Treatment of Acute Lymphoblastic Leukemia in Children
Condition: Drug/Agent Toxicity by Tissue/Organ; Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Drug-Related Side Effects and Adverse Reactions
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: L-asparaginase is an important component of treatment for childhood acute
      lymphoblastic leukemia, but is also associated with notable side-effects, including
      hypersensitivity, pancreatitis, and thrombosis. We have previously reported that patients
      with acute lymphoblastic leukemia in whom asparaginase treatment was discontinued because of
      intolerable side-effects had survival outcomes that were inferior to those who received all
      or nearly all of their intended doses. Two bacterial sources of asparaginase exist:
      Escherichia coli (E coli) and Erwinia chrysanthemia (Erwinia). Generally, the E coli-derived
      enzyme has been used as front-line therapy and the Erwinia-derived preparation has been
      reserved for patients who develop hypersensitivity reactions. Pegylated E coli asparaginase
      (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than native E
      coli L-asparaginase, and has been used as the initial asparaginase preparation in some
      pediatric acute lymphoblastic leukemia treatment regimens.

      PURPOSE: Although the pharmacokinetics of each of these asparaginase preparations:
      intravenous PEG-asparaginase (IV-PEG) and intramuscular native E coli L-asparaginase (IM-EC)
      have been well characterized, their relative efficacy and toxicity have not been studied
      extensively.
    

Detailed description: 
      RISK CLASSIFICATION:

      Patients received were classified into initial risk groups defined as:

      High Risk (HR) High risk patients had any of the following features: age 10 years and older,
      a white blood cell count of 50 000 cells per μL or higher, initial spinal fluid sample with
      the presence of lymphoblasts and five or more white blood cells per high power field [Central
      Nervous System (CNS)-3], or a T-cell phenotype.

      Standard Risk (SR) All other patients were classified as standard risk.

      Patients who achieved complete remission (CR) after 32 days of induction therapy defined as a
      marrow specimen with less than 5% marrow blasts and evidence of normal haemopoiesis, absence
      of extramedullary disease, and recovery of peripheral blood counts were randomly assigned in
      a 1:1 ratio to receive IV-PEG or IM-EC. Randomization was stratified by final risk group
      assigned based on end-induction minimal residual disease and cytogenetics as follows:

      Very High Risk (VHR)

      Any initial risk group and any of the following:

        -  MLL gene rearrangement

        -  Hypodiploidy (<45 chromosomes)

        -  B cell-ALL (high) end-induction minimal residual disease (MRD) (>/= 0.001)

      High Risk (HR)

      No VHR features, plus:

      HR initial risk group OR

      SR initial risk group with either of the following:

        -  CNS-2 or CNS-3 on day 18

        -  CNS-2 on day 32 OR

        -  t(9;22) Philadelphia chromosome positive (Ph+ ALL)

      Standard Risk (SR)

      No VHR features, plus:

      SR initial risk group AND

      * CNS-1 on day 18 and 32

      NOTE: CNS-1, Cerebral spinal fluid (CSF) without blasts; CNS-2, CSF with blasts and < 5 WBC
      per high-power field (HPF); CNS-3, CSF with blasts and ≥ 5 WBC per HPF

      THERAPY:

      INDUCTION

        -  Steroid prophase: Patients receive intrathecal (IT) cytarabine on day 1 and
           methylprednisolone IV every 8 hours on days 1-3. Patients then proceed to remission
           induction therapy.

      Patients with CNS leukemia (CNS-2, CNS-3, or traumatic lumbar puncture [LP] with blasts) on
      initial LP receive additional IT cytarabine twice weekly beginning on days 4-6 and continuing
      until cerebrospinal fluid (CSF) is clear, followed by 2 additional doses. Patients with
      cranial nerve palsy but no leukemia blasts in CSF or leukemic eye infiltrates also receive
      additional IT cytarabine as above.

      NOTE: Patients who received steroids within the past 7 days do not receive steroid prophase
      treatment; instead they proceed directly to remission induction therapy according to their
      risk group.

        -  Remission induction therapy (SR patients): Patients receive oral prednisone or
           prednisolone 2-3 times daily OR methylprednisolone IV every 8 hours on days 4-32;
           vincristine IV on days 4, 11, 18, and 25; doxorubicin hydrochloride (DOX) IV over 15
           minutes on days 4 and 5; methotrexate (MTX) IV on day 6; pegasparaginase IV over 1 hour
           on day 7; triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and
           hydrocortisone on day 18; and IT MTX on day 32.

        -  Remission induction therapy (HR and VHR patients): Patients receive
           prednisone/prednisolone OR methylprednisolone; vincristine; DOX; MTX IV;
           pegasparaginase; TIT; and IT MTX as in the SR group. Patients also receive dexrazoxane
           hydrochloride IV over 15 minutes preceding the DOX infusions on days 4 and 5.

      NOTE: Patients who do not receive steroid prophase treatment also receive IT cytarabine on
      day 4.

      NOTE: Patients who are in CR on day 32 proceed to consolidation I. Patients who do not meet
      protocol definition of CR on day 32 but have no evidence of persistent disease receive
      vincristine IV weekly until CR is achieved. Patients with persistent marrow disease (greater
      than 5% leukemic blasts) and/or persistent extramedullary disease or those who do not achieve
      CR by day 53 are removed from the study.

      NOTE: Patients with Ph+ ALL received imatinib (340 mg/m2 PO maximum 600 mg daily starting day
      18) in combination with HR chemotherapy until they proceeded to stem cell transplant.
      Patients with Ph+ ALL patients did not participate in asparaginase randomization but were
      directly assigned to receive IM-EC during post-induction therapy.

      CONSOLIDATION I

        -  Consolidation I (SR patients): Patients receive vincristine IV and IT MTX on day 1 and
           oral mercaptopurine once daily on days 1-14. Patients also receive high-dose MTX (HDM)
           IV continuously over 24 hours on day 1 and leucovorin calcium IV every 6 hours beginning
           36 hours after the start of the HDM infusion and continuing until MTX levels are
           undetectable. Patients proceed to CNS therapy after day 21.

        -  Consolidation I (HR patients): Patients receive vincristine, IT MTX, and mercaptopurine
           as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes
           followed by DOX IV over 15 minutes on day 1 and HDM with leucovorin calcium support as
           in the SR group beginning 8-24 hours after the completion of the DOX infusion. Patients
           proceed to CNS therapy after day 21.

        -  Consolidation I (VHR patients): Patients receive consolidation therapy in 3 stages.

             -  IA: Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group.
                Patients also receive dexrazoxane hydrochloride, DOX, HDM, and leucovorin calcium
                as in the HR group.

             -  IB: Patients receive cyclophosphamide IV over 1 hour and IT MTX on day 22; oral
                mercaptopurine once daily on days 22-35; and cytarabine IV on days 23-26 and 30-33.

             -  IC: Patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 43
                and 44; etoposide IV over 1 hour on days 45-47; and oral dexamethasone twice daily
                on days 43-47. Patients also receive IM-EC weekly beginning on day 48 and
                continuing for up to 30 weeks OR IV-PEG over 1 hour every 2 weeks beginning on day
                48 and continuing for up to 30 weeks. Patients proceed to CNS therapy after day 49.

      KEY RANDOMIZATION: Patients are randomized 1:1 to receive either IV-PEG or IM-EC
      post-induction. Those who achieved a complete remission after induction therapy were assigned
      a final risk group and were eligible to participate in the randomization. The randomization
      was stratified by final risk group.

      NOTE: Ph+ ALL patients did not participate in asparaginase randomization but were directly
      assigned to receive IM-EC during post-induction therapy. Patients who were eligible but
      declined randomization were also directly assigned to receive IM-EC. Patients who developed
      severe pancreatitis (defined as symptoms persisting for >72 h) during induction were not
      eligible for randomization and received no further doses of asparaginase. Patients who had
      hypersensitivity to IV-PEG during induction were also ineligible for randomization, but
      received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.

      CNS

        -  CNS therapy (SR patients): Patients receive vincristine IV on day 1; oral mercaptopurine
           once daily on days 1-14; oral dexamethasone twice daily on days 1-5; and TIT twice
           weekly for 2 weeks. Patients also receive IV-PEG OR IM-EC as above beginning on day 1
           and continuing for up to 30 weeks. Patients proceed to consolidation II after day 21.

        -  CNS therapy (HR and VHR patients): Patients receive vincristine, mercaptopurine,
           dexamethasone, and TIT as in the SR group. Patients also receive dexrazoxane
           hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. HR
           patients also receive IV-PEG OR IM-EC as above beginning on day 1 and continuing for up
           to 30 weeks. VHR patients continue to receive IV-PEG OR IM-EC as per consolidation I
           treatment. Patients proceed to consolidation II after day 21.

      NOTE: Patients with WBC > 100,000/mm³, T-cell disease, and/or CNS-3 at diagnosis or CNS-2 at
      end of remission induction therapy also undergo cranial radiation therapy daily for 8 or 10
      days.

      CONSOLIDATION II

        -  Consolidation II (SR patients): Patients receive vincristine IV on day 1; oral
           dexamethasone twice daily on days 1-5; and oral mercaptopurine once daily on days 1-14.
           Treatment repeats every 21 days until IV-PEG OR IM-EC is completed. Patients also
           receive MTX IV or IM 1 day after each IV-PEG OR IM-EC dose and TIT every 9 weeks for 6
           doses and then every 18 weeks thereafter.

        -  Consolidation II (HR and VHR patients): Patients receive vincristine, dexamethasone, and
           mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV
           over 15 minutes followed by DOX IV over 15 minutes on day 1. Treatment repeats every 21
           days until IV-PEG OR IM-EC is completed. Patients also receive MTX IV or IM as in the SR
           group and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter OR TIT every
           18 weeks.

      CONTINUATION

        -  Continuation therapy: After completion of all consolidation therapy, all patients
           receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; oral
           mercaptopurine once daily on days 1-14; and MTX IV or IM on days 1, 8, and 15. Treatment
           repeats every 21 days for up to 24 months (102 weeks) after achieving CR. Patients
           continue to receive TIT as in consolidation II until completion of therapy.

      OBJECTIVES:

      Primary

        -  To determine the relative toxicity of IV PEG asparaginase and IM E.coli asparaginase in
           children with acute lymphoblastic leukemia (ALL)

      Secondary (reported)

        -  To explore the relative efficacy of IV PEG asparaginase and IM E.coliasparaginase

        -  To determine the rate of infections (episodes of bacteremia and disseminated fungal
           infections) during the remission induction phase

        -  To compare trough serum asparaginase enzyme levels, asparagine levels and
           antiasparaginase antibody levels

        -  To evaluate the outcome of patients based upon MRD status after 28 days of multiagent
           chemotherapy within the context of a regimen which intensifies treatment for B-lineage
           patients with MRD levels >0.001 at the end of remission induction (day 32 MRD status
           used)

        -  To evaluate the outcome of patients based upon bone marrow morphology after 14 days of
           multiagent chemotherapy (day 18 marrow morphology status used)

        -  To determine the efficacy of CNS-directed treatments

      Secondary (not reported)

        -  To compare antiasparaginase antibody levels (not available due to problems with the
           assay)

        -  To correlate trough enzyme levels with outcome (toxicity, relapse)

        -  To determine CNS-related toxicity of CNS-directed treatments (data is not mature on late
           neurocognitive impairments in long-term survivors)

        -  To determine the efficacy and CNS-related toxicity (acute and long-term) of the HR
           regimen in which a subset of HR patients (B-lineage, CNS-1 or CNS-2, WBC <100,000/m3)
           are treated with intensive intrathecal chemotherapy and the remainder are treated with
           12 Gy cranial radiation (with intrathecal chemotherapy)

        -  To determine the efficacy and CNS-related toxicity (acute and long-term) of intensive
           intrathecal therapy in SR patients

        -  To determine the prognostic significance of asparaginase antibody formation

        -  To compare randomized treatment groups using health-related quality-of-life analysis
           (connected with a separate protocol 06-373)

        -  To investigate the association of dietary antioxidant micronutrient intake with the rate
           of infections (episodes of bacteremia and disseminated fungal infections) during
           remission induction therapy and the Consolidation IA phase

        -  To determine the relationship of dietary calcium intake with risk for development of
           fractures during the continuation phase of therapy

        -  To evaluate the association of dietary intake of specific nutrients with
           treatment-related toxicities during treatment

        -  To evaluate the outcome of patients based upon MRD status after 14 days of multiagent
           chemotherapy and at various other timepoints while on treatment every 18 weeks after
           achieving complete remission and at the completion of all chemotherapy

        -  To determine the prognostic significance of response to remission induction chemotherapy
           as measured by morphologic and minimal residual disease (MRD) measures within the
           context of DFCI ALL Consortium protocol therapy (data limited due to response outcomes)

        -  To compare rate of infection during remission induction in patients treated with a less
           intensive induction regimen on Protocol 05-01 (low-dose instead of high-dose
           methotrexate) with that of patients treated on prior DFCI ALL Consortium Protocol 00-01
           (induction regimen included high-dose methotrexate)

        -  To determine the concordance of MRD quantification using multi-parameter flow cytometry
           and PCR techniques

        -  To determine the prognostic significance of gene expression programs in childhood ALL
           and identify new targets for specific therapies

        -  To identify clinically relevant gene expression signatures in leukemia cells

        -  To identify gene expression signature in leukemia cells at diagnosis that predicts
           peripheral blood response to the steroid prophase

        -  To identify gene expression changes in leukemia cells induced by steroid treatment

        -  To determine the frequency and type of tyrosine kinase mutations in childhood ALL and
           identify new targets for specific therapies

        -  To explore the potential relationship between abnormal glucose homeostasis during
           therapy and the development of obesity, as well as the potential relationship between
           obesity and the age of pubertal onset (assessed in patients treated at DFCI/CHB only)

        -  To characterize the degree of hyperglycemia and insulin resistance in patients receiving
           therapy for childhood ALL

        -  To characterize the degree of insulin resistance and obesity after the completion of
           therapy for childhood ALL
    

Intervention name(s): asparaginase; cyclophosphamide; cytarabine; dexamethasone; dexrazoxane hydrochloride; doxorubicin hydrochloride; etoposide; leucovorin calcium; mercaptopurine; methotrexate; methylprednisolone; pegaspargase; prednisolone; therapeutic hydrocortisone; vincristine sulfate; radiation therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): Given IV; Given orally; Given IV
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Methylprednisolone; Prednisolone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Asparaginase; Mercaptopurine; Pegaspargase; Dexrazoxane; Razoxane; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: drug/agent toxicity by tissue/organ; untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia