Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia

• 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: St. Jude Children's Research Hospital
• 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

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

• 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

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 :

1. 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 :

1. 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)
2. 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.
3. 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
4. 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
5. 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.
6. 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

• 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

Locations

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

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

More Information

Additional Information:

St. Jude Children's Research Hospital 

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.

• 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
• 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:

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; Gemtuzumab; Cladribine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action