Clinical trial NCT00136084: Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia
Official title: A Collaborative Trial for the Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Myelocytic, Acute
Keywords: Leukemia,Erythroblastic, Acute
Erythroblastic Leukemia, Acute
Leukemia, Myeloid, Acute
Myeloid Leukemia, Acute
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-08-26
Enrollment: 238
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility 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)

Primary outcomes:
measure: Minimal Residual Disease (MRD).
timeFrame: Day 22 MRD measurement
Secondary outcomes:
measure: Proportion of Minimal Residual Disease (MRD)+ Patients Who Become MRD- After One Course of Gemtuzumab Ozogamicin (GO)
timeFrame: Consolidation I
measure: Proportion of MRD Reduction After One Course of Cytarabine + Daunomycin + Etoposide (ADE) + GO
timeFrame: Induction II
measure: Proportion of Patients Experienced Toxicity of Cytarabine + Daunomycin + Etoposide (ADE) + GO.
timeFrame: Induction II
measure: To Estimate the Overall Event-free Survival (EFS) of AML Patients Who Undergo Risk-adapted and Genotype-directed Therapy
timeFrame: Five Year
measure: To Assess Whether Inhibition of DNA Synthesis is Greater After High-dose Ara-C (HDAC) Than After Low-dose Ara-C (LDAC) Therapy
timeFrame: Measurements were assessed in Induction I chemotherapy
measure: Relationship of Inhibition of DNA Synthesis and Clinical Response
timeFrame: Measurements were assessed in Induction I chemotherapy
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan (Wayne State University)
state: Michigan
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Jeffrey Rubnitz, M.D., PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.