Bosutinib vs imatinib for newly diagnosed chronic myeloid leukemia in the BFORE trial: 24-month follow-up.

Cortés, Jorge E.; Mauro, Michael J.; Deininger, Michael W.; Chuah, Charles; Kim, Dong-Wook; Kota, Vamsi; Lipton, Jeffrey H.; Rousselot, Philippe; Milojković, Dragana; Coutre, Phillipp D. Le; Gutiérrez, Valentín García; Crescenzo, Rocco J.; Leip, Eric; An, Fiona; Bouxin, Nathalie; Hochhaus, Andreas; Brümmendorf, Tim H.; Gambacorti‐Passerini, Carlo

doi:10.1200/jco.2018.36.15_suppl.7002

Cited by 14 publications

(15 citation statements)

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“…Overall, AEs with bosutinib were manageable. The reported AEs were consistent with the known safety profile of bosutinib and no new safety issues were identified [6,[17][18][19][20][23][24][25][26][27]. Patients intolerant to previous therapies had a slightly higher incidence of grade 3/4 TEAEs and required more frequent dose adjustments to manage AEs than TKI-resistant patients.…”

Section: Discussionsupporting

confidence: 65%

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

et al. 2020

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Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs. Additional BYOND Study Investigators are listed below Acknowledgements.

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Section: Discussionsupporting

confidence: 65%

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

et al. 2020

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“…When tested in vivo, dasatinib reduced synovial inflammation, cartilage destruction and bone erosion, while bosutinib was ineffective in controlling any of the in vivo or histopathological signs of arthritis. This difference of the two TKIs could be attributed to their differential mode of action [ 47 – 49 ]. Among their differences, it is worth mentioning that dasatinib, has the potential to target KIT and platelet-derived growth factor receptor (PDGFR) [ 50 ], as well as collagen receptor tyrosine kinases discoidin domain receptors 1 and 2 (DDR1, 2) [ 51 ], PI3K and ERK, potential targets for the treatment of RA [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Ntari¹,

Nikolaou

Kranidioti³

et al. 2021

J Transl Med

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Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

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“…Approval of bosutinib for newly diagnosed patients with CP CML was based on data from the ongoing, randomized, phase 3 BFORE trial, which demonstrated a significantly higher major MR (MMR) rate at 12 months in the modified intent-to-treat (ITT) population (primary endpoint) with bosutinib (n = 246) versus imatinib (n = 241) [2]. After longer follow-up (≥ 24 months), bosutinib continued to demonstrate improved efficacy compared with imatinib, as evidenced by a higher cumulative MMR rate (68.7% vs. 59.3%; odds ratio, 1.51; 95% confidence interval, 1.06-2.16) and MR 4 rate (39.9% vs. 31.3%; odds ratio, 1.45; 95% confidence interval, 1.02-2.07) in the ITT population (bosutinib, n = 268 and imatinib, n = 268) at any time on treatment (Pfizer Inc, data on file) [13]. Treatment-emergent adverse events after ≥ 24 months' follow-up were consistent with the known safety profiles of bosutinib [14] and imatinib [15]; diarrhea and transaminase increases were more frequent with bosutinib, and musculoskeletal events were more common with imatinib (Pfizer Inc., data on file).…”

Section: Introductionmentioning

confidence: 99%

Relationship between molecular response and quality of life with bosutinib or imatinib for chronic myeloid leukemia

et al. 2020

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Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR5, emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.

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Bosutinib vs imatinib for newly diagnosed chronic myeloid leukemia in the BFORE trial: 24-month follow-up.

Cited by 14 publications

References 0 publications

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Relationship between molecular response and quality of life with bosutinib or imatinib for chronic myeloid leukemia

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