Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia
Condition: Childhood Acute Promyelocytic Leukemia With PML-RARA; Myeloid Neoplasm
MeSH terms: Leukemia; Leukemia, Promyelocytic, Acute
Study type: Interventional
Phase: Phase 3

Summary: 
      This phase III trial is studying combination chemotherapy to see how well it works in
      treating young patients with newly diagnosed acute promyelocytic leukemia. 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. Giving more than one drug (combination chemotherapy)
      may kill more cancer cells.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To decrease the total anthracycline dose from the best current published results in
      standard risk childhood acute promyelocytic leukemia (APL) while still maintaining a
      comparable event-free survival (EFS).

      SECONDARY OBJECTIVES:

      I. To assign treatment based on risk stratification by white blood cell count (WBC) at
      diagnosis.

      II. To estimate the induction failure rate, toxic death rate, disease-free survival rate and
      overall survival rate in both standard and high risk APL patients.

      III. To monitor for cardiotoxicity in an idarubicin/mitoxantrone based regimen. IV. To
      document the toxicity of a traditional chemotherapy/all-trans retinoic acid (ATRA)
      (tretinoin) based regimen combined with arsenic trioxide therapy.

      V. To study the relationship of Fms-like tyrosine kinase 3 (FLT3) mutations to clinical
      features and outcome in APL.

      VI. To study risk factors for pseudotumor cerebri in APL. VII. To study the relationship of
      early progenitor cell involvement to treatment failure in FLT3 positive APL.

      VIII. To compare the EFS of children enrolled on AAML0631 with the EFS of children enrolled
      on C9710 who were between the ages of 2 and 21 and did not receive arsenic trioxide.

      IX. To estimate the proportion of patients who carry a cryptic t(15;17), i.e., those who are
      positive for a promyelocytes.(PML)-retinoic acid receptor alpha (RARA) fusion transcript by
      polymerase chain reaction (PCR) analysis but have normal chromosomes.

      X. To estimate the proportion of patients with variant RARA partners. XI. To compare the
      outcome of patients with only a t(15;17) with that of patients who carry a t(15;17) and other
      chromosomal abnormalities.

      OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 arms based on risk
      factor (standard-risk [WBC less than 10,000/mm^3] or high-risk [WBC 10,000/mm^3 or higher]).

      ARM I (STANDARD-RISK):

      INDUCTION THERAPY: Patients receive tretinoin orally (PO) twice daily (BID) on days 1-30 and
      idarubicin intravenously (IV) over 15 minutes once on days 3, 5, and 7.

      CONSOLIDATION THERAPY:

      CONSOLIDATION 1: Patients receive arsenic trioxide IV over 2 hours on days 1-5, 8-12, 15-19,
      22-26, and 29-33 and tretinoin PO BID on days 1-14. Treatment repeats every 5 weeks for 2
      courses, followed by a 2-week break, and then treatment repeats for 2 more courses. Beginning
      1 week later or when blood counts recover, patients proceed to consolidation 2.

      CONSOLIDATION 2: Patients receive cytarabine intrathecally (IT) on day 1, tretinoin PO BID on
      days 1-14, high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and mitoxantrone
      hydrochloride IV over 15-30 minutes once on days 3 and 4. Patients proceed to consolidation 3
      1 week later or when blood counts recover.

      CONSOLIDATION 3: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14, and
      idarubicin IV over 15 minutes once daily on days 1, 3, and 5. High-risk patients and those
      standard-risk patients who are positive for minimal residual disease by real-time
      quantitative (RQ)-PCR receive consolidation 4 one week later or when blood counts recover.
      All other standard-risk patients proceed to maintenance therapy.

      MAINTENANCE THERAPY: Patients receive cytarabine IT on day 1 (course 1 only), tretinoin PO
      BID on days 1-14, mercaptopurine PO once daily (QD) on days 1-84, methotrexate PO once on
      days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 9
      courses.

      ARM II (HIGH-RISK):

      INDUCTION THERAPY: Patients receive tretinoin PO BID on days 1-30 and idarubicin IV over 15
      minutes once on days 1, 3, and 5. Patients proceed to consolidation therapy one week later or
      when blood counts recover.

      CONSOLIDATION THERAPY: Patients receive consolidation 1, 2, and 3 as in Arm I.

      CONSOLIDATION 4: Patients receive cytarabine IT on day 1, tretinoin PO BID on days 1-14,
      high-dose cytarabine IV over 3 hours every 12 hours on days 1-3, and idarubicin IV over 15
      minutes once on day 4. Patients who demonstrate molecular complete remission (CR) and remain
      in hematological CR proceed to maintenance therapy 1 week later or when blood counts recover.

      MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I.

      After completion of study treatment, patients are followed every month for 1 year, every 3
      months for 2 years, every 6 months for 2 years, and then annually for 5 years.
    

Intervention name(s): Arsenic Trioxide; Cytarabine; Diagnostic Laboratory Biomarker Analysis; Idarubicin; Mercaptopurine; Methotrexate; Mitoxantrone Hydrochloride; Tretinoin
Intervention type(s): Drug; Drug; Other; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Given IV; Given IT or IV; Correlative studies; Given IV; Given orally; Given orally; Given IV; Given orally
Other intervention name(s): Arsenic (III) Oxide; Arsenic Sesquioxide; Arsenous Acid; Arsenous Acid Anhydride; Arsenous Oxide; ATO; Trisenox; White Arsenic; .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; 4-Demethoxydaunomycin; 4-Demethoxydaunorubicin; 4-DMDR; 3H-Purine-6-thiol; 6 MP; 6 Thiohypoxanthine; 6 Thiopurine; 6-Mercaptopurine; 6-Mercaptopurine Monohydrate; 6-MP; 6-Purinethiol; 6-Thiopurine; 6-Thioxopurine; 6H-Purine-6-thione, 1,7-dihydro- (9CI); 7-Mercapto-1,3,4,6-tetrazaindene; Alti-Mercaptopurine; Azathiopurine; Bw 57-323H; Flocofil; Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mercaptina; Mercaptopurinum; Mercapurin; Mern; NCI-C04886; Puri-Nethol; Purimethol; Purine, 6-mercapto-; Purine-6-thiol (8CI); Purine-6-thiol, monohydrate; Purinethiol; Purinethol; U-4748; WR-2785; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate; Mexate-AQ; MTX; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan; 2,4,6,8-Nonatetraenoic acid, 3, 7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, (all-E)-; Aberel; Airol; Aknoten; all trans-Retinoic acid; All-trans Retinoic Acid; All-trans Vitamin A Acid; all-trans-Retinoic acid; all-trans-Vitamin A acid; ATRA; Avita; beta-Retinoic Acid; Cordes Vas; Dermairol; Epi-Aberel; Eudyna; Renova; Retin-A; Retin-A MICRO; Retin-A-Micro; Retinoic Acid; Retisol-A; Ro 5488; Stieva-A; Stieva-A Forte; Trans Retinoic Acid; Trans Vitamin A Acid; trans-Retinoic Acid; Tretinoinum; Vesanoid; Vitamin A Acid; Vitamin A acid, all-trans-; Vitinoin
Intervention MeSH terms: Vitamins; Vitamin A; Cytarabine; Methotrexate; Mercaptopurine; Mitoxantrone; Idarubicin; Tretinoin; Retinol palmitate; Arsenic Trioxide
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment