Abstract

The BCR-ABL TKI, dasatinib (D) and nilotinib (N), are effective in Philadelphia chromosome-positive (Ph+) leukemias, including all stages of imatinib-resistant CML and Ph+ ALL. For both dasatinib and nilotinib, the reported rates of MCyR are higher than the rates of CHR; that is, some pts achieve MCyR but may have cytopenias that make their hematologic response less than a CHR; this has been attributed to myelosuppression induced by TKI. At present it is not known whether pts with MCyR who do not have CHR have a similar outcome as those with a CHR. We studied 135 pts with accelerated (AP; n=84) or blast phase (BP; n=47) CML or Ph+ ALL (n=4) treated with D (59) or N (76) for imatinib resistance, to see whether the presence of cytopenias at the time of best response affected the prognosis. The median age was 55 yrs (range, 15 to 98) and 62 were female. 56 (41%) had bcr/abl mutations at the start of therapy. Overall 36 pts (27%) achieved MCyR. All the 36 pts who achieved a MCyR after treatment with N or D had received imatinib for an average time of 34 mos (range 4–78) and 24/36 pts had obtained a MCyR under imatinib. They started the new TKI 66 mos after first diagnosis (12–336). 2-yr survival rates for pts that achieved MCyR was 72% compared to 35% for those without MCyR (p<0.001). There was a trend for an inferior survival for those not having a concomitant CHR at the time of MCyR compared to those with CHR (2-yr survival 58% vs 82%; p=0.11). The rates of CHR and MCyR were 68% and 29%, respectively in AP; 32% and 21% in BP, and 50% and 50% in Ph+ ALL. Among pts in AP, 17/24 (70%) who achieved a MCyR, had a CHR at the time of best cytogenetic response; 6 of these 17 (35%) pts eventually failed (lost response or transformed), compared to 3/7 (43%) of those with no CHR at the time of MCyR (p=0.28). The results are similar when analyzing separately pts treated with N or D. 2-yr survival was 88% and 66% for those with and without concomitant CHR (p=0.29). Among the 10 pts in BP that achieved a MCyR, 5 had a CHR at the time of best cytogenetic response. Three (60%) of these pts eventually failed (lost response), compared to 4 failures among the 5 pts with no CHR at the time of MCyR (p=1.0). Survival rates at 2 yrs were 60% and 40% for those with and without concomitant CHR (p=0.29). Among the 2 patients with ALL that achieved MCyR, one had comcomitant CHR (treated with N) and the other did not have CHR (D); both of them failed. Of the 18 pts who failed after having achieved an MCyR, 7 had a mutation before starting treatment with a 2nd TKI (A433T, G250E, E355G, E459K, M244V, M315T, F317L), and 6 developed a new mutation after treatment (F317L, F311I, Y253H, G476C, E255K, H359V). Five of them occurred in pts with a concomitant CHR and 1 without a CHR. These results suggest that achievement of MCyR with residual cytopenias (ie, without a concomitant CHR) may not have the same favorable outcome as that of MCyR with concomitant CHR. Whether this is related to pt- or disease-related characteristics remains to be determined.

Author notes

Disclosure:Research Funding: HK and JC have research support from Novartis and BMS.