A Randomized Phase II Study of Single-Agent Imatinib Versus Chemotherapy Therapy in Elderly Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Including Analysis of Resistance Patterns.

Background: Elderly pts. with Ph+ALL have a very poor prognosis with a low CR rate, high induction mortality and short remission duration. Single-agent Imatinib (IM) has shown rapid anti-leukemic activity and a favorable toxicity in advanced Ph+ALL.

Study design: To determine the value of single-agent IM as induction (ind.) therapy, we designed a prospective, randomized multicenter trial comparing a 4 week course of IM at 600 mg/d (Ind^IM) with age-adapted multi-agent chemotherapy (Ind^chemo) as front-line treatment of elderly Ph+ALL (>55 yrs.) patients. In addition, we investigated the tolerability and efficacy of an IM-based consolidation therapy in which responding pts. received successive chemotherapy cycles parallel to IM, given continuously for one year.

Methods: As mutations of the BCR-ABL tyrosine kinase domain (KD) constitute the leading cause of resistance to IM, we evaluated 17/21 responding pts. at the time of hematologic relapse for the presence of these mutations using direct sequencing and denaturing HPLC.

Results: To date, 52 pts. with newly diagnosed Ph+ALL (49) or lyBC (n=3) and a median age of 68 (58–79) yrs. were randomly assigned to receive Ind^IM (n=25) or Ind^chemo (n=27). Three pts. not entered in the study but treated according to the Ind^chemo regimen are included in the analysis. Twenty-four of 25 pts. assigned to Ind^IM received a CR (96%) and 1 pt. a PR (4%). In comparison, 14 of 23 evaluable pts. allocated to Ind^chemo achieved a CR (61%) and 2 pts. a PR (9%), while 7 pts. failed treatment (30%) (p=0.004). Two deaths occurred during Ind^chemo and none during Ind^IM. Severe infections during ind. developed in 13 of 23 evaluable pts. (57%) assigned to Ind^chemo and in 3 of 25 pts.(12%) receiving Ind^IM (p=0.002). After a median follow-up of 8.2 (0.6–35.4+) mo. 17 pts. are in ongoing CR and 21 pts. have relapsed (10 pts. during study, 7 pts. after end of study and 4 pts. after discontinuation). Ten pts. died in CR a med. of 4.1 (0.4–11.7) mo. after starting treatment and 1 pt. died after allogeneic SCT. Estimated DFS and OS at 18 mo. is 27±8% and 43±8%, respectively. Seventeen of 45 pts.(38%) with serially analysed MRD-levels achieved a molecular remission during treatment. Med. DFS was 15,7 mo. in molecular responders compared to 8.3 mo. in pts. remaining MRD positive (p=0.03). At the time of relapse 10 different BCR-ABL tyrosine KD mutations were detected in 13 of 17 evaluated pts. (76.5%). P-loop mutations were detected in 77% (10 of 13 pts.), activation loop and the T315I mutation each in 15% (2 of 13) of pts. In 3 pts. (23%) two different mutations were detected. In both pts. harboring the T315I mutation, it was already present at the time of diagnosis conferring an inferior remission duration of 1.8 and 5.2 mo.

Conclusion: Single-agent IM is highly effective as ind. therapy in elderly pts. with Ph+ALL and is superior to standard chemotherapy induction with respect to tolerability, induction mortality and CR-rate. Monitoring of resistance patterns will help to identify candidates at risk of relapse and can guide treatment with 2nd generation tyrosine kinase inhibitors.