Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients

Abstract

Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of "current CCyR-survival" (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ ABL1 transcript ratio of < 10% and had significantly superior overall survival (91.3% vs 72.1%, P ‫؍‬ .02), event-free survival (49.3% vs 13.0%, P < .001), and cCCyRS (67.2% vs 11.2%, P ‫؍‬ .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intentionto-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.

Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study

“…* CML-CP, Milojkovic et al 18 found that patients achieving BCR-ABL #10% at 3 months had significantly improved rates of PFS, OS, CCyR, MMR, and CMR. This analysis supports the value of early molecular and cytogenetic responses in predicting the outcome of patients treated with second-line dasatinib therapy after imatinib failure.…”

Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study

“…These results are consistent with other landmark analyses in patients treated with TKIs. [20][21][22][23][24][25] The clinical implications of these findings require prospective analyses before they can be used to influence treatment decisions.…”

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias

“…[1][2][3] In fact, the presence of BCR-ABL1 mutations and nonrandom secondary genetic abnormalities can only partially explain the lack of long-term response and/ or development of resistance to TKIs (including ponatinib) and other therapeutic options. 1,[4][5][6][7][8] Thus, the biological processes underlying emergence and maintenance of CML-blast crisis (BC) and Ph malignancies in some of which it was described as a poor prognostic factor. [22][23][24][25][26][27][28][29][30] Different inhibitors of XPO1-mediated export through the nuclear pore complex have been developed 31 ; among these, the selective inhibitors of nuclear export (SINE, Karyopharm Therapeutics Inc) are small molecules based on leptomycin B (LMB) that irreversibly bind to Cys528 in the cargo-binding groove of XPO1 to prevent XPO1-cargo interaction.…”