Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Leukemia

Study Overview
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Brief Summary
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Allogeneic stem cell transplantation (AlloSCT) followed by targeted immune therapy Gemtuzumab Ozogamicin patients with acute myeloid leukemia (AML)/juvenile myelomonocytic leukemia (JMML)/myelodysplastic syndromes (MDS) will be safe and well tolerated.

Detailed Description
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Gemtuzumab Ozogamicin (CMA-676) is a chemotherapeutic agent consisting of a recombinant humanized anti-CD33 antibody conjugated with calicheamicin, a highly potent cytotoxic antitumor antibiotic. The antibody portion of Gemtuzumab binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein expressed on the surface of leukemic blasts, normal and leukemic myeloid colony-forming cells, including leukemic clonogenic precursors, but excluding pluripotent hematopoietic stem cells and nonhematopoietic cells. This results in formation of a complex that is internalized, upon which the calicheamicin derivative is released within the lysosomes of the myeloid cell. The free calicheamicin derivative then binds to deoxyribonucleic acid (DNA), resulting in DNA double strand breaks and consequential cell death. Over 80% of AML patients possess myeloid blast cells with CD33 surface antigen expression.

Official Title
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Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (AML/MDS/JMML)

Conditions
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Busulfan
* Drug: GVHD Prophylaxis
* Drug: Gemtuzumab Ozogamicin
* Drug: Anti-Thymocyte Globulin
* Drug: Isotretinoin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Status AML 1st complete remission (CR) with a matched family donor (excluding Downs Syndrome, acute promyelocytic leukaemia (APL), poor cytogenetics (12p, 5q, -7 and FMS-like tyrosine kinase 3 (FLT3) mutations or duplication t(9;11) and others)) and patients consented to and registered on an upfront AML COG study with a matched family donor) AML 1st CR (excluding Downs Syndrome, APL, and chromosome translocation (8;21) or inversion (16) or poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication t(9;11) and others)) with unrelated donor AML 2nd CR Myelodysplastic Syndrome (MDS) and ≤ 5% bone marrow myeloblasts at diagnosis (de novo patients only) Juvenile Myelomonocytic Leukemia (JMML) and ≤ 5% bone marrow myeloblasts at diagnosis In regards to disease immunophenotype, disease must express a minimum of ≥10% Cell Differential 33 (CD33) positivity for patients with AML Organ Function: Patients must have adequate organ function as defined below: Adequate renal function defined as: Serum creatinine < 1.5 x normal, or Creatinine clearance or radioisotope glomerular filtration rate (GFR) 40 ml/min/m2 or > 60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range Adequate liver function defined as total bilirubin 2.0 x upper limit of normal (ULN), or serum glutamic-oxaloacetic transaminase (SGOT)(aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT)(alanine aminotransferase (ALT)) < 5.0 x ULN Adequate cardiac function defined as: Shortening fraction of ≥ 25% by echocardiogram, or Ejection fraction of ≥ 45% by radionuclide angiogram or echocardiogram Adequate pulmonary function defined as: Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 40% by pulmonary function tests (PFT) (Uncorrected) For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% on room air Exclusion Criteria: Patients with active central nervous system (CNS) AML/JMML disease at time of preparative regimen Secondary MDS Poor cytogenetics (12p, 5q, -7, FLT3 mutation or duplication) Female patients who are pregnant (positive human chorionic gonadotropin(hCG)) Karnofsky <70% or Lansky <50% if 10 years or less Age >30 years Seropositive for Human Immunodeficiency Virus (HIV) Patients consented to and registered on an upfront Children's Oncology Group (COG) AML study with a matched family donor

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 30 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Matched Family Donor<br>Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from a related family donor using bone marrow or cord blood stem cells. Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin). During and following transplantation patients will receive methylprednisolone for immune suppression. Graft-versus-host-disease (GVHD) prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants. | Drug: Fludarabine<br>* Conditioning Regimen<br>* Other names: Fludara®;Drug: Busulfan<br>* Conditioning Regimen<br>* Other names: Busulfex®;Drug: GVHD Prophylaxis<br>* Can be FK506 (Tacrolimus/Prograf®), mycophenolate mofetil ((MMF)/Cellcept®), or methotrexate (MTX, amethopterin)<br>Drug: Gemtuzumab Ozogamicin<br>* Dose Escalation<br>* Other names: Mylotarg®;|
| Experimental: Unrelated Donor<br>Patients will receive a reduced intensity fludarabine (6 days)/busulfan (2 days) conditioning regimen followed by a stem cell transplant from an unrelated donor using matched bone marrow or cord blood stem cells.Then followed by Gemtuzumab Ozogamicin, once at about 2-6 months post alloSCT and once at least 2 months after the first dose. Patients with JMML will also receive cis-retinoic acid (Isotretinoin). During and following transplantation patients will receive methylprednisolone for immune suppression and unrelated donor transplant recipients will additionally receive Anti-Thymocyte Globulin. GVHD prophylaxis will consist of tacrolimus, mycophenolate mofetil and additionally methotrexate in recipients of unrelated adult transplants. | Drug: Anti-Thymocyte Globulin<br>* Unrelated Donors only<br>* Other names: Thymoglobulin®;Drug: Isotretinoin<br>* JMML patients only<br>* Other names: 13-cis-Retinoic Acid (cis-RA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) | To determine the maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) (anti CD33 immunotoxin) therapy following reduced intensity (RI) allogeneic stem cell transplantation (alloSCT) in patients with average risk AML/JMML/MDS. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of minimal residual disease | To measure the changes, if applicable, of minimal residual disease prior to and after consolidation therapy with targeted immunotherapy in average risk AML/JMML/MDS post RI AlloSCT. | Day 60, Day 100, Day 180, 1 year, 2 years | 
| Incidence of minor histocompatibility antigen (MHA) expression on acute myeloid leukemia (AML) tissue | To measure the minor histocompatibility antigen expression on AML tissue, donor and recipient, and the incidence of development of MHA specific cytotoxic T-lymphocytes (CTLs). | Up to 2 years | 
| Degree of mixed/complete donor chimerism | To determine the degree of mixed/complete donor chimerism after RI AlloSCT in patients with average risk AML/JMML/MDS. | Up to 2 years | 
| Event free survival (EFS) rate | To determine event free survival (EFS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS. | Up to 2 years | 
| Overall survival (OS) rate | To determine overall survival (OS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Stem Cell Transplantation, Targeted Immune Therapy, Acute Myelogenous Leukemia, Myelodysplastic Syndrome, Juvenile Myelomonocytic Leukemia, AML, MDS, JMML