ORLANDO – Adding imatinib to standard therapy for Philadelphia chromosome–positive acute lymphoblastic leukemia significantly improves overall, event-free, and relapse-free survival, investigators reported at the annual meeting of the American Society of Hematology.
Dr. Adele Fielding
A comparison of outcomes in the pre- and post-imatinib (Gleevec) eras for patients treated under the same standard therapy protocol (induction therapy followed by allogeneic hematopoietic stem cell transplant [alloHSCT]) showed that 3-year overall survival improved from 25% before imatinib was introduced to 43% after its introduction (P = .0001).
Similarly, 3-year event-free survival rates nearly doubled, from 19% to 37% (P less than .0001), and relapse-free survival went from 36% to 53% (P = .0001), said Dr. Adele Fielding of University College London.
The addition of imatinib increased the complete remission rate by 10% with no increase in transplant-related mortality, and allowed for a near doubling in the rate of alloHSCT.
"Although there are a number of studies which have now been published detailing the value of imatinib in this disease, this is the largest such study, and because of the very large number of patients treated on the same study without imatinib, it allows us to make certain and very sensible conclusions," Dr. Fielding said.
The trial, designated UKALL12/ECOG2993, initially enrolled 266 patients from 1993 to 2003. These patients (the pre-imatinib cohort) received two phases of induction therapy over 2 months, followed by matched sibling or unrelated donor myeloablative allogeneic hematopoietic stem cell transplant, unless the patient was medically unfit or had no suitable donor.
In March 2003, an additional 86 patients had consolidation with imatinib 600 mg daily after the second induction chemotherapy (late-imatinib cohort). Beginning in late 2005, an additional 89 patients received imatinib concurrently with the second phase of induction chemotherapy (early-imatinib cohort).
All patients who received imatinib resumed the drug, if they were able to tolerate it, for an additional 2 years following the alloHSCT.
Patients who did not undergo transplantation could be put on 2 years of imatinib maintenance at the discretion of the treating institution.
In the pre-imatinib cohort, 82% of patients had a complete response following induction. The addition of imatinib significantly improved responses, with 92% of patients in each of the imatinib cohorts having a complete response (P = .004).
The 3-year follow-up data from the trial show that in addition to the gains in overall, event-free, and relapse-free survival mentioned earlier, patients who received imatinib and who also underwent a per-protocol bone marrow transplant had a 59% 3-year overall survival, compared with 28% for those who received imatinib but not a transplant. Patients who underwent a transplant that differed from the specified protocol had a 49% 3-year overall survival. Rates of event-free survival were similar to those in the overall survival analysis.
Risk of relapse over 3 years among patients who received imatinib and a per-protocol transplant was 25%, compared with 49% for imatinib/non-protocol transplant, and 73% for imatinib but no transplant.
The investigators also found that the early imatinib dosing strategy was associated with better outcomes than the late strategy, with 3-year overall survival rates of 48% vs. 34%, respectively (P = .05), event-free survival of 45% vs. 29% (P = .04), and relapse-free survival of 62% vs. 45% (P = .02).
In a comparison of all patients who achieved a complete response to induction but did not undergo bone marrow transplant, imatinib was associated with an improvement in overall survival (24% vs. 18% for patients treated pre imatinib; P = .02 in multivariate model controlling for age and white blood cell count). But when patients who relapsed or died within the median time to bone marrow transplant were excluded from this analysis, the investigators found no significant difference between the groups, with overall survival of 24% for imatinib and 22% pre imatinib.
"It appears that the improved outcome relates principally to a higher rate of allogeneic transplantation, with a very modest or possibly no long-term benefit to imatinib if transplant is not achieved," Dr. Fielding concluded in her data presentation.
Dr. Fielding had no disclosures. A coauthor, Dr. Anthony H. Goldstone, disclosed receiving honoraria from Roche.