BCR-ABL1 M244V

The present study demonstrated that a half of baseline conc ABPIs in combination with ASC is as effective as other ABPIs not just in WT but also in other ABL1 KDM CML cell lines. Different CML cell lines harboring different ABL KDM has different treatment spectrum on optimal ABPI drug as well as optimal drug conc. This result will be useful to design future clinical trial of dual blockade of ASC with other ABPIs considering the ABL KDM profiles.

ASCEMBL trial showed superior efficacy of ASC to Bosutinib (BOS) with a higher molecular response rate, and a lower rate of discontinuation due to lack of efficacy (24.2% vs 35.5% at week 96)...A phase 1 study attempted to determine appropriate dose of ASC in combination with fixed dose of ABPIs including Imatinib (IMA), Dasatinib (DAS) and Nilotinib (NIL)...Each cell lines does have its inherent resistance level to double blockades, which needs to be further explored. A phase 1 study with reduced dose of ABPI in combination with fixed dose ASC is strongly warranted to define an optimal dose for combination.

In conclusion, there is no significant difference in BCR-ABL1 KD mutations between Han and ethnic minority patients. NGS has a higher mutation detection rate than SS, and can detect compound variants and genes with lower mutation frequency that are not detected by SS.

TKIs received in 3L were dasatinib (32%), nilotinib (19%), imatinib (18%), ponatinib (17%), and bosutinib (14%). The mean number of AEs per patient was 2.7; infections (18%) and asthenia (13%) were the more commonly documented AEs. Conclusion CP-CML patients continue to experience a substantial disease burden and poor prognosis after 3L treatment with available TKIs, underscoring the need for novel therapies that are well tolerated and can achieve durable responses.

Y253F mutation was not seen in the present study sample. In the present cohort of 83 patients, 29 (35%) cases were positive for single mutation, 12 (14%) had two mutations and 3 (4%) had three mutations.

For new diagnosis patients, the TKIs imatinib, dasatinib, nilotinib, bosutinib, and ponatinib ranked in the top 8 drugs...In 2 patients harboring NRAS mutations, IC50 for trametinib was less than 0.1 µM as compared to patients without NRAS mutations, where the IC50s were higher...Conclusion . In vitro drug sensitivity testing provides data for potential agents for patients with resistance or intolerance to FDA approved TKIs, or those that have entered accelerated phase or blast phase.

This study shows the incidence and pattern of mutations in one of the largest sets of Indian CML patients. It has been demonstrated that T315I is the most common mutation observed in the Indian population. However the access to the only eligible TKI- Ponatinib by the economically challenged must be addressed .

P, N=200, Recruiting, Wuhan Union Hospital, China

In patient #6, G645delinsGWfs was found at the diagnosis and on the 3rd line nilotinib treatment...In patient #3, the CSF3R mutation A593V was found at diagnosis and confirmed 14 months after the imatinib initiation...Despite the clonal hematopoiesis with somatic mutations is considered as age-related phenomenon, in AYA CML patients, it may represent a critical problem in achieving sustained molecular response on solo TKI therapy, or even worse, it may result in higher risk of therapy failure and disease progression. Supported by MZCR 00023736

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting...NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation.