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

    Table 3. Outcome According to Treatment Protocol for Adolescents and Young Adults with ALL continued...

    Treatment options

    Pre-tyrosine kinase inhibitor era

    Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[42,43,44] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome than standard (pre-imatinib mesylate) chemotherapy.[40] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and OS was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.[41]

    Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included the following:

    • Younger age at diagnosis.[41]
    • Lower leukocyte count at diagnosis.[41]
    • Early response measures.[41,45,46]
    • Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction therapy.[41,45]

    Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may also be useful to help predict outcome for Ph+ patients.[47,48,49]

    Tyrosine kinase inhibitor era

    Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[50,51]

    Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[52,53,54] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[55,56,57,58]

    Evidence (imatinib mesylate):

    1. The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[54]
      • The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate is 87.7% ± 10.9%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplantation. Longer follow-up is necessary to determine whether this novel treatment improves cure rate or merely prolongs DFS.
    2. A nonrandomized study reported the outcome in 16 pediatric patients with Ph+ ALL who were treated with chemotherapy, imatinib, and allogeneic HSCT.[58]
      • With a median follow-up of 65 months, the 5-year EFS was 81% for patients who received imatinib compared with 30% (P = .01) for a historic control group treated similarly, but without imatinib.[59] Of note, only one of the 16 patients received prophylactic imatinib posttransplant.
    3. The EsPhALL trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improves outcome for pediatric Ph+ ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk based on early response measures and remission status at the end of induction. Good- risk patients (N = 90) were randomly assigned to receive imatinib or not; poor-risk patients (N = 70) were directly assigned to imatinib. Interpretation of this study is limited due to the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual due to publication of the results of the COG AALL1131 trial on which imatinib had been given continuously with chemotherapy. The overall DFS of patients treated on this trial appeared to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good-risk patients who received imatinib had a superior DFS. The EsPhALL trial has since been amended to test continuous dosing of imatinib; results are pending.[60]
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