Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia

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ClinicalTrials.gov Identifier: NCT00136084

Recruitment Status : Completed

First Posted : August 26, 2005

Results First Posted : March 26, 2010

Last Update Posted : December 5, 2012

Sponsor:

Collaborator:

National Cancer Institute (NCI)

Information provided by (Responsible Party):

St. Jude Children's Research Hospital

Study Description

Brief Summary:

The purpose of this study is to compare the effectiveness of two multi-agent chemotherapy regimens using different dosages of cytarabine to eliminate all detectable leukemia.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myelocytic, Acute	Drug: Cladribine, Cyclophosphamide, Cytarabine, Daunorubicin, Dexamethasone Drug: Etoposide, Cytarabine, Gemtuzumab, L-asparaginase, Mercaptopurine, methotrexate, Mitoxantrone, Prednisone, Vincristine	Phase 3

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Detailed Description:

The study compares the effectiveness of two doses of cytarabine combined with set doses of daunomycin and etoposide as an initial course of chemotherapy to eliminate minimal residual disease. Subsequent therapy is tailored according to cytogenetic risk features, assessments of minimal residual disease, and availability of a suitable donor for bone marrow transplant. Patients with higher risk disease features are given more intense therapy. For higher risk groups, transplant is given to patients with suitable donors.

Secondary objectives include:

To assess the prognostic value of biological markers in childhood Acute Myeloid leukemia (AML).
To compare the amounts of leukemia cells in the blood and bone marrow to study minimal residual disease(MRD).
To relate non-invasive cardiac evaluation with health-related quality of life in AML patients treated with cardiotoxic therapy during and following therapy.

Detailed Description of Treatment Plan Induction I Patients will be randomly assigned to receive induction therapy that consists of daunomycin, etoposide, and high-dose or low-dose cytarabine.

High-Dose Cytarabine (HDAC) arm:

Cytarabine 3 gm/m2 IV days 1, 3, 5 Daunomycin 50 mg/m2 IV days 2, 4, 6 Etoposide 100 mg/m2 IV days 2-6

Low-Dose Cytarabine(LDAC) arm:

Cytarabine 100 mg/m2 IV days 1-10 (20 doses) Daunomycin 50 mg/m2 IV days 2, 4, 6 Etoposide 100 mg/m2 IV days 2-6

Induction II

Patients who have < 1% MRD after Induction I will receive daunomycin, cytarabine, etoposide (ADE):

Daunomycin 50 mg/m2 IV days 1, 3, 5 Cytarabine 100 mg/m2 IV 1-8 (16 doses) Etoposide 100 mg/m2 IV days 1-5

Patients who have ≥ 1% MRD after Induction I will receive daunomycin, cytarabine, etoposide (ADE) + gemtuzumab ozogamicin:

Daunomycin 50 mg/m2 IV days 1, 3, 5 Cytarabine 100 mg/m2IV days 1-8 (16 doses) Etoposide: 100 mg/m2 IV on days 1-5 Gemtuzumab ozogamicin (GO) 3 mg/m2 IV on day 1.

Consolidation I (Chemotherapy course 3)

The chemotherapy administered in course 3 will be based on the participant's response and cytogenetic/morphologic subgroup

MRD+ patients (except those who received ADE + GO) Gemtuzumab ozogamicin 6 mg/m2 IV on day 1

MRD+ patients who had No response(NR) to induction I

These patients should proceed to Stem Cell Transplant (SCT) as soon as possible. In cases where SCT is delayed (e.g., during searches for unrelated donors), these patients should receive chemotherapy according to their cytogenetic or morphologic subtype until the time of SCT.

MRD- patients (i.e., patients who were MRD- after ADE or after GO) will receive risk-based intensification (RBI)

t(9;11) and inv(16) Cytarabine 500 mg/m2/day by continuous infusion for 120 hours Cladribine (2CDA) 9 mg/m2: IV over 30 minutes daily for 5 days

Amend 8 M4/M5 without t(9;11) or inv(16): CE Cytarabine 3 gm/m2 IV q12h x 6 doses (days 1-3) by continuous infusion for 3 hours. Etoposide 125 mg/m2 IV on days 2-5 by continuous infusion for at least one hour

t(8;21) and others: HAM Cytarabine 3 g/m2 IV x 6 doses (days 1-3) Mitoxantrone 10 mg/m2 IV days 3-4

Standard-risk patients with matched related donors and high-risk patients will proceed to stem cell transplant per institutional practice

Consolidation II (Chemotherapy course 4):

Cytarabine 3 gm/m2 IV q12 hours on days 1, 2, 8, 9 (8 doses) L-Asparaginase 6000 Units/m2 IM 3 hours after 4th and 8th doses of cytarabine

Consolidation III (Chemotherapy course 5) Mitoxantrone 10 mg/m2 IV days 1-3 Cytarabine 1 gm/m2 IV over 2 hours q12 hours on days 1-3 (6 doses)

Patients who are in first remission are eligible to be enrolled on the St. Jude protocols NKAML protocol and receive Natural Killer (NK) cell therapy instead of Consolidation III or after Consolidation III. At the discretion of their primary physician, these patients will be offered the option of enrolling on NKAML.

Some patients with biphenotypic leukemia respond poorly to AML-directed therapy, but respond quite well to lymphoid-directed therapy. Patients with such markers who have no response to induction I or who fail to achieve complete response (CR) after induction II will therefore receive lymphoid directed induction therapy. Other biphenotypic patients will continue to receive AML-directed therapy as described above

All patients will undergo lumbar puncture and receive an age-appropriate dose of intrathecal (IT) cytarabine at the time of diagnosis.

Patients without Central Nervous System disease (CNS)(i.e., less than 5 leukocytes per microliter of CSF (colony-stimulating factor) will receive one dose of intrathecal (IT) methotrexate, hydrocortisone, and cytarabine (MHA) with each course of chemotherapy beginning with induction II.

Patients with overt CNS leukemia (more or equal to 5 leukocytes per l microliter of CSF and the presence of leukemic blast cells on CSF cytospin) will receive weekly IT MHA therapy beginning 1 week after the initial dose of IT cytarabine and continuing until the CSF is free of blast cells (minimum number of doses, 4). These patients will then receive 4 additional doses of intrathecal therapy with methotrexate, hydrocortisone, and cytarabine (IT MHA) (minimum total number of doses, 8) at approximately 1-month intervals (generally given with each subsequent course of chemotherapy).

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	238 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Collaborative Trial for the Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia
Study Start Date :	August 2002
Actual Primary Completion Date :	July 2008
Actual Study Completion Date :	June 2012

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Familial acute myeloid leukemia with mutated CEBPA Cytogenetically normal acute myeloid leukemia Core binding factor acute myeloid leukemia

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

Drug Information available for: Cytarabine

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Myelodysplastic Syndromes Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Acute Erythroid Leukemia Di Guglielmo's Syndrome

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: HDAC (High-Dose Cytarabine) Since limited characters are allowed in this passage, please see detailed Description for HDAC.	Drug: Cladribine, Cyclophosphamide, Cytarabine, Daunorubicin, Dexamethasone Since limited characters are allowed in this passage, please see detailed Description to know the dosage, dosage form, frequency of administration for the above mentioned drugs
Experimental: LDAC (Low-Dose Cytarabine) Since limited characters are allowed in this passage, please see detailed Description for LDAC.	Drug: Etoposide, Cytarabine, Gemtuzumab, L-asparaginase, Mercaptopurine, methotrexate, Mitoxantrone, Prednisone, Vincristine Since limited characters are allowed in this passage, please see detailed Description to know the dosage, dosage form, frequency of administration for the above mentioned drugs

Outcome Measures

Primary Outcome Measures :

Minimal Residual Disease (MRD). [ Time Frame: Day 22 MRD measurement ]
Detection of Minimal Residual Disease following one course of chemotherapy where positive MRD was defined as one or more leukemic cell per 1000 mononuclear bone-marrow cells (>=0.1%).

Secondary Outcome Measures :

Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO) [ Time Frame: Consolidation I ]
To estimate the proportion of minimal residual disease (MRD)+ patients who become MRD- after one course of gemtuzumab ozogamicin (GO)
Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO [ Time Frame: Induction II ]
To estimate proportion of patients with MRD reduction after one course of Induction II (cytarabine + daunomycin + etoposide (ADE) + GO), who had no response to first course of induction therapy.
Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO. [ Time Frame: Induction II ]
To estimate proportion of patients experiencing CTC Grade 3 or 4 toxicity during Induction II (Cytarabine + Daunomycin + Etoposide (ADE) + GO), who had no response to first course of induction therapy
To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy [ Time Frame: Five Year ]
Overall event-free survival (EFS) was defined as the time from study enrollment to induction failure, relapse, secondary malignancy, death, or study withdrawal for any reason, with event-free patients censored on the date of the last follow-up
To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy [ Time Frame: Measurements were assessed in Induction I chemotherapy ]
Inhibition of DNA synthesis is defined as the percentage of DNA synthesis rate at 24-hour post-araC treatment over DNA synthesis rate pre-araC treatment.
Relationship of Inhibition of DNA Synthesis and Clinical Response [ Time Frame: Measurements were assessed in Induction I chemotherapy ]
Clinical response is defined as MRD (minimal residual disease) measured by flow cytometry at day 22. The MRD at day 22 is classified as positive (with MRD) or negative (no detectable MRD). The relation between inhibition of DNA synthesis and MRD was performed by logistic regression. In the model, logit of probability of MRD positive was regressed on inhibition of DNA synthesis.

Eligibility Criteria

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Ages Eligible for Study:	up to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of acute myeloid leukemia by immunophenotyping, morphology, and cytochemical staining; myelodysplasia; or biphenotypic leukemia.
Age less than or equal to 21 years at time of study entry.
No prior therapy for this malignancy (patients with secondary AML following treatment of primary malignancy are eligible) except for one dose of intrathecal therapy.
Negative pregnancy test
Patient does not have Down syndrome, acute promyelocytic leukemia (APL), or juvenile myelomonocytic leukemia (JMML)

Exclusion Criteria:

Positive pregnancy test
Down syndrome, acute promyelocytic leukemia (APL), or juvenile myelomonocytic leukemia (JMML)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00136084

Locations

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United States, California
Stanford University Medical Center
Palo Alto, California, United States, 94304
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
Children's Hospital of Michigan (Wayne State University)
Detroit, Michigan, United States, 48201
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Texas Children's Cancer Center
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105

Sponsors and Collaborators

St. Jude Children's Research Hospital

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Jeffrey Rubnitz, M.D., PhD	St. Jude Children's Research Hospital

More Information

Additional Information:

St. Jude Children's Research Hospital This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Elsayed AH, Rafiee R, Cao X, Raimondi S, Downing JR, Ribeiro R, Fan Y, Gruber TA, Baker S, Klco J, Rubnitz JE, Pounds S, Lamba JK. A six-gene leukemic stem cell score identifies high risk pediatric acute myeloid leukemia. Leukemia. 2020 Mar;34(3):735-745. doi: 10.1038/s41375-019-0604-8. Epub 2019 Oct 23. Erratum in: Leukemia. 2020 Apr 16;:.

Gamazon ER, Lamba JK, Pounds S, Stark AL, Wheeler HE, Cao X, Im HK, Mitra AK, Rubnitz JE, Ribeiro RC, Raimondi S, Campana D, Crews KR, Wong SS, Welsh M, Hulur I, Gorsic L, Hartford CM, Zhang W, Cox NJ, Dolan ME. Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients. Blood. 2013 May 23;121(21):4366-76. doi: 10.1182/blood-2012-10-464149. Epub 2013 Mar 28.

Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, Pounds S, Razzouk BI, Lacayo NJ, Cao X, Meshinchi S, Degar B, Airewele G, Raimondi SC, Onciu M, Coustan-Smith E, Downing JR, Leung W, Pui CH, Campana D. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010 Jun;11(6):543-52. doi: 10.1016/S1470-2045(10)70090-5. Epub 2010 May 5.

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Responsible Party:	St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:	NCT00136084
Other Study ID Numbers:	AML02 5R01CA113482 ( U.S. NIH Grant/Contract )
First Posted:	August 26, 2005 Key Record Dates
Results First Posted:	March 26, 2010
Last Update Posted:	December 5, 2012
Last Verified:	November 2012

Keywords provided by St. Jude Children's Research Hospital:


Leukemia,Erythroblastic, Acute Erythroblastic Leukemia, Acute Leukemia, Myeloid, Acute Myeloid Leukemia, Acute

Additional relevant MeSH terms:

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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Cytarabine Dexamethasone Prednisone Cyclophosphamide Methotrexate	Etoposide Vincristine Daunorubicin Asparaginase Mercaptopurine Mitoxantrone Cladribine Gemtuzumab Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action

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