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This is a prospective, open-label, nonrandomized, prospective clinical trial evaluating a fixed regimen of treosulfan, fludarabine and low-dose total body irradiation (TBI) in children with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). The primary hypothesis is that HCT with a preparative regimen consisting of treosulfan, fludarabine and low-dose TBI will result in overall survival (OS) comparable to historical rates observed with conventional myeloablative regimens in the pediatric population. The preparative regimen will result in adequate incidence of neutrophil and platelet engraftment, and acceptable rates of graft-versus-host disease (GVHD), relapse and survival. The pharmacokinetic (PK) profile of treosulfan in children will be comparable to that of adults previously studied.
Full description
The proposed study will evaluate a regimen using treosulfan, fludarabine and low-dose TBI in children and adolescents with AML or MDS undergoing allogeneic HCT. We expect this regimen to yield lower toxicity and at least equivalent rates of disease control and overall survival, compared to current standard myeloablative regimens. The primary objective of this study is to determine the safety and preliminary efficacy of a transplant preparative regimen consisting of treosulfan, fludarabine and low-dose TBI for children with AML and MDS. The primary endpoint will be overall survival (OS) at one year. Secondary objectives to be studied include: pharmacokinetic (PK) profile of treosulfan in children < 40 kg, non-relapse mortality, disease-free survival, incidences of neutrophil and platelet engraftment, donor chimerism, acute and chronic graft-versus-host disease (GVHD), and relapse.
Enrollment
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Inclusion criteria
Age < 21 years.
Disease and disease status:
Karnofsky Index or Lansky Play-Performance Scale > 70 % on pre-transplant evaluation. Karnofsky scores must be used for patients > 16 years of age and Lansky scores for patients < 16 years of age.
Able to give informed consent if > 18 years, or with a legal guardian capable of giving informed consent if < 18 years.
Negative pregnancy test (serum, urine β-HCG, or other test per institutional guidelines) for females of childbearing potential.
A single previous autologous or allogeneic HCT is allowed as long as the time from first to second transplant hematopoietic cell infusion is no less than 6 months.
With a suitable allogeneic hematopoietic cell donor including, as available:
HLA-identical related donor matched for HLA-A, and -B at the serologic level at minimum and -DRB1 at high resolution by molecular typing. A single locus mismatched related donor (7/8 matched) is permitted only if there are no 8/8 matched unrelated donors available.
Unrelated volunteer donor matched for HLA-A, -B, -C and -DRB1 defined by high resolution molecular typing. A single HLA antigen or allele mismatch (7/8 matched) is permitted.
Unrelated cord blood (UCB) matched to the recipient at a minimum of 4 of 6 loci at HLA-A, and -B by intermediate resolution and -DRB1 by high resolution. Cord blood unit(s) will be selected using the following criteria:
The UCB unit with the least HLA disparity with the patient, followed by the larger cell dose for equivalently matched units, will be considered unit #1 (selection priority is 6/6 match >5/6 match>4/6 match).
An additional UCB unit may be required to achieve the required cell dose, as outlined in the table below. The second unit will be the one that most closely HLA matches the patient and meets minimum size criteria as outlined below (i.e. a smaller and more closely matched unit will be selected over a larger less well matched unit as long as minimum cell dose criteria are met).
Each UCB unit MUST contain at least 1.5 x 10^7 TNC per kilogram recipient weight.
Use of unlicensed cord blood units will adhere to current federal regulatory requirements for procurement.
Units will be selected based on the TNC dose and HLA matching.
A UCB unit that is 4/6 or 5/6 mismatched but homozygous at the locus of mismatch should be chosen over a 5/6 unit with bidirectional mismatch even if the latter unit provides a larger cell dose. This is only applicable to choosing units within a given match grade.
Within the best HLA match grade, the unit containing the greatest number of cells will be chosen. If there are two units of equivalent cell dose within a match level, choose the unit with best match by higher resolution molecular typing, if known.
Other factors to be considered:
i. Within the same HLA match grade, matching at both DR loci is preferable. ii. UCB units sourced from cord blood banks located in the United States are preferred.
iii. Younger units are preferred over older units, all other factors being equal.
Adequate organ function, defined as:
Co- enrollment in PBMTC ONC 1001 (CIBMTR 09-MRD) protocol and/or CIBMTR 10-CBA protocol (NMDP cord blood IND) is allowed. Co-enrollment on any other studies where experimental therapy is being administered will be handled on a case-by-case basis and must be discussed with the study chair or designee prior to enrollment.
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
40 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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