Outcome of Salvage Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML) Who Failed Imatinib after Developing BCR-ABL Kinase Mutation.
Authors: Jabbour Elias , Kantarjian Hagop , Talpaz Moshe , Jones Dan , O’Brien Susan , Giles Francis , Garcia-Manero Guillermo , Ravandi Farhad , Faderl Stefan , Verstovsek Srdan , Rios Mary Beth , Cortes Jorge 
Published: April 2020

Abstract
Resistance to imatinib among pts with CML is most often associated with point mutations in the Bcr-Abl kinase domain. Novel kinase inhibitors have shown activity against both imatinib resistant BCR-ABL mutant and non-mutant kinases. Other investigational agents have been used to treat pts who develop resistance to imatinib. We assessed the outcome of different salvage therapies in 40 pts with CML (chronic phase [CP] n=21, accelerated phase [AP] n=16, blast phase [BP] n=3) harboring 20 different protein kinase mutations. The most common mutations were G250E (n=5, 13%), E355G/A (n=4, 10%), and F317L (n=4, 10%). Seventeen (42%) had P-loop mutations and 3 (8%) had T315I. Salvage therapy after imatinib failure included allogeneic stem cell transplantation (ASCT) in 9 pts (CP n=3, AP n=3, BP n=3); combination of tipifarnib (a farnesyl transferase inhibitor [FTI]) and imatinib in 10 pts; lonafarnib (an FTI) and imatinib combination in 9 pts (CP n=2, AP n=7), decitabine and imatinib in 3 pts (CP n=1, AP n=2); single agent decitabine or lonafarnib in 2 pts each (CP n=1, AP n=1); homoharingtonine (HHT) in 2 pts in CP; and high-dose imatinib in 3 pts (CP n=1, AP n=2). All pts undergoing ASCT achieved a molecular remission; 2 later relapsed after 7 months, one in BP (Q252H) and one in AP (T315I). Six of the 10 pts treated with tipifarnib/imatinib responded (4 partial cytogenetic response [CGPR] and 2 complete hematologic response [CHR]); 4/6 lost their response after a median of 5 months (range, 2–8 months) and two patients in CP have remained in CGPR (M244V) and CHR (G250E) after 8 and 3 months, respectively. Three pts in AP treated with lonafarnib/imatinib had a response lasting a median of 6 months (range, 4–8 months); responses were CGPR (Y253H), CHR (F359V), and partial hematologic response (PHR) (E292V). Two patients treated with HHT achieved, respectively, a complete cytogenetic response (CGCR) (D276G), and a CHR (G250E+Y253H); responses were lost after 7 months. High dose imatinib was effective in all patients treated: one patient in CP achieved a CGPR (L298V) that lasted for 11 months, one in AP achieved a transient CHR (M244V) for 3 months, and one in AP (V299L) achieved a minor cytogenetic response sustained for 21 months. None of the patients treated with lonafarnib monotherapy or decitabine based therapy responded. Of the 3 pts with T315I, one received tipifarnib/imatinib and achieved a CGPR for 3 months, followed by ASCT with a sustained molecular remission for 12+ months; the second had an ASCT and relapsed 7 months later; and the third received decitabine/imatinib with no response. We conclude that ASCT remains an important salvage option for pts who develop resistance to imatinib through Bcr-Abl mutations. Although responses were transient, the combination of imatinib and FTI therapies may overcome resistance in some pts. Early introduction of such therapies may result in better outcome.