The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up

Abstract

Responses can be achieved with dasatinib or nilotinib after failure of 2 prior tyrosine kinase inhibitors (TKIs). We report on 48 chronic myeloid leukemia patients sequentially treated with 3 TKIs: 34 with dasatinib after imatinib/nilotinib failure and 14 with nilotinib after imatinib/dasatinib failure. Before the third TKI, 25 patients were in chronic phase (CP), 10 in accelerated phase (AP), and 13 in blast phase (BP). Best response to third TKI in CP was 5 major molecular responses (MMR), 3 complete cytogenetic (CCyR), 2 partial cytogenetic (PCyR), 3 minor cytogenetic (mCyR), 6 complete hematologic responses (CHR), and 6 with no response (NR). In AP, 1 patient achieved MMR, 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR. In BP, 1 achieved MMR, 2 CCyR, 1 PCyR, 1 mCyR, 2 returned to CP, and 6 NR. Median CCyR duration was 16.3 months; 3 CP patients achieving CCyR had a response more than 12 months. Median failure-free survival was 20 months for patients in CP, 5 months in AP, and 3 months in BP. Use of second-generation TKI after failure to 2 TKIs may induce responses, but these are usually not durable except in some CP patients. New treatment options are needed.

Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy

“…Failure to second line was defined as previously described by others. 7 Patients harboring a T315I mutation in the BCR-ABL kinase domain (KD) were not included in this study. All patients consented to the use of their data.…”

“…Currently patients who fail to respond to second-line dasatinib or nilotinib may either undergo allogeneic stem cell transplantation or receive third-line therapy with a different tyrosine kinase inhibitor (TKI). It has been shown that the efficacy of third line dasatinib or nilotinib is limited, 7 so it is of paramount importance to identify those patients most likely to benefit from a third-line TKI. In this study we present our experience managing with a third TKI patients still in CP who have failed both imatinib and second-line dasatinib or nilotinib.…”

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

“…Despite the significant clinical activity demonstrated in clinical trials, a number of patients do not show durable response (Garg et al, 2009). One reason for the lack of durable response could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKIs (Branford et al, 2009;Garg et al, 2009).…”

“…Despite the significant clinical activity demonstrated in clinical trials, a number of patients do not show durable response (Garg et al, 2009). One reason for the lack of durable response could be explained by the emergence of new kinase domain mutations as patients are exposed to sequential TKIs (Branford et al, 2009;Garg et al, 2009). The challenge for development of an effective Ph-positive leukemia therapy is therefore to develop an alternative treatment strategy that does not rely solely on kinase domain inhibition but rather results in degradation of the offending BCR-ABL protein regardless of its mutation status.…”

“…F359V and the P-loop mutants Y253H and E255K/V are associated with relapse to nilotinib, and F317A/L and V299L are found in dasatinib-resistant patients (Branford et al, 2009). Imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of ABL TKIs (Garg et al, 2009). The challenge for development of an effective Phpositive leukemia therapy is therefore to develop an alternative treatment strategy that does not rely solely on kinase domain inhibition but rather results in degradation of the offending BCR-ABL protein regardless of its mutation status.…”