Bosulif (bosutinib)

In a murine wound infection with vancomycin-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion...Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.

Nevertheless, we identified promising drug candidates, such as tirofiban, pirenzepine, erlotinib, and bosutinib, which exhibit potential in reversing this resistance. Additionally, potential molecular mechanisms underlying adhesion-related resistance are proposed, along with viable strategies to overcome such resistance. These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

P1/2, N=9, Terminated, Fundacion Espanola para la Curacion de la Leucemia Mieloide Cronica | N=36 --> 9 | Recruiting --> Terminated; The study has been prematurely terminated due to the onset of 2 dose limiting toxicities in 2 patients.

P=N/A, N=600, Not yet recruiting, Pfizer

The results of this study demonstrated that AE signals differ among the five BCR-ABL1 TKIs. Furthermore, each BCR-ABL1 TKI displayed several new signals. These findings provide valuable information for clinicians aiming to reduce the risk of AEs during BCR-ABL1 TKI treatment.

We showed that ALL samples with fusions of any of the four tyrosine kinase genes were relatively sensitive to imatinib. In contrast, PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with ALL immunophenotype, 5' fusion partner, the presence or absence of the Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant for TKI sensitivity and is relevant for specific TKI selection.

P1/2, N=60, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2024 --> Jul 2028 | Trial primary completion date: Dec 2024 --> Jul 2028

Using patient-derived organoids (PDOs), we discover that UPP1high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

Following relapse, the patient was treated with imatinib and bosutinib, resulting in a deep molecular response and successfully discontinued treatment. Additional analysis including whole-exome sequencing and RNA sequencing provided some insights on the molecular mechanisms of the relapse: the identification of the fusion transcript KANSL1::ARL17A (KANSARL), a cancer predisposition fusion gene, could justify a condition of genomic instability which may be associated with the onset and/or probably the late relapse of his CML.

The well-established, long-term side-effect profile and the potential to make dose adjustments with bosutinib make it an appropriate treatment option for patients with CML. Bosutinib has demonstrated a positive impact on health-related quality of life and an important role in the long-term treatment of patients with CML.

Our study revealed the relationship between OXPHOS and tendency of cuproptosis in ESCC, and malignant cells with this characteristic exerted immunosuppressive signals and indicated poor prognosis. Furthermore, we constructed the constructed the regulatory network in high cuproptosis-OXPHOS ESCC and identified HMGA1 as a potential regulator molecule of cuproptosis mediated by elesclomol.

TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile.

In addition, GSE173839, GSE25066, GSE41998, and GSE194040 dataset analyses of the underlying CCC signature suggested that durvalumab with olaparib and paclitaxel, taxane-anthracycline chemotherapy, neoadjuvant cyclophosphamide/doxorubicin with ixabepilone or paclitaxel, and immunotherapeutic strategies might be suitable for COAD patients with higher CCC score. Eventually, the GDSC database analysis showed that lower CCC scores were likely to be more sensitive to 5-fluorouracil, bosutinib, gemcitabine, gefitinib, methotrexate, mitomycin C, and temozolomide, while patients with higher CCC score seemed to have a higher level of sensitivity to bortezomib and elesclomol. The novel CCC signature exhibited a good ability for prognosis prediction for COAD patients, and the CCC score was found to be highly correlated with molecular features, immune-related characteristics, and therapeutic responses, which would greatly promote clinical management and precision medicine for COAD.

On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.

P1, N=19, Active, not recruiting, Georgetown University | Trial completion date: Dec 2023 --> Nov 2025 | Trial primary completion date: Dec 2022 --> Nov 2023

P2, N=100, Recruiting, Baylor College of Medicine | Trial completion date: Nov 2023 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2025

P1/2, N=60, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

Each of the 5 ATP-competitive inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) has a well-defined spectrum of resistance mutations. Growing clinical experience will soon allow to also elucidate the full spectrum of mutations conferring resistance to asciminib (that appear not to be confined to the myristate binding pocket)...Novel technologies like next-generation sequencing and digital polymerase chain reaction have recently been explored for BCR::ABL1 KD mutation testing; they have both advantages and disadvantages that are discussed in this article. This review also provides suggestions for interpretation and clinical translation of mutation testing results, which may not always be straightforward, particularly in cases of low-level or unknown mutations.

In September 2023, based on clinical data from patients aged ≥ 1 to < 18 years, bosutinib was approved in the USA for the Query ID="Q2" Text="Kindly check and confirm the processed article note" treatment of pediatric patients aged ≥ 1 year with CP Ph+ CML that is ND or R/I to prior therapy. This article summarizes the milestones in the development of bosutinib leading to this first pediatric approval.

Background ASCEMBL trial has demonstrated superior efficacy of Asciminib (ASC) over Bosutinib in terms of molecular response, and event-free survival. These findings contribute valuable insights to the understanding of ASC and PON treatments in pts with specific disease characteristics and may have implications for personalized therapy decisions in the absence of clinical trials comparing these drugs. Our aim is to expand our PSM cohort.

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.

51% of patients (n=56) discontinued from imatinib, 31% from nilotinib (n=34), 16% from dasatinib (n=17), and 1% from bosutinib and ponatinib (1 patient each). We confirmed previous observations that the biological factors BCR: : ABL1 positivity at stop and longer HT were associated with molecular relapse although no difference was found for short HT. The impact of clinical factors on TFR, including duration of MR4 and MR4. 5 prior to stop, were also confirmed in our real-life series with a long follow-up, while total TKI duration was not prognostic.

Forty-one pts were enrolled from September 2020 to July 2023, with a median age of 61 years (23-85), 60% men, 33% Sokal low risk, 50% intermediate, 17% high; 78% with b3a2 BCR: : ABL1 transcript type; 85% using imatinib, 7. 5% dasatinib, 5% nilotinib, and 2. 5% bosutinib... Loss of MR4. 5 during the de-escalation phase or molecular status not in MR4. 5 before discontinuation was predictive of subsequent loss of MMR.

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.

Eighteen patients (in which no mutations were found) switched to third-line treatment after a median time of 11 months (0-45) (ponatinib, 8 pts; nilotinib, 1 pt; dasatinib, 3 pts; imatinib, 3 pts; bosutinib, 1 pts; asciminib, 2 pts). Our findings, collected from the prospective cohort of the CML Italian observational registry, show that CP-CML patients failing frontline 2G-TKI therapy, despite a complex management, may have still an acceptable prognosis and survival due to the availability of both multiple TKI options and SCT.

229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Also, with >2 years of follow-up, ASC demonstrated superior efficacy and better safety and tolerability compared with bosutinib in pts with CML-CP without the T315I mutation after ≥2 prior TKIs in the phase 3 ASCEMBL study (NCT03106779)...In addition to pts receiving ASC as their 2L TKI, a separate cohort of newly diagnosed pts will be included, and these pts may receive up to 4 weeks of prior treatment with imatinib or an approved second-generation TKI (Table)...Dose escalation of ASC in 2L and 1L is another treatment strategy and results from ASC2ESCALATE will add to the growing body of evidence for using ASC to treat pts with CML-CP. Recruitment for pts using ASC as their 2L TKI began November 2022, and as of July 10, 2023, 5 pts have been enrolled in this cohort; Up to 92 and 90 pts are estimated to enroll in the 2L and 1L cohorts, respectively, across 90 sites.

T315I mutation in ABL KD confers broad-spectrum resistance to all 1st- and 2nd-generation ABPIs including Imatinib (IMA), Dasatinib (DAS), Nilotinib (NIL) and Bosutinib (BOS). This result suggests synergistically enhanced inhibitory activity of dual blockade using AXI combined with ASC specifically for T315I mutant CML. This approach will be promising against CML cells carrying compound mutation with T315I mutation, which is highly resistant even to Ponatinib or Asciminib.

The following terms were searched: (Leukemia, Myelogenous, Chronic and BCR-ABL Positive), chronic myeloid leukemia, tyrosine kinase inhibitor, TKI, imatinib, dasatinib, nilotinib, bosutinib, and radotinib. In conclusion, our findings suggest that cutaneous adverse events occur more frequently with second-generation TKIs than with imatinib. Therefore, effective management of the cutaneous outcome is necessary to achieve high patient adherence to medication and successful treatment with TKIs.

Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.

The recent update of the ASCEMBL study demonstrated a superior efficacy with a good tolerability of Asc compared to bosutinib in chronic phase chronic myeloid leukemia (CP-CML) patients (pts) intolerant or refractory to ≥2 TKIs (Rea et al., 2022) Here we present the real-world clinical outcomes of 77 3rd + line Italian CP-CMLpts who received Asc through a Managed Access Program (MAP) approved by Novartis in 41 Italian institutions...Forty-three pts (55.8%) had a prior exposure to ponatinib and 38 of them (88.4%) had ponatinib as last TKI before switching to Asc...In this heavily pre-treated population of CML pts most of whom with a high comorbidity burden, Asc demonstrated fast and sustained responses. Collectively, these results continue to confirm that Asc has a promising role as standard of care in pts with CP-CML treated with ≥2 prior TKI.

The results of this study indicate that disulfidptosis is related to the prognosis and treatment of GC, while APOD represents a potential therapeutic target for GC.

P2, N=84, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2028 --> Jul 2028 | Trial primary completion date: Jan 2024 --> Jul 2024

Only one patient switched to another TKI to deepen the response before attempting a second pregnancy (imatinib to nilotinib)...Except for the patient described earlier, and a patient who had a suboptimal response to the 2nd line and switched to bosutinib 3rd line, patients recommenced the same TKI discontinued before pregnancy...The Italy-TFR protocol is still enrolling in the prospective cohort and updating. We plan to include more cases and present an exhaustive analysis.

Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

At sampling, 21/104 (20%) patients were treated with imatinib, 14/104 (13.5%) with nilotinib, 6/104 (5.5%) with dasatinib, 1/104 with bosutinib (1%), 27/104 (26%) with intermittent TKI therapy, and 24/104 (23%) were in treatment free remission (TFR). It opens to the identification of different sub-sets of patients presenting different vesicular BCR::ABL1 transcript levels. The different sub-sets could be related to the therapy response as well as the eligibility to TKI suspension, two of the main hot points in the present CML patients' management.

With >2 years of follow-up in the phase 3 ASCEMBL study, asciminib (ASC) has continued to demonstrate superior efficacy vs bosutinib (BOS) in pts with CML-CP after ≥2 prior TKIs, and analysis of cancer gene somatic mutations in this population has the potential to reveal additional insights into pts' response to study treatments or characteristics of the disease in later lines of therapy... Adults with CML-CP previously treated with ≥2 TKIs with intolerance of their last TKI or lack of efficacy per 2013 European LeukemiaNet recommendations and without BCR::ABL1 T315I or V299L mutations were randomized 2:1 to ASC 40 mg twice daily or BOS 500 mg once daily... ASXL1 mutations are most frequently detected at CML diagnosis and were enriched at BL in this study of pts with CML-CP previously treated with ≥2 TKIs, which is consistent with a role in TKI resistance. RUNX1 and IKZF1 mutations, which are associated with progression to accelerated or blast phase in CML, were very rare in this pt population, supporting their role in CML disease progression. The high frequency of co-occurrence of BCR::ABL1 mutations and blood cancer gene mutations in CML-CP is an important finding since cancer gene mutations could modify response to TKIs in individual pts.

Use of TKIs prior to asciminib included dasatinib (85.6%), imatinib (63.9%), bosutinib (61.9%), nilotinib (53.6%), and ponatinib (15.5%). This is the first real-world study describing treatment patterns and clinical outcomes among patients with Ph+ CML-CP treated with asciminib in the US. The findings of real-world treatment efficacy based on achieving BCR::ABL1 ≤0.1% were consistent with the ASCEMBL trial. Patients who initiated asciminib after 2 previous TKIs had higher persistence and treatment response rates than those initiated on asciminib after ≥3 previous TKIs.

Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.