagnosed with acquired anemia hemolytic?
You may be eligible to participate in a acquired anemia hemolytic clinical trial.
Have you or your loved ones been diagnosed with acquired anemia hemolytic? You may be eligible to participate in a acquired anemia hemolytic clinical trial.
Active not recruiting
Male & Female
3 Months - 39 Years
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.
Details for the study
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 <br /> to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte <br /> globulin (rATG) to determine the minimum effective dose required for reliable engraftment for <br /> 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.
Treatments and/or Procedures
Thiotepa single daily dose
Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
Thiotepa escalated dose
Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
Outcome Measures
Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.
Primary
Assessment of minimum effective dose (MED) of Thiotepa
Assess the MED of thiotepa in combination with reduced-dose busulfan, fludarabine and rATG required to achieve engraftment in >90% subjects undergoing hematopoietic stem cell transplantation for non-malignant disorders.
Secondary
Change in transplant-related complications
Complications gathered via CIBMTR (Center for International Blood & Marrow Transplant Research) post-transplant form will be tabulated and described by treatment received.
Secondary
Evaluation of overall survival (OS)
Change in confidence interval (CI) of all subjects who initiated conditioning regimen and are alive (OS).
Secondary
Evaluation of transplant-related mortality
Change in CI of subjects who initiated conditioning regimen and who die due to a cause unrelated to the underlying disease.
Secondary
Evaluation of disease free survival (DFS)
Change in confidence interval (CI) of all subjects who initiated conditioning regimen and are without evidence of underlying disease (DFS).
Secondary
Evaluation of risk of graft rejection/failure.
Change in confidence interval (CI) of all subjects who initiated conditioning regimen and have sustained engraftment failure.
Secondary
Rate of acute graft-versus-host disease (GVDH) scale
Rank of Modified Glucksberg Staging Criteria. (Scale 0-4; with 4 being most severe)
Secondary
Rate of chronic graft-versus-host disease (cGVHD) scale
Rank of cGVHD grading. (Scale mild, moderate, severe)
Study 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 loci). - 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 mismatch). - 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 as: - 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 cyclophosphamide). - 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