Including Imatinib in Initial Therapy of Adults With Philadelphia-positive Acute Lymphoblastic Leukemia Significantly Enhances Long-Term Outcomes
ORLANDO, Fla.—Imatinib should be included in initial therapy of adult patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL), final results of the largest single study of patients with Ph+ ALL have found. Receiving any imatinib during induction for Ph+ ALL significantly enhances complete remission (CR) rate and increases the allogeneic hematopoietic stem cell transplant (alloHSCT) rate, which translates into a highly significant event-free survival, overall survival, and relapse-free survival advantage.
In fact, the best outcome is observed when imatinib is followed by myeloablative alloHSCT: nearly 60% of patients survive 3 years from diagnosis, Adele K. Fielding, MBBS, PhD, FRCPath, FRCP, Haematology, University College London, London, UK, and colleagues reported.
The Ph+ arm of the international adult ALL trial (UKALL12/ECOG2993), which opened in 1993, includes 441 participants. The first cohort was treated prior to availability of imatinib (n=266; “pre-imatinib”) with 2 phases of induction therapy given over 2 months, followed by matched sibling or unrelated donor myeloablative alloHSCT whenever possible. In March 2003, a second cohort had imatinib 600 mg daily added as a consolidation block after the second induction chemotherapy (n=86; “late imatinib”). From late 2005, a final cohort within the trial was given imatinib earlier, in conjunction with the second induction phase (n=89, “early imatinib”).
Patients in both the late and early imatinib cohorts resumed imatinib for an additional 2 years following alloHSCT, if tolerated. If alloHSCT was not possible, imatinib was permitted for 2 years with maintenance therapy. The trial closed to recruitment in December 2006 (USA) and October 2008 (UK). All except 8 patients have now completed therapy, Dr. Fielding said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.
While an earlier analysis did not indicate a clear long-term advantage to receiving imatinib, results of the 3-year follow-up now being reported shows large differences in outcome among the 3 groups. The total CR rate for the imatinib cohorts was significantly higher than for the pre-imatinib cohort (P=0.004). Pre-imatinib, only 28% of patients went on to receive allo-HSCT, per protocol. With any imatinib, 44% of patients received alloHSCT per protocol.
Survival outcomes of patients in the 3 cohorts are shown in Table 1.Please click here for more study data.Three-year overall survival (OS) for patients who received alloHSCT per protocol was 59% vs 28% (with no plateau on the curve) for those who did not receive alloHSCT per protocol (Figure 1).Please click here for more study data.In comparison, pre-imatinib 5-year OS was 40% for patients who did receive a transplant and 19% for those who did not. Therefore, the extent to which imatinib without subsequent alloHSCT can improve outcome for patients with adult Ph+ ALL is not yet clear.
Dr. Fielding added that an earlier start to imatinib is significantly better than a later start and, although comparisons between study cohorts were not randomized, the large differences observed are unlikely to be explained by factors other than treatment. There were no preexisting differences among the 3 cohorts in terms of gender, presenting white blood cell counts, or presence of central nervous system disease at diagnosis. However, the pre-imatinib cohort was younger than the two imatinib cohorts, due to an increase in the upper age limit for study entry.