Myeloablative Haploidentical BMT With Post-transplant Cyclophosphamide for Pediatric Patients With Hematologic Malignancies
Condition: Myeloablative Conditioning; HLA-mismatched Bone Marrow Transplantation; Graft Survival; Transplantation, Bone Marrow
MeSH terms: Hematologic Neoplasms
Intervention: Cyclophosphamide; TBI; Busulfan; Unmanipulated Bone Marrow; Tacrolimus; Mycophenolate mofetil
Intervention description: Chemotherapy administration; Radiation Therapy; Chemotherapy Administered; Bone Marrow Transplant; Immunosuppressive Drug Administered; Immunosuppressive Drug Administered
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Busulfan; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 6 Months
Maximum age: 25 Years
Healthy volunteers: No
Keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Juvenile myelomonocytic leukemia; Treatment related leukemia; Biphenotypic leukemia

Summary:

      This is a multi-institutional phase II haploidentical T cell replete bone marrow transplant
      (BMT) study in children with high-risk leukemia. The myeloablative conditioning regimen
      prescribed will be Total body irradiation (TBI)-based for lymphoid leukemia and
      busulfan-based for myeloid leukemia. 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 (NRM), hypothesizing that NRM is < 18%.
    

Eligibility criteria:

        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:

          -  Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following:

        hypodiploidy, induction failure,Minimal residual disease (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 Children's Oncology Group (COG) AAML1031 study 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 Leukemia in 2nd or subsequent CR (CR>2)

          -  Mixed phenotype/Undifferentiated Leukemia in 1st or subsequent CR*

          -  Secondary or therapy related leukemia in CR > 1

          -  Natural Killer (NK) cell lymphoblastic leukemia CR > 1

          -  Myelodysplastic syndrome (MDS)

          -  Juvenile myelomonocytic leukemia (JMML) (patients are eligible if they are not
             eligible for COG1221 study)

          -  Prior transplant eligible if < 18yo, >6 months has elapsed since BMT, and patient is
             off immunosuppression for > 3 months with no Graft versus host disease (GVHD)

          -  No known active Central nervous system (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:

          -  Poor cardiac function: left ventricular ejection fraction <45% as determined by
             Multigated acquisition scan (MUGA) or Echocardiogram (ECHO). For pediatric patients
             Left ventricular ejection fraction (LVEF) <45% or a shortening fraction below normal
             limits for age.

          -  Symptomatic pulmonary disease. Poor pulmonary function: Forced expiratory volume
             (FEV1), Forced vital capacity (FVC), and Diffusing capacity for carbon monoxide (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
             Pulmonary function tests (PFTs) because of developmental stage pulse oximetry < 92% on
             Room air (RA).

          -  Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary
             malignancy). Alanine aminotransferase (ALT) or Aspartate transaminase (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: creatinine clearance
             (CrCl) will be estimated by the Schwartz formula. A measured CrCl or a Glomerular
             filtration rate (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 Respiratory syncytial virus (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