ABL1 F317L

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.

This retrospective study had suggested promising effects of flumatinib, which showed induced high rates of CCyR and MMR or DMR in patients resistant or intolerant to imatinib. The incidence of AEs during flumatinib treatment was tolerable.

The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth)...Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation...Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

Dasatinib in combination with a two-week vincristine and glucocorticoids regimen were administered, followed by sequential infusions of CD19 and CD22 CAR-T cells. Conclusions Dasatinib in combination with CAR-T cell therapy has enabled chemotherapy-free treatment in newly diagnosed Ph-positive ALL. This treatment is characterized by high complete molecular response, high long-term survival, low toxicity and short treatment cycles.

In summary, our newly developed assay can be used for kinase domain mutation analysis from clinical samples and with very good sensitivity of 2%, which is in a well-acceptable range of 1% to 3% and is available on commonly used the Ion Torrent platform. This ability of the assay in detecting low-level variants and even compound variants makes it very important for selection of appropriate TKIs for CML patients.

One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.

P1, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

Ba/F3 cells expressing a range of the most prevalent on-target BCR::ABL1 resistance mutants indicated that with the exception of certain P-loop mutations and F317L, ELVN-001 maintained potency, including for the myristoyl pocket mutations A344P and P465S and was active against the M244V mutation, an ATP pocket mutation known to confer resistance to asciminib. This FIH study will evaluate dosing, safety, tolerability, PK profile, and preliminary efficacy of ELVN-001 in CP-CML with and without T315I mutation. Study sponsor: Enliven Therapeutics. NCT05304377 BCR::ABL, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Phase I

Most pts had received prior imatinib (n=80; 75%) and/or dasatinib (n=79; 74%)...Treatments that resulted in the clearance of T315Im were ponatinib (n=10; 27%), ASCT (n=10; 27%), omacetaxine (n=5; 14%), chemotherapy + TKI (n=4; 11%), asciminib (n=3; 8%), and other investigational agents (n=5; 14%)... Pts with CML who remain in CP at the time of T315Im may have an indolent disease course with a long-term OS of 70%. In contrast, those who develop T315Im in AP/BP tend to have poor outcomes. Newer-generation TKIs and novel agents are needed in pts with advanced phase T315m CML.

Highly pre-treated CML pts with T315I mutation are able to achieve a response with asciminib 200 mg BID,especially in ponatinib-naive group. In our pts a safety profile was good with no evidence of severe toxicity. Asciminib shows effectiveness in highly resistant pts with T315I mutation with/without other genetic events (combined mutations, ACAs), though some of them still a challenge for clinicians.

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.

The probability of treatment discontinuation did not significantly differ for ponatinib in second, third or subsequent line of therapy (p=0.58). Conclusion This real-life investigation shows that ponatinib dose reductions were mainly performed in the absence of reported toxicity rather than owing to the occurrence of adverse reactions.

P1, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2021 --> Jun 2023 | Trial primary completion date: Jun 2021 --> Jun 2023

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

Vodobatinib was evaluated over 9 escalating doses. Comparable and promising efficacy was noted in both PT (50% CCyR) and PN (67% CCyR) groups, meriting further study of vodobatinib as a potential new agent for treatment of previously treated CP-CML.

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

P1, N=12, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2020 --> Jun 2021 | Trial primary completion date: Jun 2020 --> Jun 2021