Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients.

Mario Tiribelli,Gianluca Festini,Federico De Marchi,Luigi Scaffidi,Manuela Stulle,Anna Guella,Gianpietro Semenzato,Elisabetta Calistri,Luca Frison,Massimiliano Bonifacio,Elena Maino,Francesca Cibien,Claudia Minotto,Marta Medeot,Nicola Orofino,Gianni Binotto,Rosaria Sancetta,Alessandra Iurlo,Renato Fanin,Cristina Bucelli,Giovanni Pizzolo,Mauro Krampera,Achille Ambrosetti,E De Biasi ,Filíppo Gherlinzoni

doi:10.18632/oncotarget.24478

Abstract

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a “real-life” setting.We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients.Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib.In a “real-life” setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.

Highlights

The introduction and worldwide diffusion of imatinib (IM) and, subsequently, second-generation tyrosine kinase inhibitors (2G-TKIs) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients
One patient in each cohort displayed a 2G-TKIsensitive ABL mutation at the time of IM failure, namely one M351T in a patient treated with DAS and one L364P in a patient treated with NIL (Table 1)
Patients switched to 2G-TKIs for IM intolerance had better rates of response as compared to patients switched for IM resistance: complete cytogenetic response (CCyR) 90% vs 72% (p = 0.09), major molecular response (MMR) 77% vs 56% (p = 0.07), deep molecular response (DMR) 59% vs 34% (p = 0.009) We compared cytogenetic and molecular responses obtained with DAS or NIL in IM-intolerant and IM-resistant patients separately, and we found no differences between the two 2G-TKIs (Figure 1)

Summary

Introduction

The introduction and worldwide diffusion of imatinib (IM) and, subsequently, second-generation tyrosine kinase inhibitors (2G-TKIs) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients. Long-term follow-up of the IRIS study and the German CML-IV study reported estimated overall survival (OS) rates at 10 years with IM-based therapy around 82–83% [1, 2], close to that of the general population [3]. This excellent outcome is obtained despite that, in those two studies, 40 to 50% of patients interrupted IM therapy for unsatisfactory therapeutic efficacy or adverse events (AEs), outlining the efficacy of secondline treatment. The two molecules have a favorable safety profile [6] and specific spectrum of activity against BCR-ABL1 kinase domain mutants [7]

Methods

Results

Conclusion