BCR-ABL1 mutation

A linear relationship was found between reported and assigned values for all levels of the reference standards when tested across 3 different BCR-ABL RT-qPCR assays, enabling the calculation of an assay-specific CF to allow harmonized reporting on the International Scale (%IS). The BCR-ABL p210 Panel was validated for accuracy, precision, robustness, and traceability, and can be used as a WHO traceable reference standard to create assay-specific CF to enable standardized reporting on the International Scale (%IS).

P3, N=173, Recruiting, Il-Yang Pharm. Co., Ltd. | Trial completion date: Apr 2025 --> Dec 2027 | Trial primary completion date: Jan 2025 --> Jun 2026

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

The RM was used to evaluate inter-laboratory reproducibility in eight different laboratories, demonstrating that participating laboratories could consistently produce copy concentrations of b3a2 and ABL1-ref, as well as the BCR-ABL1/ABL1 ratio (CV < 2.0%). This work suggests that the RM can be employed in establishing metrological traceability for detecting mutations in the BCR-ABL1 fusion gene, as well as in quality control for testing laboratories.

Ocular findings related to CML are rare, with the lowest incidence when compared to other leukemias, and are associated with worse outcomes. Posterior segment findings include intraretinal hemorrhages, Roth spots, and retinal infiltrates. This unique case describes an RRD in CML retinopathy with an aggressive course and poor anatomical result.

P1/2, N=68, Active, not recruiting, Takeda | Trial completion date: Aug 2027 --> Jan 2027 | Recruiting --> Active, not recruiting

Intriguingly, when the son developed MPAL, the mother did not develop donor-derived leukemia and remained in remission. Our cases provide valuable insights to guide future research on familial MPAL.

The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in APC are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver BCR-ABL1 fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.

Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (p < 0.05) and 8 patients with T315I mutation presented OS of 0%. T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.

Importantly, the results suggest the existence of tumour drug addiction, where cancer cells become dependent on the drug for (optimal) survival, which could be exploited through a treatment holiday. All simulation code is available at https://github.com/Sandalmoth/dual-adaptation.

Common nonhematologic adverse events included hepatotoxicity, nephrotoxicity, myalgia, arthralgia, rash, and edema, of which most were mild. Conclusion Olverembatinib-based therapies are generally well tolerated and efficacious for patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia.

Case 1 is a 56years old woman, with methotrexate(MTX)-treated rheumatoid arthritis...The diagnosis of aCML was made and low dose Hydroxyurea (HU) started...aCML is a rare disease whose diagnosis has become easier through NGS, which may also allow to detect actionable mutations. Immune driven tumorigenesis as well as AD treatments might play a role in the development of myeloproliferative neoplasms.

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.

P=N/A, N=440, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2028 --> Feb 2024 | Trial primary completion date: Jul 2028 --> Feb 2024

17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients...The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.

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.

P1/2, N=68, Recruiting, Takeda | Active, not recruiting --> Recruiting

To the best of our knowledge this is the first study to investigate ASXL1 mutation in -TKI-resistant CML patients in Tunisia. Despite the limits of our study, our finding highlights that this truncating ASXL1 mutation may be a potential biomarker for predicting therapeutic efficacy, and a treatment strategy for CML with ASXL1 mutation should be established. Moreover, future studies need to comprehensively identify the landscape and clinical relevance of genetic and epigenetic alterations in CML, which can be used to develop novel therapeutic strategies or to prognosticate treatment response.

P3, N=115, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

In patients who have inadequate responses, we analyze the patient's BCR-ABL1 mutational profile, which is beneficial if that patient harbors a specific tyrosine kinase inhibitor responsive mutation, such as T315I. Using these steps, we can provide a generalizable approach to choosing the appropriate second-line tyrosine inhibitor for chronic myeloid leukemia.

Bosutinib at the RP2D was well-tolerated and its preliminary efficacy in R/I and ND pediatric patients seems comparable to that recorded in adult patients treated with the same drug and in line with other second generation TKIs. Pediatric, Chronic myeloid leukemia, Clinical trial

In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone). The novel third-generation TKI Olverembatinib is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with molecular or hematological R/R disease, especially in pts with T315I mutation. In addition, bridging allo-HSCT after MRD clearance could be a better choice to improve PFS and OS. These results laid an essential foundation for subsequent prospective clinical trials.

BCR::ABL1 was not tested at diagnosis, and the patient was commenced on hydroxycarbamide...Coexistence of CALR mutation and BCR::ABL1 is rare and has not been not reported in the context of Ph+ B-ALL. Our institution now recommends screening for BCR::ABL1 by PCR and FISH in all cases of thrombocytosis even if a conventional MPN mutation is found.

Results for clinical trials in patients with chronic myeloid leukemia that have received 2 or more tyrosine kinase inhibitors (randomized against bosutinib) or who have a T315I mutation (single arm study) have shown high levels of activity and a favorable toxicity profile. The novelty of its mechanism of action and the exciting early data offers the potential for asciminib to address some of the remaining needs in the management of patients with chronic myeloid leukemia, including second line therapy after resistance to a frontline second generation tyrosine kinase inhibitors and improving in the success of treatment free remission. Multiple studies are ongoing in these areas and one can only hope that the desired randomized trial comparing to ponatinib will occur soon.

Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.

P3, N=115, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

Our study demonstrates that ddPCR is a highly sensitive and accurate mutation detection method and the presence of T315I mutations before treatment shows prognostic significance in the context of first- or second-generation TKIs.

Considering the patient's age and medical comorbidities, he was started on imatinib 400 mg once daily...He was then started on aspirin 81 mg and hydroxyurea 500 mg once daily, which was later increased to 1000 mg daily...Therefore, testing for JAK2 should be performed accordingly. Combining cytoreductive therapy with tyrosine kinase inhibitors (TKIs) is a therapeutic option when both mutations are present, and TKI alone is not sufficient to control peripheral blood cell counts.

P1, N=22, Recruiting, Institute of Hematology & Blood Diseases Hospital | Not yet recruiting --> Recruiting

P2, N=65, Completed, Gruppo Italiano Malattie EMatologiche dell'Adulto | Active, not recruiting --> Completed

P3, N=115, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2023 --> Jul 2024 | Trial primary completion date: Jun 2022 --> Jul 2023

P2, N=92, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

In AdP CML, TKIs do not show long-lasting results, and the outcome of HSCT is less optimal without pretransplant therapy. In these patients the induction of chP2 with TKIs, either alone (AP) or in combination with intensive chemotherapy (BC), followed by HSCT should be pursued.

Cytoreductive therapy was given to 14 TNT patients (Hydroxycarbamide, n=12; Pegasys, n=1,; Anagrelide, n=1) dictated by physician choice.In evaluable patients with TNT (n=69), NDM was found in only 9 patients (13.2%) and associated with older age (median age 69.3 yr)...We hence favour the term idiopathic thrombocytosis in selected for patients with TNT patients. Further studies are warranted to examine the role of cytoreduction and anti-platelet therapy in TNT in selected patient groups, e.g. previous thrombosis , cardiovascular risk factors, older age and extreme thrombocytosis.

P1/2, N=68, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

These developments include the increased availability of effective and safe generic imatinib at affordable prices, studies showing that doses of tyrosine kinase inhibitors (TKIs) lower than the approved dose are effective and less toxic, studies showing that dose-adjusted ponatinib therapy at a reduced dose is effective and substantially safer than approved doses, and the approval of asciminib as third-line therapy in 2021. The role of third-generation TKIs as second-line therapy following front-line resistance to second-generation TKIs needs to be evaluated. New and mature data with TKI therapy in chronic myeloid leukaemia are producing observations that encourage continuous discussion of the optimal treatment recommendations and frameworks in chronic myeloid leukaemia.

Although it is unclear whether this mutation would occur in T-ALL patients undergoing dasatinib treatment, our findings point to the need for evaluating multiple LCK inhibitors as a treatment option. In conclusion, we comprehensively characterized pharmacokinetic and pharmacodynamic profile of dasatinib and ponatinib in preclinical models of T-ALL, and our exposure-response modeling established human dosage levels for future trials of LCK inhibitor for this cancer.

Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution...Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib...Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts.