ABL1 E255K

Highly polymorphic BCR-ABL kinase domains have been reported to harbor more than a hundred mutations, and among these, 40-60% have been identified as influencers of imatinib mesylate (IM) resistance...A haplotype frequency distribution pattern analysis of ABL1 loci further identified the CGC haplotype as an independent predictor for IM resistance. As such the study highlights the importance of patient characteristics, genotype distribution, and haplotype frequency distribution in predicting the response to IM treatment and clinical outcomes of CML patients.

Its efficacy and safety profile in patients with chronic-phase chronic myeloid leukaemia (CML) have been shown in the Phase 3 ASCEMBL study, comparing asciminib 40 mg twice daily versus bosutinib 500 mg once daily...All had received prior chemotherapy in combination with a TKI (imatinib, N=3; dasatinib, N=5; ponatinib, N=5), with 3 patients having undergone allogeneic haematopoietic stem cell transplantation (allo-HSCT)...ConclusionAsciminib demonstrated promising clinical efficacy with satisfactory tolerance in this cohort of Ph+ leukaemias failing multiple lines of therapy. Further investigation of its therapeutic role in Ph+ ALL is warranted.

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.

As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected...At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT...In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

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.

ABL1 is subject to auto-inhibition mediated by myristoylation-triggered conformational change, which can be exploited to overcome resistance, as validated by allosteric inhibitors such as GNF2, GNF5 and asciminib. Furthermore, TGRX-678 and ponatinib synergize to overcome the clinically challenging resistance conferred by T315M or T315I-inclusive compound mutations. This data warrant further clinical investigation of TGRX-678 for the treatment of resistant or refractory CML patients.

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

CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

The study comprised samples from patients enrolled in the phase II GIMEMA LAL2116 chemotherapy-free protocol for newly diagnosed adult Ph+ ALL and based on the administration of the second generation TKI dasatinib followed by the bispecific monoclonal antibody blinatumomab 2 . The ddPCR proved as reliable and accurate as SS to detect the T315I BCR::ABL1 KD mutation. Furthermore, the ddPCR proved to be more sensitive for predict molecular relapse before the increase in MRD where, in some cases, the SS failed to detect the T315I mutation. Further efforts are ongoing to expandthis screening also to other ABL1 mutations, considering the always more frequent use of ponatinib in the first-line setting.

A technology of DNA-based NGS alternative to standard RNA-based approaches has shown promising results inKD ABL1 mutations detection, with results highly matching to SS or RNA-based NGS detection. The method is reproducible and can be easily implemented in the laboratory routines. The advantages of the technology are evident in the conditions of limited access to RNA-based NGS or other restrictions (costs, long distance/ time transportation, DNA based laboratory sample collections for retrospective analysis).

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.

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.

It has been demonstrated better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL...Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly...Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after remission induction course...Conclusion The combination of the second-generation TKI flumatinib and chemotherapy is quite effective and safe in Chinese adult pts with newly diagnosed Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated.

Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The triplet combination of DAC, VEN and ponatinib was well-tolerated in pts with advanced Ph+ myeloid leukemias. In this poor-risk population, a marrow remission rate of 75% was achieved, although durations of remission were modest in the absence of consolidative SCT. This study continues to accrue pts.

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.

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.

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

Multidrug-resistant mutations within the BCR-ABL1 kinase domain are an emerging clinical problem for patients receiving sequential TKIs therapy. Acquisition of E255K/V-inclusive mutations is usually associated with ponatinib resistance, thus it is necessary to screen out new real pan-inhibitor compounds for all BCR/ABL mutations and figure out the potential efficacy of asciminib-based drug combinations in the future.

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 .

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.

Detection of kinase domain mutations is a reliable method for choosing the best treatment strategy based on patients' conditions, avoiding ineffective treatments, and running high-cost protocols in patients with acquired resistance to TKIs.

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