Imatinib (Gleevec) improves the ability to proceed with allogeneic stem cell transplantation and improves 5-year overall survival (OS) when used as induction therapy in patients with Philadelphia chromosome– positive (Ph ) acute lymphoblastic leukemia (ALL), according to final results of the UKALLXII/ECOG2993 trial. This is the largest international study to evaluate allogeneic stem cell transplantation in patients with Ph ALL initially treated with imatinib.
“The Philadelphia chromosome is the single most common chromosome abnormality for adults with ALL, and therefore it is important to know that a targeted therapy like imatinib can help improve outcomes in these patients,” said Adele K. Fielding, MBBS, Senior Lecturer at University College London, England, United Kingdom. “These study results demonstrate for the first time that there is a long-term survival advantage of being treated with imatinib earlier in the treatment protocol.”
ALL is the most common type of leukemia in the United States, with about 3930 new cases diagnosed annually. Between 20% to 25% of all adults with ALL test positive for the Ph genetic abnormality, which is associated with an aggressive type of ALL and poor prognosis. Induction chemotherapy does not achieve prolonged remission, so an allogeneic stem cell transplant is typically recommended once a patient first achieves remission.
The UKALLXII/ECOG2993 study was initiated in 1993, before the widespread availability of imatinib to evaluate the role of allogeneic stem cell transplant in 266 adult patients with Ph ALL. Over 2 months, patients received 2 phases of induction chemotherapy, which was followed by an allogeneic stem cell transplant. When the study was expanded in 2003 to include imatinib-treated cohorts, this group of 266 patients became known as the “pre-imatinib” arm.
In March 2003, the study was modified to incorporate a 600- mg daily dose of imatinib as part of consolidation therapy after a second induction regimen but prior to allogeneic stem cell transplant (late-imatinib arm; n = 86) or as part of standard induction therapy prior to the transplant (early-imatinib arm; n = 89). The data from the pre-imatinib patients (ie, control arm) were then applied as a benchmark for the modified study.
The 3 groups had no preexisting differences between them in relation to sex, white blood cell counts at baseline, and confirmed central nervous system involvement at diagnosis. The pre-imatinib cohort was younger than the imatinib cohorts, however, because investigators increased the study’s upper age limit in 2003.
Only 28% of patients in the pre-imatinib group went on to receive allogeneic stem cell transplant as planned, compared with 44% of patients who received imatinib (Table). At 3 years of follow-up, the complete remission (CR) rate in the pre-imatinib cohort was 82% versus 92% in the patients who received imatinib. Event-free survival (EFS), 3-year overall survival (OS), and relapse-free survival (RFS) were significantly better for the patients that received imatinib compared with those who did not. At 3 years, the OS rate was 25% in the pre- imatinib group versus 42% for imatinib-treated patients (P = .0001). The 3-year OS rate was better in the early-imatinib group than in the late-imatinib arm (48% vs 34%, respectively; P = .05).
The rate of 3-year EFS was 19% for the pre-imatinib cohort versus 36% for all imatinib-treated patients (P = .0001); it was 29% for the late-imatinib arm and 45% for the early-imatinib group (P = .05). The3-yearRFSratewas36%forthepre-imatinibgroupversus54% for all imatinib-treated patients (P = .0001); the rate of 3-year RFS was 45% in the late-imatinib arm compared with 65% in the early- imatinib cohort (P = .02).
Overall, the 3-year OS rate was 59% for patients who received allogeneic stem cell transplant per protocol compared with 28% for patients who did not undergo transplant per protocol. Looking just at the control group, the 5-year OS rate was 40% for patients who underwent transplant and 19% for those who did not.
Fielding said the extent to which imatinib improves outcome for adults with Ph ALL who do not undergo subsequent allogeneic stem cell transplant is not clear. She noted that although the comparisons between patients in the pre-imatinib group and patients treated with imatinib were not randomized, imatinib almost certainly accounts for the large differences observed between the groups.
“There can be no basis for omitting imatinib from the initial therapy of adults with Ph ALL,” Fielding said. “Our data show that the best outcome is achieved by imatinib, followed by allogeneic stem call transplant, where nearly 60% [of patients] survived 3 years after diagnosis.”