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    Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Postinduction Treatment for Childhood ALL

    continued...

    High-risk ALL

    In high-risk patients, a number of different approaches have been used with comparable efficacy.[11,19]; [17][Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.

    Evidence (intensification for high-risk ALL):

    1. The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine and L-asparaginase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[20]
      • The augmented therapy regimen in the CCG-1882 trial produced a significantly better EFS than did standard CCG modified BFM therapy.
      • There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).[21]
    2. In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[22]
    3. The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
      • Augmented therapy was associated with an improvement in EFS; there was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[23][Level of evidence: 1iiA]
      • The cumulative incidence of osteonecrosis of bone at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[24][Level of evidence: 1iiC]
    4. The use of the cardioprotectant agent dexrazoxane has been shown to prevent cardiac toxic effects without adversely impacting EFS in high-risk ALL patients. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2 /dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[25,26]
      • The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
      • A greater long-term protective effect was noted in girls than in boys.
      • The Pediatric Oncology Group (POG)-9404 trial also demonstrated no difference in EFS between patients with T-cell ALL who were treated with dexrazoxane and patients who did not receive dexrazoxane.[27]
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