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

Condition(s) targeted: Acute Myelogenous Leukemia; Myelodysplastic Syndrome; Juvenile Myelomonocytic Leukemia

Intervention: Fludarabine (Drug); Busulfan (Drug); FK506/MMF/ MTX (Drug); GEMTUZUMAB OZOGAMICIN (Drug); Thymoglobulin (Drug); cis-RA (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Columbia University

Official(s) and/or principal investigator(s):
Monica Bhatia, MD, Principal Investigator, Affiliation: Columbia University

Overall contact:
Monica Bhatia, MD, Phone: 212-305-9138, Email: mb2476@columbia.edu

Allogeneic stem cell transplantation (AlloSCT) followed by targeted immune therapy Gemtuzumab Ozogamicin patients with AML/JMML/MDS will be safe and well tolerated.

Official title: Allogeneic Stem Cell Transplantation Followed By Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (Aml/Mds/Jmml)

Study design: Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To determine the feasibility and toxicity of a Reduced Intensity (RI) regimen, AlloSCT followed by targeted immune therapy, Gemtuzumab Ozogamicin (GO) , in average risk AML/JMML/MDS.

Secondary outcome:

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

To measure the minor histocompatibility antigen expression on AML tissue, donor and recipient, and the development of MHA specific CTLs post

To determine the degree of mixed/complete donor chimerism after RI AlloSCT in patients with average risk AML/JMML/MDS.

To determine event free survival (EFS) and overall survival (OS) after RI AlloSCT and targeted immunotherapy in patients with average risk AML/JMML/MDS

To estimate the risk of acute and chronic GVHD following RI AlloSCT and FK506/MMF GVHD prophylaxis in patients with average risk AML/JMML/MDS

To determine the maximal tolerated and/or biologically active dose of Gemtuzumab Ozogamicin (GO) (anti CD33 immunotoxin) therapy following RI AlloSCT in patients with average risk AML/JMML/MDS.

Detailed 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 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.

Minimum age: 1 Month. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Disease Status

- AML 1st CR with a matched family donor (excluding Downs Syndrome, APL, 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)] with unrelated donor

- AML 2nd CR

- MDS and < 5% bone marrow myeloblasts at diagnosis (de novo patients only)

- JMML and < 5% bone marrow myeloblasts at diagnosis

- Disease must express a minimum of >10% CD33 positivity for patients with AML

- 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 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 ULN, or SGOT (AST) or SGPT (ALT) < 5. 0 xULN

- 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:

- DLCO > 40% by 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 CNS AML/JMML disease at time of preparative regimen

- Secondary MDS

- Female patients who are pregnant (positive HCG)

- Karnofsky <70% or Lansky <50% if 10 years or less

- Age >65 years

- Seropositive for HIV

- Patients consented to and registered on an upfront COG AML study with a matched

family donor

Monica Bhatia, MD, Phone: 212-305-9138, Email: mb2476@columbia.edu

Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Mitchell Cairo, MD, Phone: 212-305-8316, Email: mc1310@columbia.edu
Monica Bhatia, MD, Principal Investigator

Starting date: September 2002
Last updated: February 8, 2010