Dexamethasone Compared With Prednisone During Induction Therapy and Methotrexate With or Without Leucovorin During Maintenance Therapy in Treating Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      This randomized phase III trial is studying dexamethasone to see how well it works compared
      to prednisone during induction therapy. This trial is also studying methotrexate and
      leucovorin calcium to see how well they work compared to methotrexate alone during
      maintenance therapy in treating patients with newly diagnosed acute lymphoblastic leukemia
      (ALL). Drugs used in chemotherapy, such as dexamethasone, prednisone, methotrexate, and
      leucovorin calcium, work in different ways to stop cancer cells from dividing so they stop
      growing or die. Giving more than one drug may kill more cancer cells. It is not yet known
      which combination chemotherapy regimen is more effective in treating acute lymphoblastic
      leukemia.
    

Detailed description: 
      OBJECTIVES:

      I. Improve the outcome of children with high-risk acute lymphoblastic leukemia treated with 2
      different chemotherapy regimens.

      II. Determine the relative safety and efficacy of dexamethasone given for 14 days vs
      prednisone given for 28 days during induction.

      III. Determine the relative safety and efficacy of high-dose methotrexate (5gm/m^2) with
      leucovorin rescue compared to escalating methotrexate without leucovorin rescue (Capizzi I)
      during interim maintenance I.

      IV. Correlate Day 29 minimal residual disease (MRD) with event-free survival (EFS) and
      overall survival (OS).

      V. Correlate early marrow response status with day-29 MRD status. VI. Improve outcome by
      identifying additional high risk patients by Day 29 MRD for treatment with fully augmented
      Berlin-Frankfurt-Munster (BFM).

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to early
      response (slow early response [SER] vs rapid early response [RER]). Induction therapy:
      Patients are randomized to 1 of 4 treatment arms.

      ARM I: Patients receive cytarabine intrathecally (IT) on day 1, vincristine intravenously
      (IV) and daunorubicin IV on days 1, 8, 15, and 22, dexamethasone orally (PO) or IV twice
      daily (BID) on days 1-14, methotrexate (MTX) IT on days 8 and 29* and pegaspargase
      intramuscularly (IM) once on day 4, 5, or 6.

      NOTE: *Patients with CNS3 disease (WBC > 5/mL in cerebrospinal fluid and positive for blasts
      on cytospin) also receive MTX IT on days 15 and 22.

      ARM II: Patients receive induction therapy as in Arm I.

      ARM III: Patients receive cytarabine, vincristine, daunorubicin, and pegaspargase as in Arm
      I. Patients also receive prednisone PO or IV BID on days 1-28 and MTX IT on days 8 and 29.

      ARM IV: Patients receive induction therapy as in Arm III.

      Patients in all arms are evaluated at day 29 of induction therapy. Patients with M3 disease
      are removed from study. Patients with M1 disease and less than 1% minimal residual disease
      (MRD) proceed to consolidation therapy beginning on day 36. Patients with M2 disease OR with
      MI disease and at least 1% MRD receive extended induction therapy for 2 additional weeks.
      Patients with SER disease and MLL rearrangements are removed from the study but may be
      eligible for treatment on protocol COG-AALL0031.

      Extended induction therapy: Patients continue to receive therapy on the arm to which they
      were originally randomized.

      ARMS I and II: Patients receive dexamethasone PO or IV BID on days 1-14, vincristine IV on
      days 1 and 8, daunorubicin IV on day 1 and pegaspargase IM on day 4, 5, or 6 and are then
      reevaluated.

      ARMS III and IV: Patients receive prednisone PO or IV BID on days 1-14, and vincristine,
      daunorubicin, and pegaspargase as in Arms I and II and are then reevaluated.

      Patients on all arms who have M1 disease and less than 1% MRD after extended induction
      proceed to consolidation therapy and continue as SER patients. All other patients are removed
      from study.

      Consolidation therapy: All patients receive cyclophosphamide IV over 30 minutes on days 1 and
      29, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine
      (MP) PO on days 1-14 and 29-42, vincristine IV on days 15, 22, 43, and 50; pegaspargase IM on
      days 15 and 43 and MTX* IT on days 1, 8, 15, and 22. Patients with testicular disease also
      receive radiotherapy to the testes.

      NOTE: *Patients with CNS3 disease receive MTX on days 1 and 8 only.

      Interim maintenance therapy I: Patients continue to receive treatment on the arm to which
      they were originally randomized.

      ARM I: (escalating-dose MTX) Patients receive vincristine IV and escalating-dose MTX IV on
      days 1, 11, 21, 31, and 41, pegaspargase IM on days 2 and 22 and MTX IT on days 1 and 21.

      ARM II: (high-dose MTX) Patients receive vincristine IV and high-dose methotrexate IV over 24
      hours on days 1, 15, 29, and 43, MP PO on days 1-56 and IT MTX on days 1 and 29. Patients
      also receive leucovorin calcium IV every 6 hours for at least 3 doses, beginning 42 hours
      after start of each MTX infusion.

      ARM III: (escalating-dose MTX) Patients receive interim maintenance I therapy as in Arm I.

      ARM IV: (high-dose MTX) Patients receive interim maintenance I therapy as in Arm II.

      DELAYED INTENSIFICATION THERAPY I: All patients receive vincristine IV on days 1, 8, 15, 43,
      and 50, dexamethasone PO or IV BID on days 1 to 21 for patients age 1 to 12 OR on days 1-7
      and 15-21 for patients age 13 and over, doxorubicin IV on days 1, 8, and 15, pegaspargase IM
      on day 4, 5, or 6 AND day 43, cyclophosphamide IV over 30 minutes on day 29, cytarabine IV or
      SC on days 30-33 and 37-40, thioguanine PO on days 29-42 and MTX IT on days 1, 29, and
      36.After delayed intensification I, SER patients proceed to interim maintenance II and
      delayed intensification II. RER patients proceed directly to maintenance.

      INTERIM MAINTENANCE THERAPY II: All patients receive vincristine IV and MTX IV on days 1, 11,
      21, 31, and 41, pegaspargase IM on days 2 and 22; and MTX IT on days 1 and 21. Patients then
      proceed to delayed intensification II.

      DELAYED INTENSIFICATION THERAPY II: All patients receive therapy as in delayed
      intensification I, arm I. CNS3 patients also receive radiotherapy for 3-10 days, beginning on
      day 29. All other SER patients, patients with MLL rearrangements, and some patients
      pretreated with steroids (> 48 hours within the week prior to diagnosis) receive prophylactic
      cranial radiotherapy (CRT) for 8 days, beginning on day 29. Patients then proceed to
      maintenance therapy.

      MAINTENANCE THERAPY: All patients receive vincristine IV on days 1, 29, and 57, dexamethasone
      PO BID on days 1-5, 29-33, and 57-61, MP PO on days 1-84, MTX IT on day 1*; and MTX PO on
      days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

      NOTE: *RER (who did not undergo CRT) patients also receive MTX IT on day 29 for maintenance
      courses 1-4.

      In all arms, maintenance therapy repeats every 12 weeks until total duration of therapy is 2
      years from the start of interim maintenance I for female patients and 3 years from the start
      of interim maintenance I for male patients. Patients with testicular disease may receive
      testicular radiotherapy for 8 days during one of the first 3 courses of maintenance therapy.
      Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1
      year, every 6 months for 1 year, and then annually thereafter.
    

Intervention name(s): Cyclophosphamide; Cytarabine; Daunorubicin Hydrochloride; Dexamethasone; Doxorubicin Hydrochloride; Leucovorin Calcium; Mercaptopurine; Methotrexate; Pegaspargase; Prednisone; Radiation Therapy; Thioguanine; Vincristine Sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation; Drug; Drug
Intervention description(s): Given IV; Given IT, SC, or IV; Given IV; Given PO or IV; Given IV; Given IV; Given PO; Given IT or IV; Given IM; Given PO or IV; Undergo radiation therapy; Given PO; Given IV
Other intervention name(s): (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; .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; Cerubidin; Cerubidine; Cloridrato de Daunorubicina; Daunoblastin; Daunoblastina; Daunoblastine; Daunomycin Hydrochloride; Daunomycin, hydrochloride; Daunorubicin.HCl; Daunorubicini Hydrochloridum; FI-6339; Ondena; RP-13057; Rubidomycin Hydrochloride; Rubilem; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycadron; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron; Decadron DP; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone Intensol; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dxevo; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; TaperDex; Visumetazone; ZoDex; 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI); ADM; Adriacin; Adriamycin; Adriamycin Hydrochloride; Adriamycin PFS; Adriamycin RDF; ADRIAMYCIN, HYDROCHLORIDE; Adriamycine; Adriblastina; Adriblastine; Adrimedac; Chloridrato de Doxorrubicina; DOX; DOXO-CELL; Doxolem; Doxorubicin HCl; Doxorubicin.HCl; Doxorubin; Farmiblastina; FI 106; FI-106; hydroxydaunorubicin; Rubex; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; folinic acid; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Wellcovorin; 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; L-Asparaginase with Polyethylene Glycol; Oncaspar; Oncaspar-IV; PEG-Asparaginase; PEG-L-Asparaginase; PEG-L-Asparaginase (Enzon - Kyowa Hakko); PEGLA; Polyethylene Glycol L-Asparaginase; Polyethylene Glycol-L-Asparaginase; .delta.1-Cortisone; 1, 2-Dehydrocortisone; Adasone; Cortancyl; Dacortin; DeCortin; Decortisyl; Decorton; Delta 1-Cortisone; Delta-Dome; Deltacortene; Deltacortisone; Deltadehydrocortisone; Deltasone; Deltison; Deltra; Econosone; Lisacort; Meprosona-F; Metacortandracin; Meticorten; Ofisolona; Orasone; Panafcort; Panasol-S; Paracort; Perrigo Prednisone; PRED; Predicor; Predicorten; Prednicen-M; Prednicort; Prednidib; Prednilonga; Predniment; Prednisone Intensol; Prednisonum; Prednitone; Promifen; Rayos; Servisone; SK-Prednisone; Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; 2-Amino 6MP; 2-Amino-1,7-dihydro-6H-purine-6-thione; 2-Amino-6-mercaptopurine; 2-Amino-6-purinethiol; 2-Aminopurin-6-thiol; 2-Aminopurine-6(1H)-thione; 2-Aminopurine-6-thiol; 2-Aminopurine-6-thiol Hemihydrate; 2-Mercapto-6-aminopurine; 6-Amino-2-mercaptopurine; 6-Mercapto-2-aminopurine; 6-Mercaptoguanine; 6-TG; 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI); BW 5071; Lanvis; Tabloid; Thioguanine Hemihydrate; Thioguanine Hydrate; Tioguanin; Tioguanine; Wellcome U3B; WR-1141; X 27; Kyocristine; Leurocristine Sulfate; Leurocristine, sulfate; Oncovin; Vincasar; Vincosid; Vincrex; Vincristine, sulfate
Intervention MeSH terms: Calcium, Dietary; Leucovorin; Folic Acid; Cytarabine; Dexamethasone; Dexamethasone acetate; Prednisone; Cortisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Thioguanine; BB 1101; Calcium; 2-Aminopurine; Levoleucovorin
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment