Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving combination chemotherapy together with gemtuzumab may kill more cancer cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab in treating patients with newly diagnosed acute myeloid leukemia. PURPOSE: This randomized phase III trial is studying combination chemotherapy and gemtuzumab to see how well they work compared with combination chemotherapy alone in treating young patients with newly diagnosed acute myeloid leukemia.

Detailed Description
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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 human leukocyte antigen (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. Determine the prevalence and prognostic significance of molecular abnormalities of KIT, CCAAT-enhancer binding protein alpha (CEBPα) and MLL-Partial tandem duplications (PTD) genes in these patients. Determine the leukemic involvement of hematopoietic early progenitor and its role in defining response to therapy. 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. 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 Central Nervous System (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 in complete remission (CR) proceed to intensification 1. Patients with refractory disease 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 in remission proceed to intensification 2, followed by intensification 3. Patients in remission 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 not in remission 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 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. PROJECTED ACCRUAL: A total of 1,012 patients will be accrued for this study.

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: asparaginase
* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: etoposide
* Drug: gemtuzumab ozogamicin
* Drug: mitoxantrone hydrochloride


Participation Criteria
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Eligibility Criteria
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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 beta chain (-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

Ages Eligible for Study
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Maximum Age: 29 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Standard Arm - No GMTZ, AML Pts w/out Down Syndrome<br>Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9. | Drug: asparaginase<br>* Given intramuscularly<br>* Other names: NSC 109229;Drug: cytarabine<br>* Given IV<br>* Other names: NSC # 63878;Drug: daunorubicin hydrochloride<br>* Given IV over 6 hours<br>* Other names: NSC #82151;Drug: etoposide<br>* Given IV over 1-4 hours<br>* Other names: NSC #141540;Drug: mitoxantrone hydrochloride<br>* Given IV over 1 hour<br>* Other names: NSC #301739;|
| Experimental: Arm B: Experimental - with GMTZ, AML Pts w/out Down Syndrome<br>Pts receive IT ARA-C at diagnosis or on day 1 of treatment or twice a week for up to six doses. They also receive an infusion of ARA-C on days 1-10; a 6-hr infusion of daunorubicin on days 1, 3, & 5; a 4-hr infusion of etoposide on days 1-5; and a 2-hr infusion of GMTZ - gemtuzumab ozogamicin (Mylotarg) on day 6. After 3 wks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 wks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hr infusion of mitoxantrone hydrochloride on days 3-6. They also receive a 2-hr infusion of gemtuzumab on day 7. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9. | Drug: asparaginase<br>* Given intramuscularly<br>* Other names: NSC 109229;Drug: cytarabine<br>* Given IV<br>* Other names: NSC # 63878;Drug: daunorubicin hydrochloride<br>* Given IV over 6 hours<br>* Other names: NSC #82151;Drug: etoposide<br>* Given IV over 1-4 hours<br>* Other names: NSC #141540;Drug: gemtuzumab ozogamicin<br>* Given IV over 2 hours<br>* Other names: GMTZ;Drug: mitoxantrone hydrochloride<br>* Given IV over 1 hour<br>* Other names: NSC #301739;|
| Active Comparator: Arm A: Standard Arm - No GMTZ, AML Patients with Down Syndrome<br>Patients receive intrathecal (IT) cytarabine (ARA-C) at diagnosis or on day 1 of treatment or twice a week for up to 6 doses. They also receive an infusion of ARA-C on days 1-10; a 6-hour infusion of daunorubicin hydrochloride on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, patients receive IT ARA-C on day 1. They also receive an infusion of ARA-C on days 1-8; a 6-hr infusion of daunorubicin on days 1, 3, and 5; and a 4-hr infusion of etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1 and 1-hr infusions of ARA-C and etoposide on days 1-5. After 3 weeks of rest, some patients receive IT ARA-C on day 1; a 2-hr infusion of ARA-C on days 1-4; and a 1-hour infusion of mitoxantrone on days 3-6. After 3 weeks of rest, they receive a 3-hr infusion of ARA-C on days 1, 2, 8, and 9 and an injection of asparaginase on days 2 and 9. | Drug: asparaginase<br>* Given intramuscularly<br>* Other names: NSC 109229;Drug: cytarabine<br>* Given IV<br>* Other names: NSC # 63878;Drug: daunorubicin hydrochloride<br>* Given IV over 6 hours<br>* Other names: NSC #82151;Drug: etoposide<br>* Given IV over 1-4 hours<br>* Other names: NSC #141540;Drug: mitoxantrone hydrochloride<br>* Given IV over 1 hour<br>* Other names: NSC #301739;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival at 3 Years | The Kaplan-Meier method will be used to calculate estimates of Event Free Survival (EFS). The log-rank test will be used to compare survival between treatment groups. Analysis of EFS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to Overall Survival (OS) and EFS will utilize monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error. | Time from study entry to time of induction failure, relapse, or death, assessed at 3 years | 
| Overall Survival at 3 Years | The Kaplan-Meier method will be used to calculate estimates of OS. Analysis of OS of Down syndrome patients will be performed separately. Monitoring for efficacy of GMTZ with respect to OS and EFS will utilize monitoring based on the Lan-DeMets criterion with α-spending function αt^2 (truncated at 3 standard deviations) and 2.5% type I error. | Time from study entry, assessed at 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission Induction Rate After 2 Courses of Induction Therapy | Patients without an evaluable bone marrow at the end of Induction I will be excluded from the calculation of remission rate after 2 courses of therapy because their responses are not evaluable. The following patients will be considered to not be in complete remission (CR) after 2 courses of therapy: (1) patients who die during Induction I and II; (2) patients with ≥ 5% blasts or extramedullary disease at the end of Induction II. | After 2 courses of induction (I and II) therapy, assessed for up to 10 years | 
| Disease-free Survival (DFS) | Time from end of Intensification I to relapse, death or last contact | At 3 years from end of Intensification I | 
| Mortality | Number of participants who died during the first three courses of therapy. | During the first three courses of therapy | 
| Time to Marrow Recovery | Mean time to ANC recovery - defined as ANC greater than 500/MicroLiter for 3 consecutive days. | At 25 days after treatment with Induction I, Induction II, and Intensification I | 
| Toxicities, Including Infectious Complications | Number of participants with at least one grade 3 or higher adverse event during therapy. | From the time therapy is initiated, assessed up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), untreated adult acute myeloid leukemia, untreated childhood acute myeloid leukemia and other myeloid malignancies, adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7), childhood acute basophilic leukemia, childhood acute eosinophilic leukemia, childhood acute minimally differentiated myeloid leukemia (M0), childhood acute myeloblastic leukemia without maturation (M1), childhood acute myeloblastic leukemia with maturation (M2), childhood acute myelomonocytic leukemia (M4), childhood acute monocytic leukemia (M5b), childhood acute monoblastic leukemia (M5a), childhood acute erythroleukemia (M6), childhood acute megakaryocytic leukemia (M7)