Patient case: 13-year-old male with acute myeloid leukemia; genetic feature: FLT3

Clinical trial: Phase II Trial of Myeloablative Conditioning & Transplantation of Partially HLA-mismatched Marrow With Post-transplant Cyclophosphamide for Peds Pts w/ Hematologic Malignancies

Summary: We propose a multi-institutional phase II haplo-identical T cell replete BMT study in children with high-risk leukemias. The myeloablative conditioning regimen prescribed will be TBI-based for lymphoid leukemias and busulfan-based for myeloid leukemias. Our goal is to establish an easily exportable, inexpensive platform for haplotransplantation that has a safety profile equivalent to matched related and unrelated BMTs. The primary objective will be to estimate the incidence of 6-month non-relapse mortality, hypothesizing that NRM is < 18%.

Detailed description: This is a phase II prospective study designed to evaluate the incidence of 6 month non- relapse mortality, safety, and feasibility of haploidentical bone marrow transplantation (BMT) after myeloablative conditioning with post-transplant Cy. Conditioning regimens include a total body irradiation-based prep for lymphoid leukemias and a chemotherapy based prep for myeloid leukemias.
  To estimate the incidence of non-relapse mortality at 180 days following myeloablative haploidentical BMT for children and young adults with high risk hematologic malignancies.

Eligibility: Inclusion Criteria:
  -  Patient age 0.5-25years
  -  Patients must have a first-degree related donor or half-sibling who is at minimum HLA haploidentical. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
  -  An unrelated donor search is not required for a patient to be eligible for this protocol, or a donor search and donor mobilization may be abandoned if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor. Patients with an eligible HLA-matched RELATED should not be enrolled on this trial.
  -  Patients must have at least one of the following high-risk conditions listed below (criteria are meant to complement existing criteria within COG protocols):
  -  Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following:
  hypodiploidy, induction failure, MRD after consolidation
  - Acute myeloid leukemia (AML) in CR1 with high risk features defined as: High allelic ratio FLT3/ITD+, Monosomy 7, Del (5q), Standard risk cytogenetics with positive minimal residual disease at the end of Induction I chemotherapy (for patients being treated on or according to COG AAML1031 who have had MRD studies sent to Seattle or performed at their local institution where the flow assay is sensitive enough to detect > 0.1% blasts)
  -  Acute Leukemias in 2nd or subsequent CR (CR>2)
  -  Mixed phenotype/Undifferentiated Leukemias in 1st or subsequent CR*
  -  Secondary or therapy related leukemias in CR > 1
  -  NK cell lymphoblastic leukemia CR > 1
  -  Myelodysplastic syndrome (MDS)
  -  JMML (patients are eligible if they are not eligible for COG1221)
  -  Prior transplant eligible if < 18yo, >6 months has elapsed since BMT, and patient is off immunosuppression for > 3 months with no GVHD
  -  No known active CNS involvement or extramedullary involvement by malignancy. Such disease treated into remission is permitted.
  -  Acute Leukemia - Remission is defined as morphology with < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity.
  Exclusion Criteria:
  -  Patients will not be excluded on the basis of sex, racial or ethnic background.
  -  Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age.
  -  Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO <50% predicted (corrected for hemoglobin) for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 92% on RA.
  -  Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy). ALT or AST > 3 x laboratory upper normal limits.
  -  Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated creatinine clearance is permitted) < 60 mL/min based on Traditional Cockcroft-Gault formula: 140 - age (yrs) x Smaller of Actual Weight vs. Ideal Body Weight (kg) / 72 x Serum creatinine (mg/dl) Multiply by another factor of 0.85 if female Intended for ages 18-110, serum creatinine 0.6-7 mg/dl For patients <18 years: CrCl will be estimated by the Schwartz formula. A measured CrCl or a GFR may be substituted to determine the subject's CrCl.
  -  Schwartz equation: CrCl (ml/min/1.73m2)=[length (cm) x k] /serum creatinine K = 0.45 for infants 1 to 52 weeks old k = 0.55 for children 1 to 13 years old k = 0.55 for adolescent females 13-18 years old k = 0.7 for adolescent males 13-18 years old
  -  HIV-positive
  -  Positive leukocytotoxic crossmatch Specifically, complement dependent cytotoxicity and flow cytometric crossmatch assays must be negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be <3000. Consult with PI for the clinical significance of any anti-donor antibody.
  -  Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception or who are breastfeeding
  -  Uncontrolled viral, bacterial, or fungal infections (currently taking medication and have progression of clinical symptoms)
  -  Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay

Relevance to patient case: not relevant