Postinduction Treatment for Specific ALL Subgroups
Philadelphia Chromosome-Positive ALL
Prior to use of imatinib mesylate (see below), hematopoietic stem cell transplantation (HSCT) from a matched sibling donor was the treatment of choice for patients with Philadelphia chromosome-positive (Ph+) ALL.[40,41,42] 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 compared with standard (pre-imatinib) chemotherapy. 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 era), transplantation with matched-related or matched-unrelated donors were equivalent. Disease-free survival at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and overall survival was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.
Factors significantly associated with favorable prognosis in the pre-imatinib era included younger age and lower leukocyte count at diagnosis. Early response measures were also shown to be prognostically significant in patients with Ph+ ALL in the pre-imatinib era.[44,45,46] Patients with Ph+ ALL who showed a rapid morphologic response or peripheral blood response to induction therapy had an improved outcome compared with patients who showed a slow response.[44,45] 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]
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 for results for adults with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[55,56,57]
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 SCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases. The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib was 87.7% � 10.9%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib), and at least as well as the other patients on the trial who underwent allogeneic transplantation. Longer follow-up is necessary to determine if this novel treatment improves cure rate or merely prolongs DFS.