Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients
Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients
Allogeneic transplant can sometimes be an effective treatment for leukemia. In a traditional
 allogeneic transplant, patients receive very high doses of chemotherapy and/or radiation
 therapy, followed by an infusion of their donor's bone marrow or blood stem cells. The
 high-dose chemotherapy drugs and radiation are given to remove the leukemia cells in the
 body. The infusion of the donor's bone marrow or blood stem cells is given to replace the
 diseased bone marrow destroyed by the chemotherapy and/or radiation therapy. However, there
 are risks associated with allogeneic transplant. Many people have life-threatening or even
 fatal complications, like severe infections and a condition called graft-versus-host disease,
 which is caused when cells from the donor attack the normal tissue of the transplant patient.

 Recently, several hospitals around the world have been using a different type of allogeneic
 transplant called a microtransplant. In this type of transplant, the donor is usually a
 family member who is not an exact match. In a microtransplant, leukemia patients get lower
 doses of chemotherapy than are used in traditional allogeneic transplants. The chemotherapy
 is followed by an infusion of their donor's peripheral blood stem cells. The objective of the
 microtransplant is to suppress the bone marrow by giving just enough chemotherapy to allow
 the donor cells to temporarily engraft (implant), but only at very low levels. The hope is
 that the donor cells will cause the body to mount an immunologic attack against the leukemia,
 generating a response called the "graft-versus-leukemia" effect or "graft-versus-cancer"
 effect, without causing the potentially serious complication of graft-versus-host disease.

 With this research study, the investigators hope to find out whether or not
 microtransplantation will be a safe and effective treatment for children, adolescents and
 young adults with relapsed or refractory hematologic malignancies
PRIMARY OBJECTIVES:

 -  To assess the safety and feasibility of standard chemotherapy plus GCSF-mobilized
 Hematopoietic Progenitor Cell, Apheresis (HPC-A) in pediatric patients with relapsed or
 refractory hematologic malignancies.

 -  To estimate the response rates to standard chemotherapy plus GCSF-mobilized HPC-A in
 pediatric patients with relapsed or refractory hematologic malignancies.

 SECONDARY OBJECTIVES:

 -  To describe the event-free and overall survival of patients treated with standard
 chemotherapy plus GCSF-mobilized HPC-A.

 -  To estimate the time to neutrophil and platelet recovery after treatment with standard
 chemotherapy plus GCSF-mobilized HPC-A.

 -  To determine the cumulative incidence of acute and chronic graft-versus-host disease
 (GVHD).

 OTHER PRESPECIFIED OBJECTIVES:

 -  To characterize donor chimerism and microchimerism.

 Patients will receive standard chemotherapy followed by infusion of donor peripheral blood
 mononuclear cells 2 days after the completion of chemotherapy. Patients who have at least a
 partial response are eligible to receive a second cycle.

 Diagnostic lumbar puncture and intrathecal (IT) chemotherapy will be given prior to cycle 1.
 Patients without evidence of central nervous system (CNS) leukemia will receive no further IT
 therapy during cycle 1. Patients with CNS disease will receive weekly IT therapy
 (age-adjusted methotrexate, hydrocortisone, and cytarabine) until the cerebrospinal fluid
 (CSF) becomes free of leukemia (minimum of 4 doses).

 Bone marrow aspiration (BMA) and biopsy to assess response will be performed on approximately
 day 29 of therapy.

 For hematopoietic stem cell mobilization, donors will receive G-CSF (Filgrastim) (Neupogen®)
 each day for 5 days given subcutaneously (SQ) prior to HPC-A collected by leukapheresis on
 day 6.
INCLUSION CRITERIA - AML and MDS PARTICIPANTS

 -  Participants must have a diagnosis of AML or myelodysplastic syndrome (MDS), ALL, and
 must have disease that has relapsed or is refractory to chemotherapy, or that has
 relapsed after HSCT.

 -  Refractory disease is defined as persistent disease after at least two courses of
 induction chemotherapy.

 -  Patients with AML must have ≥ 5% leukemic blasts in the bone marrow or have
 converted from negative minimal residual disease (MRD) status to positive MRD
 status in the bone marrow as assessed by flow cytometry. If an adequate bone
 marrow sample cannot be obtained, patients may be enrolled if there is
 unequivocal evidence of leukemia in the peripheral blood.

 -  Participant is ≤ 21 years of age (i.e., has not reached 22nd birthday).

 -  Adequate organ function defined as the following:

 -  Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin is >
 ULN, direct bilirubin is ≤ 1.5 mg/dL

 -  AST (SGOT)/ALT (SGPT) < 5 x ULN

 -  Calculated creatinine clearance > 50 ml/min/1.73m^2 as calculated by the Schwartz
 formula for estimated glomerular filtration rate >

 -  Left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25%.

 -  Has an available HPC-A donor.

 -  Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥
 50% for patients who are > 16 years old.

 -  Does not have an uncontrolled infection requiring parenteral antibiotics, antivirals,
 or antifungals within one week prior to first dose. Infections controlled on
 concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per
 institutional guidelines is acceptable.

 -  Patient has fully recovered from the acute effects of all prior therapy and must meet
 the following criteria.

 -  At least 14 days must have elapsed since the completion of myelosuppressive
 therapy.

 -  At least 24 hours must have elapsed since the completion of hydroxyurea, low-dose
 cytarabine (up to 200 mg/m^2/day), and intrathecal chemotherapy.

 -  At least 30 days must have elapsed since the use of investigational agents.

 -  For patients who have received prior HSCT, there can be no evidence of GVHD and
 greater than 60 days must have elapsed since the HSCT. Patients cannot be
 receiving therapy, including steroids, for GVHD.

 -  Post-menarchal female has had negative serum pregnancy test within 7 days prior to
 enrollment.

 -  Male or female of reproductive potential has agreed to use effective contraception for
 the duration of study participation.

 -  Not breastfeeding

 INCLUSION CRITERIA - HPC-A CELL DONOR

 -  At least 18 years of age.

 -  Family member (first degree relatives).

 -  Not pregnant as confirmed by negative serum or urine pregnancy test within 7 days
 prior to enrollment (if female).

 -  Not breast feeding.

 -  Meets donation eligibility requirements as outlined by 21 CFR 1271.