Prolonged Survival and Carcinoma as Frequent Cause of Death in Patients Treated with Sustained Imatinib Mesylate for Advanced Chronic Phase CML Intolerant or Refractory to Interferon.

Introduction: Imatinib mesylate (IM) proved effective in patients (pts) with CML in advanced chronic phase (CP) not responsive/intolerant to recombinant alfa-interferon (IFN) and not candidate to allogeneic stem cell transplantation (SCT). The long term outcome of these pts, including blastic phase (BP) evolution and cause of death, is still partially known. Since their bcr/abl transcript levels were reduced by the prolonged use of IM, even in the absence of a karyotypic response (KR) (Cariani, Ann Hematol, 2003), we have treated them, irrespective of their karyotypic response, with sustained IM until death or evolution to blastic crisis, and have analysed their outcome in comparison with earlier pts treated at our institution with IFN when IM was not available, and with more recent pts receiving IM upfront.

Patients and methods: The study group (“IFN>IM”) included 28 pts initially treated with IFN for CP CML between 09/95 and 04/00, who switched to IM (400mg/daily) after a median of 18 months (range: 4–73) because of intolerance in 6, or lack/loss of major/complete KR in 22. IM was continued in all pts until BP or death. Controls were represented by a cohort of 30 pts, treated with IFN only (“IFN”) before the availability of IM, and by a cohort of 17 pts (“IM”), receiving IM at diagnosis since 08/00. Eight pts in group “IFN” underwent allogeneic SCT. The median age of “IFN>IM” pts. was 53 (range 22–66), significantly higher than “IFN” (43; range 19–64; P=0.002), but similar to “IM” pts (56; range 24–81).

Results: The complete KR rate in group “IFN>IM” increased from 14,3% with IFN to 50% with IM. Eleven cytogenetic unresponsive pts have been receiving IM for 35 months (range 5–50). After a median of 67.5 months (23–161), evolution to BP occurred in three pts and death in five. Leukemia was the cause of death in two, whereas three pts, median age 61 (range 60–69), died of carcinoma (lung 1, stomach 1, and pancreas 1), diagnosed while they were in late CP and on IM treatment for a median of 21 months (15–37). In addition, one 48-year old pt developed endometrial carcinoma, treated with surgery and radiation therapy, after 4 years of IFN, before switching to IM. The 8-year actuarial survival of “IFN>IM” was 77,4% ± 10,2%, with no differences between cytogenetic responsive or unresponsive pts. When compared with “IFN” pts, “IFN>IM” pts had a lower frequency of BP evolution (10.7% vs 43.3%; P=0.008) and longer leukemia-specific survival (NR vs 111 months; log-rank: P=0.025), while overall survival did not differ significantly. The actuarial risk of dying of carcinoma was increased in group “IFN>IM” (P=0.047). No significant differences in BP evolution, leukemia-specific and overall survival were found comparing “IFN-IM” to “IM”. Overall, the actuarial risk of developing carcinoma in pts receiving IFN vs IM was not significantly different.

Conclusions: Pts intolerant/refractory to IFN achieved prolonged survival in CP CML with sustained IM therapy, independently from KR. Evolution to BP was significantly less frequent than in younger historical controls treated with IFN ± SCT. Causes of death different from BP are emerging, particularly carcinomas, probably as a result of older age and longer survival of pts.