Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Donor Stem Cell Transplantation Using α/β+ T-lymphocyte Depleted Grafts From HLA Mismatched Donors

Summary: This study is being done to learn whether a new method to prevent rejection between the donor immune system and the patient's body is effective.


Eligibility: Subject Inclusion Criteria:
  -  Patients with any of the following hematologic malignancies who are considered to be eligible for allogeneic transplantation:
  -  Acute lymphoid leukemia (ALL) in first complete remission (CR1) with high risk for relapse including:
  -  Detectable minimal residual disease by either multicolor flow cytometry or by genomic assay after initial induction therapy
  -  t(9;22) or detected BCR-ABL1 translocation by genomic methodologies
  -  BCR-ABL1-Like B-ALL [23] including mutations of IKZF1 or CRLF2
  -  Translocations or mutations involving 11q23 (MLL) gene.
  -  Hypodiploid karyotype
  -  Deletion of 9p
  -  Loss of 17p or TP53 mutation
  -  T-lymphocyte lineage antigen expression (T-ALL)
  -  Prior CNS or other extramedullary involvement
  -  WBC count ≥ 100,000 cells/μL at diagnosis
  -  Acute biphenotypic or bilineal leukemia in CR1
  -  Acute myeloid leukemia (AML) in CR1 with
  -  Detectable minimal residual disease (MRD) by either multicolor flow cytometry or by genomic assay after initial induction therapy
  -  In the absence of MRD any intermediate or high risk features according to the European LeukemiaNet 2017 guidelines indlucing:
  -  Mutated FL T3-ITD or FL T3-TKD
  -  Cytogenetic abnormalities not classified as favorable
  -  Cytogenetic abnormalities associated with myelodysplastic syndrome including abnormalities of chromosome 5, 7, or 17p
  -  Complex karyotype or monosomal karyotype
  -  t(9;11)(p21.1;q23.3); MLL-KMT2A or other rearrangements of KMT2A
  -  t(9;11); BCR-ABL1
  -  Inversions or translocations of chromosome 3
  -  T(6;9)(p23;q34.1); DEK-NUP214
  -  Somatic mutation of RUNX1, ASX1 or TP53
  -  Extramedullary involvement
  -  WBC count ≥100,000 cells/μL at diagnosis
  -  Relapsed acute leukemia with ≤ 5% blasts in the bone marrow prior to transplantation (i.e. CR2 or greater).
  -  Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN overlap syndrome with ≤ 10% blasts and at least one of the following:
  -  Revised International Prognostic Scoring System risk score of INT, HIGH, or VERY HIGH at the time of transplant evaluation.
  -  Life-threatening cytopenias
  -  Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype.
  -  Therapy related disease or disease evolving from other malignant processes.
  -  Chronic myelomonocytic leukemia (CMML) with ≤ 10% blasts prior to transplantation.
  -  Chronic myeloid leukemia (CML) meeting one of the following criteria:
  -  Failed or are intolerant to BCR-ABL tyrosine kinase inhibitors.
  -  CML with BCR-ABL mutation consistent with poor response to tyrosine kinase inhibition (e.g. T351I mutation).
  -  CML with accelerated or blast phase with <10% blasts after therapy.
  -  Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the EBMT consensus criteria
  -  Hodgkin lymphoma meeting both of the following criteria:
  -  Responding to therapy prior to enrollment
  -  Relapse after autologous bone marrow transplant or are ineligible for autologous bone marrow transplant.
  °Non-Hodgkin lymphoma meeting both of the following criteria:
  -  Responding to therapy prior to enrollment.
  -  Relapse after prior autologous bone marrow transplant or are ineligible for autologous bone marrow transplant.
  -  Patients aged from birth through 65 years old are eligible.
  -  Patients must have Karnofsky/Lanksy performance status ≥70%.
  -  Cardiac left ventricular ejection fraction ≥50% at rest.
  -  Serum bilirubin ≤ 2 mg/dL. Patients with Gilbert's disease or ongoing hemolytic anemia are acceptable if the direct bilirubin is ≤ 2 mg/dL.
  -  AST and ALT ≤ 2.5 x ULN unless thought to be disease related
  -  Estimated or measured creatinine clearance > 50 mL/min/1.73 m^2 body surface area.
  -  Adult patients and pediatric patients capable of performing pulmonary function studies must have hemoglobin adjusted pulmonary DLCO ≥50% of predicted.
  Subject Exclusion Criteria:
  -  Persons with a HLA matched sibling donor or a 8/8 allele level HLA-matched unrelated donor.
  -  Female patients who are pregnant or breast-feeding.
  -  Persons with an infection that is not responding to antimicrobial therapy.
  -  Persons who are seropositive for HIV.
  -  Persons with active/detectable central nervous system malignancy.
  -  Persons who do not meet the age and organ function criteria specified above.
  -  Presence of psychiatric or neurologic disease, or lack of social support that limits the patient's ability to comply with the treatment protocol including supportive care, followup, and research tests.
  -  Prior allogeneic hematopoietic cell transplantation are ineligible.
  -  Patients with history of other malignancy within 5 years of study therapy are ineligible with the following exceptions: Low grade prostate cancer (Gleason's ≤6) treated with curative intent, breast ductal carcinoma in situ treated with curative intent, or nonmelanomatous skin carcinomas.
  Donor Inclusion and Exclusion Criteria:
  -  Partially HLA-matched unrelated volunteers (allele level matched at 6-7 of 8 HLA loci: -A, -B, -C, and -DRB1) are eligible.
  -  Related, haploidentical donors are eligible.
  -  Able to provide informed consent to the donation process
  -  Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines.

Relevance to patient case: not relevant