Clinical Significance of Dose Reductions of Second-Generation Tyrosine Kinase Inhibitors (TKI) in Patients (Pts) with Chronic Myeloid Leukemia (CML)

Abstract Background: Second-generation TKI (dasatinib, nilotinib) are effective in patients with all phases of CML. However, dose reductions and treatment interruptions of those drugs are frequently required due to toxicity. The impact such dose reductions may have on outcome is not well known. Aims: To determine the impact of dose reduction of 2nd-generation TKI in response, overall survival and event free-survival. Methods: The records of 236 pts with CML who received therapy with the 2nd-generation TKI dasatinib and nilotinib were analyzed. We considered dose reductions only those below what is considered standard dose today (standard daily dose for dasatinib was defined as 140 mg for blast-phase/accelerated-phase and 100 mg for chronic phase; standard daily dose for nilotinib was 800 mg). Overall survival was defined from the time treatment was started to death from any cause or last follow-up. Event-free survival was defined as the time from start of treatment to the occurrence of an event or last follow-up. An event was defined as death, transformation to accelerated or blast phase, loss of major cytogenetic response, loss of complete cytogenetic response, increase in white blood cell count (>20×109/L), loss of complete hematological response, treatment discontinuation because of failure and treatment discontinuation because of toxicity. Results: A total of 236 patients were included, with median age 52 yrs (range, 18 to 81). They were divided into: blastphase or Philadelphia-chromosome positive acute lymphoblastic leukemia (BP; N=34), accelerated phase (AP; N=34), late chronic phase after imatinib failure (LCP; N=70), and early chronic phase (ECP; N=98). Ninety-six pts (41%) received nilotinib and 140 (59%) received dasatinib. For the purposes of this analysis they were all considered together. Overall, 96 (46%) patients had one or more dose reductions. Dose reductions occurred in 10 pts with BP (30%), 20 with AP (59%), 32 with LCP (46%) and 34 with ECP (34%). The most common cause for dose reduction was myelosuppression (41%) The results for major cytogenetic responses, event-free survival and median overall survival according to whether pts had a dose reduction or not are presented in table 1 Table 1. No. % MCyR EFS % at 2 yr (median mo) OS % at 2 yr (median mo) ECP DR 34 94 88% (NR) 100% (NR) No DR 64 88 78% (NR) 100% (NR) p value 0.25 0.35 1 LCP DR 32 59 57% (28) 97% (NR) No DR 38 55 48% (22) 80% (NR) p value 0.91 0.58 0.009 AP DR 20 50 23% (10) 45% (23) No DR 14 21 21% (2) 47% (24) p value 0.09 0.34 0.85 BP DR 10 60 30% (17) 50% (31) No DR 24 29 0% (3) 18% (7) p value 0.06 0.0005 0.02 ECP=Early chronic phase; LCP=Late chronic phase; AP=Accelerated phase; BP=BP (includes Ph+ ALL); DR=Dose reduced; No DR=Not dose reduced; MCyR=Major cytogenetic response; EFS=Event free survival; OS=Overall survival. Conclusion: Dose reductions of 2nd-generation TKI in patients with CML do not have a negative impact in the response rate and survival of patients treated with these agents. Thus, pts who need dose reductions due to toxicity should be managed accordingly. Further studies are required to determine whether there might be a minimum adequate dose of these agents.