Microtransplantation to Treat Refractory or Relapsed Hematologic Malignancies in Younger Patients

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Phase II Study of Microtransplantation in Patients With Refractory or Relapsed Hematologic Malignancies

Conditions
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Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Intrathecal Triples
* Biological: HPC-A


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Myeloid Malignancies<br>Includes participants with AML and MDS. Participants receive chemotherapy based on diagnosis followed by infusion of donor HPC-A. Participants with CNS disease receive weekly age-adjusted intrathecal triples therapy until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses). Interventions: Cycle 1: cytarabine, HPC-A donor infusion Cycle 2: Participants who have at least a partial response to Cycle 1 are eligible to receive Cycle 2: cytarabine, HPC-A infusion | Drug: Cytarabine<br>* Given by either intrathecal (IT) or intravenous (IV) route.<br>* Other names: Cytosar®;Drug: Intrathecal Triples<br>* given IT.<br>* Other names: Methotrexate/hydrocortisone/cytarabine;Biological: HPC-A<br>* Given IV.<br>* Other names: Hematopoietic Progenitor Cell, Apheresis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants by Stratum Who Complete 2 Cycles of Therapy | If two or more patients die from causes other than leukemia progression or experience ≥ Grade 3 GVHD that is associated with detectable donor chimerism due to this protocol, or demonstrate persistent engraftment defined as >5% donor chimerism at the time of count recovery (ANC > 0.3 x 10^9/L and platelet count > 30 x 10^/L), then the cohort will close due to intolerability. Any subject who transfers to transplant prior to completion of two courses without experiencing an unacceptable toxicity is considered inevaluable for purposes of evaluating tolerability. Accrual will be halted for intolerability if there are two or more failures in tolerability among the first six subjects who are evaluable for tolerability. | At the end of therapy cycle 2 (approximately 2-3 months) | 
| Proportion of Participants Who Experience Therapeutic Success | All patients will be counted towards this two-stage design. Therapeutic success for patients at time of enrollment is defined as: Patients with fewer than 5% blasts, a ≥ 10-fold decrease in level of minimal residual disease after completion of 1 or 2 cycles of therapy. Patients with greater than 5% in leukemic blasts in the marrow, achieving CR or CRi after completion of 1 or 2 cycles of therapy. In terms of efficacy, patients who die before achieving therapeutic success will be counted as a failure, and all patients who receive ≥ 1 dose of protocol chemotherapy will be counted as a failure or success. Only subjects who withdraw or die prior to receiving the first dose of protocol chemotherapy will be considered inevaluable and replaced. The evaluation of tolerability and this phase II design will be performed concurrently, i.e., the first enrollees will be counted for both tolerability and efficacy. | At the end of therapy cycle 2 (approximately 2-3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Event Free Survival (EFS) | We will use the Kaplan-Meier method to describe event-free survival. EFS will be defined as the time from enrollment to death, relapse, or refractory disease with event-free subjects' time censored at the date of last follow-up. | 3 years after enrollment of the last participant | 
| 3-year Overall Survival (OS) | We will use the Kaplan-Meier method to describe overall survival. Overall survival will be defined as the time from enrollment to death, with living subjects' time censored at the date of last follow-up | 3 years after enrollment of the last participant | 
| Median Time to Neutrophil Recovery | The time to neutrophil recovery will be summarized using descriptive statistics. If there are no deaths prior to recovery of neutrophils, nonparametric confidence intervals for the median time to recovery will be computed by inverting the sign test. Otherwise, we will compute cumulative incidence curves to describe the time to platelet and neutrophil recovery while adjusting for competing events. | From start of therapy to completion of therapy (approximately 1 year) | 
| Time to Platelet Recovery | The time to platelet recovery will be summarized using descriptive statistics. If there are no deaths prior to recovery of platelets, nonparametric confidence intervals for the median time to recovery will be computed by inverting the sign test. Otherwise, we will compute cumulative incidence curves to describe the time to platelet and neutrophil recovery while adjusting for competing events. Due to the small number of patients enrolled, the data is presented by patient. | From start of therapy to completion of therapy (approximately 1 year) | 
| 1-year Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) | Children's Oncology Group (COG) Stem Cell Committee Consensus Guidelines for Establishing Organ Stage and Overall Grade of Acute Graft Versus Host Disease (GVHD) were used. Overall clinical grade was based on the highest stage obtained: Grade 0: no stage 1-4 of any organ Grade I: stage 1-2 skin and no liver or gut involvement Grade II: stage 3 skin, or stage 1 liver involvement, or stage 1 GI Grade III: stage 0-3 skin, with stage 2-3 liver, or stage 2-3 GI Grade IV: stage 4 skin, liver or GI involvement | From start of therapy through completion of therapy (approximately 1 year) | 
| 1-year Cumulative Incidence of Chronic Graft Versus Host Disease (GVHD) | All grades of GVHD will be reported. | From start of therapy through completion of therapy (approximately 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescent, Children, Microtransplant, Leukemia