AAML0531: A Phase III Randomized Trial of Gemtuzumab Ozogamicin (Mylotarg") Combined with Conventional Chemotherapy for De Novo Acute Myeloid Leukemia (AML) in Children, Adolescents, and Young Adults
| Type | Status | Age Range | Sponsor | Protocol ID |
|---|
| Treatment | Active | <1mo – 29 yrs | COG | AAML0531 |
Outline
This is a randomized, multicenter study. Patients are stratified according to relapse risk (high vs intermediate vs low). Patients are randomized to 1 of 2 treatment arms. Patients with Down syndrome are nonrandomly assigned to arm I (but do not undergo allogeneic stem cell transplant [SCT]).
Arm I (standard therapy):
- Induction 1: Patients receive cytarabine IT at the time of diagnosis or on day 1*. Patients also receive cytarabine IV on days 1-10, daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide IV over 4 hours on days 1-5. After 3 weeks of rest, all patients (regardless of remission status) proceed to induction 2.
NOTE: *Patients with CNS disease receive cytarabine IT twice weekly until the cerebrospinal fluid is clear, followed by two additional IT treatments. Patients with refractory CNS leukemia after 6 doses of IT treatment are removed from the study.
- Induction 2: Patients receive cytarabine IT on day 1, cytarabine IV on days 1-8, daunorubicin hydrochloride IV over 6 hours on days 1, 3, and 5, and etoposide IV over 4 hours on days 1-5. After 3 weeks of rest, patients achieving complete remission (CR) (< 5% blasts in the bone marrow) proceed to intensification 1. Patients with ≥ 5% blasts in the bone marrow are removed from protocol therapy.
- Intensification 1: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 1 hour on days 1-5, and etoposide IV over 1 hour on days 1-5. After 3 weeks of rest, patients with low-risk disease or patients with intermediate-risk disease with no matched family donor (MFD) or high-risk disease with no MFD or no alternative donor who remain in CR (< 5% blasts in the bone marrow) proceed to intensification 2, followed by intensification 3. Patients with intermediate-risk disease or high-risk disease with a MFD proceed to allogeneic SCT 2-8 weeks after blood counts recover. Patients with high-risk disease with an alternative donor proceed to intensification 2 and 3, followed by allogeneic SCT. Patients with any risk disease who have ≥ 5% blasts in the bone marrow are removed from protocol therapy.
- Intensification 2: Patients receive cytarabine IT on day 1, high-dose cytarabine IV over 2 hours on days 1-4, and mitoxantrone hydrochloride IV over 1 hour on days 3-6. After 3 weeks of rest, patients proceed to intensification 3.
- Intensification 3: Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly on days 2 and 9.
Arm II:
- Induction 1: Patients receive treatment as in induction 1 of arm I. Patients also receive gemtuzumab ozogamicin (GMTZ) IV over 2 hours on day 6.
- Induction 2: Patients receive treatment as in induction 2 of arm I.
- Intensification 1: Patients receive treatment as in intensification 1 of arm I.
- Intensification 2: Patients receive treatment as in intensification 2 of arm I. Patients also receive GMTZ IV over 2 hours on day 7.
- Intensification 3: Patients receive treatment as in intensification 3 of arm I.
Allogeneic SCT (for patients with intermediate- or high-risk disease):
- MFD: Patients receive a conditioning regimen comprising busulfan IV over 2 hours every 6 hours on days -9 to -6 and cyclophosphamide IV over 1 hour on days -5 to -2. Patients undergo allogeneic SCT on day 0. Patients receive cyclosporine IV over 1-4 hours or orally twice daily on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11. Patients receive graft-vs-host disease (GVHD) prophylaxis comprising cyclosporine IV over 1-4 hours or orally twice daily on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11.
- Matched alternative donor: Patients receive a conditioning regimen comprising busulfan and cyclophosphamide as above. Patients also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. Patients then undergo allogeneic SCT and receive GVHD prophylaxis as above.
After completion of study treatment, patients are followed periodically for 3 years and then annually thereafter.
Objectives
Primary
- Compare the event-free survival (EFS) and overall survival (OS) of young patients with newly diagnosed acute myeloid leukemia (AML) treated with conventional combination chemotherapy with vs without gemtuzumab ozogamicin (GMTZ).
Secondary
- Compare the remission induction rates after two courses of therapy in these patients.
- Compare disease-free survival and OS in patients who are eligible for an HLA-matched family donor (MFD) stem cell transplant (SCT) by virtue of their risk classification, with patients assigned to MFD SCT if a MFD is available, or to chemotherapy if a MFD is not available.
- Determine the outcome of patients with Down syndrome who are 4 years of age or older at diagnosis and treated with conventional combination chemotherapy without GMTZ.
- Compare the EFS and OS of patients with de novo AML treated with conventional combination chemotherapy with vs without GMTZ censoring MFD SCT recipients.
- Identify the optimal cutoff of FLT3/internal tandem duplication (ITD) allelic ratios to predict patients at high risk for relapse.
- Assess the ability of a second-generation flow cytometric assay to predict patients at high risk for relapse during periods of clinical remission.
- Examine whether GMTZ significantly improves EFS and OS in patients with higher CD33 concentrations/intensity.
- Examine whether GMTZ significantly improves complete remission, EFS, and OS in each of the cytogenetic risk groups (high-, intermediate-, and low-risk) identified in prior Medical Research Council trials.
- Utilize fluorescence in situ hybridization (FISH) analysis to identify variant patterns among subgroups of patients who demonstrate the same G-banded chromosomal abnormality (e.g., inv[16]/t[16;16], t[8;21], 11q23 abnormality) and determine whether these variant patterns account for the heterogeneity of responses to therapy.
- Examine the impact of complex karyotypes (≥ 3, ≥ 4, and ≥ 5 abnormalities) on OS and EFS in intermediate-risk patients for whom no high-risk or low-risk cytogenetic abnormalities exist.
Projected Accrual
A total of 1,012 patients will be accrued for this study.
Mechanism of Action
Gemtuzumab ozogamicin is a recombinant, humanized anti-CD33 monoclonal antibody attached to the cytotoxic antitumor antibiotic calicheamicin. In this conjugate, the antibody binds to and is internalized by tumor cells expressing CD33 antigen (a sialic acid-dependent glycoprotein commonly found on the surface of leukemic blasts), thereby delivering the attached calicheamicin to CD33-expressing tumor cells. Calicheamicin binds to the minor groove of DNA, causing double strand DNA breaks and resulting in inhibition of DNA synthesis.
Entry Criteria
Disease Characteristics:
- Newly diagnosed acute myeloid leukemia (AML)
- Meets customary criteria for AML with ≥ 20% bone marrow blasts (by WHO classification)
- Patients with < 20% bone marrow blasts and cytopenia or myelodysplastic syndromes (e.g., chronic myelomonocytic leukemia, refractory anemia [RA], RA with excess blasts, RA with ringed sideroblasts) are eligible provided 1 of the following criteria is met:
- Karyotypic abnormality characteristic of de novo AML (t[8;21][q22;q22], inv[16][p13q22], t[16;16][p13;q22], or 11q23 abnormalities)
- Unequivocal presence of megakaryoblasts (by WHO classification)
- Isolated myeloid sarcoma (i.e., myeloblastoma or chloroma) allowed regardless of bone marrow results
- Infants < 1 month of age with progressive disease* are eligible NOTE: *Infants < 1 month of age with AML may be given supportive care until it is clear that the leukemia is not regressing (i.e., the disappearance of peripheral blasts and the normalization of peripheral blood counts)
- Patients with Down syndrome ≥ 4 years of age are eligible
- No juvenile myelomonocytic leukemia
- No Fanconi's anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
- No promyelocytic leukemia (M3)
- No secondary or treatment-related AML
- Matched family donor criteria (for patients with intermediate-risk or high-risk disease):
- HLA-A, -B, -C, and -DRB1, identical or 1 antigen or allele mismatched by molecular high resolution technique
- All available first-degree family members (parents and siblings) must be HLA typed
- No syngeneic donors
- Matched alternative donor criteria (for patients with high-risk disease):
- HLA-A, -B, -C, and -DRB1, identical or 1 antigen or allele mismatched donor
- HLA-A, -B, and -DRB1 4 of 6 antigen matched unrelated cord blood donor
- Mismatched family member donor with ≥ 1 haplotype match or 5 of 6 antigen phenotypic match
Patient Characteristics:
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
Prior Concurrent Therapy: - No prior chemotherapy, radiation therapy, or any antileukemic therapy
- Topical or inhalation steroids for other conditions allowed
- Intrathecal cytarabine given at diagnosis allowed
- No other prior treatment for AML
- No concurrent peripheral blood stem cell transplantation in patients with matched family donor
Contact Information:
Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
