Molecular Response According to Type of Preexisting BCR-ABL Mutations after Second Line Dasatinib Therapy in Chronic Phase CML Patients.

Abstract

Dasatinib (SPRYCEL®) has demonstrated significant efficacy in a high proportion of imatinib-resistant or -intolerant chronic phase CML patients (pts) concerning achievement of hematologic and cytogenetic responses. We sought to establish a relationship between type of preexisting BCR-ABL mutations associated with imatinib resistance and achievement of major molecular response (MMR, BCR-ABL ≤0.1% according to International Scale, IS) after 12 months of dasatinib therapy in pts with chronic phase CML. We have investigated 1,605 peripheral blood samples from 202 pts (n=62 imatinib-intolerant, n=140 imatinib-resistant; 52% male, median age 60 yrs, range 21–78) who had been enrolled in an international phase II study (START-C study, CA180–013) investigating the activity of 70mg dasatinib BID after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. During follow up, pts were monitored in 3-monthly intervals by RQ-PCR for BCR-ABL mRNA transcripts and by mutation analysis to determine the quantitative course of the preexisting mutation or the emergence of new mutations. Prior to dasatinib therapy, 34 different BCR-ABL mutations involving 29 amino acids were detected in 85/202 pts (42%) with a striking predominance in imatinib-resistant (77/140 pts, 55%) over imatinib-intolerant pts (8/62 pts, 13%). 75 pts showed one, 8 pts two and 2 pts three mutations. RQ-PCR data after 12 months of therapy was available from 154 pts (76%), samples from 48 pts (24%) were not available for monitoring after one year due to progressive disease. MMR was achieved in 28 imatinib-intolerant (45%) and 19 imatinib-resistant pts (14%, p<0.0001). The overall rate of imatinib-resistant pts with mutations was comparable in pts achieving MMR (group 1) vs pts not achieving MMR within 12 months (group 2; 53% vs 57%, p=0.80). Several mutations in imatinib-resistant pts are associated with differential response (group 1 vs group 2 response) and are presented with their IC50 values to dasatinib: H396R (n=0 vs n=6; IC50 0.6–1.3nM), M351T (n=1 vs n=7; 1.1nM), G250E/V (n=1 vs n=8; 1.8nM), Y253H (n=0 vs n=5; 1.3–10nM), L387M (n=0 vs n=2; 2nM), F359I/V (n=0 vs n=4; 2.2nM), E255K/V (n=1 vs n=4; 5.6–13nM), F317L (n=0 vs n=3; 7.4–18nM), T315I (n=0 vs n=3; >1,000nM). Of 85 pts without sufficient molecular response to dasatinib (BCR-ABL IS >5%) after 12 months (median, range 9–15) mutation analysis revealed the emergence of new mutations in 17 formerly imatinib-resistant pts (T315I, n=2; T315A, n=1; F317L, n=6; V299L, n=2; M351T, n=2; L248V, n=1; G250E, n=1; K271R, n=1; Y320C, n=1). We conclude that dasatinib is capable of inducing high rates of major molecular response after one year treatment particularly in imatinib-intolerant pts. Response dynamics depend on the individual type of mutation which may be a basis for individual dose adjustment according to the mutation pattern.

Tailoring Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

“…Among 202 patients with CML-CP enrolled in the START-C trial, MMRs were achieved after 12 months of treatment in 14% of imatinib-resistant patients and in 45% of imatinib-intolerant patients. 108 As discussed above, the MMR rate in imatinib-intolerant patients rose to almost 80% following 2 years of follow-up. 92 Moreover, within the imatinib-resistant population, response dynamics differ according to the various underlying mechanisms of resistance.…”

“…Only 10% of evaluable patients with CML-CP and P-loop mutations achieved a CCyR at 9 months compared with 37% patients with non-P-loop mutations and 47% with no mutation. 108 This may explain in part the 18-month time-to-progression rate of 64%, which is somewhat inferior to comparable data for dasatinib CP studies. 92,105 Nilotinib was well tolerated in clinical trials.…”

“…92 Moreover, within the imatinib-resistant population, response dynamics differ according to the various underlying mechanisms of resistance. 108 Another area under investigation is the most appropriate treatment if second-line TKI treatment fails. It has recently been shown that both dasatinib and nilotinib have activity in patients who have failed treatment with the other drug, ie, dasatinib following nilotinib failure and nilotinib following dasatinib failure.…”

P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia

“…With regard to individual P-loop mutations, CCyR rates were similar to or above those of patients without mutated BCR-ABL: G250E, 37% (19 of 51); Y253F/H, 52% (12 of 23); and E255K/V, 33% (8 of 24) (Table 2 ). Patients with CP CML enrolled in the phase 2 START-C trial were also evaluated by baseline mutational status [ 37 ]. The results from this trial were similar to those above.…”

“…However, only F317V and T315I were isolated at intermediate drug concentrations, and T315I was the only mutation to be detected at maximal achievable plasma concentrations [ 38 ]. In clinical studies, T315A/I, F317I/L and V299L are the most frequent mutations associated with dasatinib resistance [ 37 , 39 - 41 ]. In the phase 2 START-C trial of patients with CP disease, new mutations were detected in 11% of patients (22 of 201), including 6% (13 of 201) with T315A/I, F317L or V299L (4 of 201, 7 of 201 and 2 of 201 patients, respectively) [ 38 ].…”