Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Leukemia (AML/MDS/JMML)

Columbia University

Status and phase: Completed; Phase 1

Conditions: Acute Myelogenous Leukemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndrome

Treatments: Drug: Gemtuzumab Ozogamicin; Drug: Busulfan; Drug: GVHD Prophylaxis; Drug: Anti-Thymocyte Globulin; Drug: Isotretinoin; Drug: Fludarabine

Study type: Interventional

Funder types: Other

Identifiers

NCT01020539

CHNY-504 (Other Identifier)

AAAA6378

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 18 patients

Sex: All

Ages: 1 month to 30 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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18 participants in 2 patient groups

Matched Family Donor

Experimental group

Description:

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.

Treatment:

Drug: Fludarabine

Drug: Busulfan

Drug: GVHD Prophylaxis

Drug: Gemtuzumab Ozogamicin

Unrelated Donor

Experimental group

Description:

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.

Treatment:

Drug: Isotretinoin

Drug: Anti-Thymocyte Globulin