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

• ClinicalTrials.gov Identifier: NCT00372593
• Recruitment Status: Completed
• First Posted: September 7, 2006
• Results First Posted: January 13, 2015
• Last Update Posted: March 24, 2021
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: September 6, 2006
• First Posted Date: September 7, 2006
• Results First Submitted Date: January 6, 2015
• Results First Posted Date: January 13, 2015
• Last Update Posted Date: March 24, 2021
• Study Start Date: August 2006
• Actual Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2015)

• Event-free Survival at 3 Years [ Time Frame: Time from study entry to time of induction failure, relapse, or death, assessed 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.
• Overall Survival at 3 Years [ Time Frame: Time from study entry, assessed 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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: March 28, 2017)

• Remission Induction Rate After 2 Courses of Induction Therapy [ Time Frame: After 2 courses of induction (I and II) therapy, assessed for up to 10 years ]
  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.
• Disease-free Survival (DFS) [ Time Frame: At 3 years from end of Intensification I ]
  Time from end of Intensification I to relapse, death or last contact
• Mortality [ Time Frame: During the first three courses of therapy ]
  Number of participants who died during the first three courses of therapy.
• Time to Marrow Recovery [ Time Frame: At 25 days after treatment with Induction I, Induction II, and Intensification I ]
  Mean time to ANC recovery - defined as ANC greater than 500/MicroLiter for 3 consecutive days.
• Toxicities, Including Infectious Complications [ Time Frame: From the time therapy is initiated, assessed up to 10 years ]
  Number of participants with at least one grade 3 or higher adverse event during therapy.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combination Chemotherapy With or Without Gemtuzumab in Treating Young Patients With Newly Diagnosed Acute Myeloid Leukemia
• Official Title: 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

Brief Summary

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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia

Intervention

• Drug: asparaginase
  Given intramuscularly
  Other Names:

  • E.coli
  • E.coli L-asparaginase
  • EC 3.5.2.2
  • colaspase
  • L-asnase
  • Elspar
  • Kidrolase
  • Crasnitin
  • Leunase
  • NSC 109229
• Drug: cytarabine
  Given IV
  Other Names:

  • Cytosine arabinoside
  • Ara-C
  • Cytosar
  • NSC # 63878
• Drug: daunorubicin hydrochloride
  Given IV over 6 hours
  Other Names:

  • Daunomycin
  • rubidomycin
  • Cerubidine
  • NSC #82151
• Drug: etoposide
  Given IV over 1-4 hours
  Other Names:

  • VePesid
  • Etopophos
  • VP-16
  • NSC #141540
• Drug: gemtuzumab ozogamicin
  Given IV over 2 hours
  Other Names:

  • Mylotarg
  • GMTZ
• Drug: mitoxantrone hydrochloride
  Given IV over 1 hour
  Other Names:

  • Novantrone
  • CL 232315
  • DAD
  • DHAD
  • Mitozantrone
  • NSC #301739

Study Arms

• Active Comparator: Arm A: Standard Arm - No GMTZ, AML Pts w/out Down Syndrome

  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.

  Interventions:

  • Drug: asparaginase
  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
  • Drug: etoposide
  • Drug: mitoxantrone hydrochloride
• Experimental: Arm B: Experimental - with GMTZ, AML Pts w/out Down Syndrome
  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.
  Interventions:

  • Drug: asparaginase
  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
  • Drug: etoposide
  • Drug: gemtuzumab ozogamicin
  • Drug: mitoxantrone hydrochloride
• Active Comparator: Arm A: Standard Arm - No GMTZ, AML Patients with Down Syndrome

  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.

  Interventions:

  • Drug: asparaginase
  • Drug: cytarabine
  • Drug: daunorubicin hydrochloride
  • Drug: etoposide
  • Drug: mitoxantrone hydrochloride

Publications *

• Pollard JA, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID, Raimondi SC, Hirsch B, Franklin J, Walter RB, Gamis A, Meshinchi S. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood. 2012 Apr 19;119(16):3705-11. doi: 10.1182/blood-2011-12-398370. Epub 2012 Feb 29.
• Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. doi: 10.1200/JCO.2014.55.3628.
• Elgarten CW, Wood AC, Li Y, Alonzo TA, Brodersen LE, Gerbing RB, Getz KD, Huang YV, Loken M, Meshinchi S, Pollard JA, Sung L, Woods WG, Kolb EA, Gamis AS, Aplenc R. Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2021 Dec;68(12):e29281. doi: 10.1002/pbc.29281. Epub 2021 Oct 1.
• Brodersen LE, Gerbing RB, Pardo ML, Alonzo TA, Paine D, Fritschle W, Hsu FC, Pollard JA, Aplenc R, Kahwash SB, Hirsch B, Ramondi S, Wells D, Kolb EA, Gamis AS, Meshinchi S, Loken MR. Morphologic remission status is limited compared to DeltaN flow cytometry: a Children's Oncology Group AAML0531 report. Blood Adv. 2020 Oct 27;4(20):5050-5061. doi: 10.1182/bloodadvances.2020002070.
• Voigt AP, Brodersen LE, Alonzo TA, Gerbing RB, Menssen AJ, Wilson ER, Kahwash S, Raimondi SC, Hirsch BA, Gamis AS, Meshinchi S, Wells DA, Loken MR. Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children's Oncology Group protocol AAML0531. Haematologica. 2017 Dec;102(12):2058-2068. doi: 10.3324/haematol.2017.169029. Epub 2017 Sep 7.
• Eidenschink Brodersen L, Alonzo TA, Menssen AJ, Gerbing RB, Pardo L, Voigt AP, Kahwash SB, Hirsch B, Raimondi S, Gamis AS, Meshinchi S, Loken MR. A recurrent immunophenotype at diagnosis independently identifies high-risk pediatric acute myeloid leukemia: a report from Children's Oncology Group. Leukemia. 2016 Oct;30(10):2077-2080. doi: 10.1038/leu.2016.119. Epub 2016 May 2. No abstract available.
• Sung L, Aplenc R, Alonzo TA, Gerbing RB, Lehrnbecher T, Gamis AS. Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children's Oncology Group. Blood. 2013 May 2;121(18):3573-7. doi: 10.1182/blood-2013-01-476614. Epub 2013 Mar 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 25, 2014): 1070
• Original Enrollment: Not Provided
• Actual Study Completion Date: September 30, 2020
• Actual Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)

Eligibility 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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 29 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, Switzerland, United States

Administrative Information

• NCT Number: NCT00372593
• Other Study ID Numbers: AAML0531; COG-AAML0531 ( Other Identifier: Children's Oncology Group ); CDR0000487497 ( Other Identifier: Clinical Trials.gov ); NCI-2009-00320 ( Registry Identifier: Clinical Trials Reporting Program )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Alan S. Gamis, MD, MPH; Children's Mercy Hospital Kansas City
• Study Chair: Richard Aplenc, MD, MSCE; Children's Hospital of Philadelphia

• PRS Account: Children's Oncology Group
• Verification Date: February 2017