83 results on '"Eric Leip"'
Search Results
2. S196: ELRANATAMAB, A B-CELL MATURATION ANTIGEN (BCMA)-CD3 BISPECIFIC ANTIBODY, FOR PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: EXTENDED FOLLOW UP AND BIWEEKLY ADMINISTRATION FROM MAGNETISMM-3
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Mohamad Mohty, Michael H. Tomasson, Bertrand Arnulf, Nizar J Bahlis, Paula Rodríguez-Otero, Joaquín Martinez-Lopez, Cyrille Touzeau, Hang Quach, Julien Depaus, Hisayuki Yokoyama, Salomon Manier, Noopur Raje, Marc S. Raab, Emma Searle, Eric Leip, Sharon T. Sullivan, Akos Czibere, Andrea Viqueira, and Alexander Lesokhin
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. P880: EFFICACY AND SAFETY OF ELRANATAMAB BY AGE AND FRAILTY IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): A SUBGROUP ANALYSIS FROM MAGNETISMM-3
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Xavier Leleu, Noopur Raje, Alexander Lesokhin, Mohamad Mohty, Ajay Nooka, Eric Leip, Sharon T. Sullivan, Andrea Viqueira, and Salomon Manier
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. P907: EFFICACY AND SAFETY OF ELRANATAMAB IN HIGH-RISK PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: A SUBGROUP ANALYSIS FROM MAGNETISMM-3
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Cyrille Touzeau, Nizar J Bahlis, Christopher Maisel, Lionel Karlin, Asya Nina Varshavsky-Yanovsky, Eric Leip, Umberto Conte, Andrea Viqueira, and Sarah M. Larson
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. P870: EFFICACY AND SAFETY OF ELRANATAMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA AND PRIOR B-CELL MATURATION ANTIGEN (BCMA)-DIRECTED THERAPIES: A POOLED ANALYSIS FROM MAGNETISMM STUDIES
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Salomon Manier, Alexander Lesokhin, Mohamad Mohty, Ruben Niesvizky, Christopher Maisel, Bertrand Arnulf, Sarah M. Larson, Asya Nina Varshavsky-Yanovsky, Xavier Leleu, Lionel Karlin, David H. Vesole, Nizar J Bahlis, Carlos Fernandez de Larrea, Noopur Raje, Eric Leip, Sharon T. Sullivan, Mohamed Elmeliegy, Andrea Viqueira, and Ajay Nooka
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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6. P930: ELRANATAMAB MONOTHERAPY OR IN COMBINATION WITH DARATUMUMAB VS DARATUMUMAB + POMALIDOMIDE + DEXAMETHASONE FOR PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: PHASE 3 MAGNETISMM-5 STUDY, PART 2
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Xavier Leleu, Shinsuke Iida, C. Ola Landgren, Alexander Lesokhin, Eric Leip, Arthur Kudla, Gregory Finn, and Lugui Qiu
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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7. Cross-intolerance with bosutinib after prior tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia: long-term analysis of a phase I/II study
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Jorge E. Cortes, Jeff H. Lipton, Vamsi Kota, Fausto Castagnetti, Sarit Assouline, Tim H. Brümmendorf, Eric Leip, Andrea Viqueira, and Carlo Gambacorti-Passerini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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8. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study
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Carlo Gambacorti-Passerini, Jorge E. Cortes, Jeff H. Lipton, Hagop M. Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Rocco Crescenzo, Nathalie Bardy-Bouxin, Mark Shapiro, Kay Noonan, Eric Leip, Liza DeAnnuntis, Tim H. Brümmendorf, and H. Jean Khoury
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6–96.3) and 25.6 (0.2–96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3–5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
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- 2018
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9. Efficacy and Safety of Elranatamab in Patients with Relapsed/Refractory Multiple Myeloma Naïve to B-Cell Maturation Antigen (BCMA)-Directed Therapies: Results from Cohort a of the Magnetismm-3 Study
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Nizar Jacques Bahlis, Michael H. Tomasson, Mohamad Mohty, Ruben Niesvizky, Ajay K. Nooka, Salomon Manier, Christopher Maisel, Yogesh Jethava, Joaquin Martinez-Lopez, H Miles Prince, Bertrand Arnulf, Paula Rodriguez Otero, Guenther Koehne, Cyrille Touzeau, Noopur Raje, Shinsuke Iida, Marc-Steffen Raab, Eric Leip, Sharon Sullivan, Umberto Conte, Andrea Viqueira, and Alexander M Lesokhin
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Efficacy and Safety of Bosutinib Vs Imatinib By Charlson Comorbidity Index in Newly Diagnosed Patients with Chronic Myeloid Leukemia
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Michael W. Deininger, Tim H Brummendorf, Jeffrey H. Lipton, Dragana Milojkovic, Leif Stenke, Eric Leip, Simon Purcell, Andrea Viqueira, and Jorge E. Cortes
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. Supplementary Figure 1 from Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors
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Wells A. Messersmith, Charles Zacharchuk, Kathleen Turnbull, Eric Leip, Poe-Hirr Hsyu, Nathalie Bardy-Bouxin, Shefali Agarwal, Richat Abbas, Gregory M. Springett, Elena G. Chiorean, Philip J. Gold, Mitesh J. Borad, Barbara J. Gitlitz, Mansoor N. Saleh, Smitha S. Krishnamurthi, and Adil I. Daud
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PDF file - 89K
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- 2023
12. An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia
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Carla Mamolo, Eric Leip, Joseph C. Cappelleri, B. Muresan, Andrea Viqueira, and Bart Heeg
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Oncology ,medicine.medical_specialty ,First line ,Dasatinib ,Antineoplastic Agents ,Newly diagnosed ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Nitriles ,medicine ,Humans ,030212 general & internal medicine ,Protein Kinase Inhibitors ,Aniline Compounds ,business.industry ,Myeloid leukemia ,General Medicine ,Chronic phase chronic myeloid leukemia ,Indirect comparison ,Pyrimidines ,Treatment Outcome ,Nilotinib ,Quinolines ,business ,Bosutinib ,medicine.drug - Abstract
Bosutinib, nilotinib and dasatinib are approved for the treatment of patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). In the absence of head-to-head comparisons between second-generation tyrosine kinase inhibitors (TKIs), the objective of this study was to indirectly compare the efficacy of bosutinib with nilotinib and dasatinib in first-line (1L) CP-CML.Cross-trial heterogeneity in terms of patient baseline characteristics and imatinib dose escalation are difficult to adjust for in network meta-analyses and anchored matching-adjusted indirect treatment comparisons (MAICs). Therefore, an unanchored MAIC was performed using patient level data from bosutinib (BFORE trial) and published aggregated data from nilotinib (ENESTnd) and dasatinib (DASISION) trials. After matching, cytogenetic and molecular responses, and disease progression, after a minimum follow-up of 24 months were compared between nilotinib versus bosutinb and dasatinib versus bosutinib.The comparison of nilotinib versus bosutinib resulted in no statistically significant differences for MMR at and by 24 months, MR4 by 24 months, MR4.5 at and by 24 months, CCyR by 24 months, and disease progression, however, a decreased odds of MR4 at 24 months in favor of bosutinib versus nilotinib was observed. The comparison of dasatinib versus bosutinib by 24 months resulted in no statistically significant differences for MMR, disease progression, and CCyR, however a decreased odds of MR4.5 in favor of bosutinib versus dasatinib was observed.Overall, in these analyses bosutinib demonstrates equivalent efficacy to nilotinib and dasatinib in the treatment of patients with newly diagnosed CP-CML.
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- 2021
13. Elranatamab in Combination with Daratumumab for Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 3 Magnetismm-5 Study Safety Lead-in Cohort
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Sebastian Grosicki, Ulf-Henrik Mellqvist, Łukasz Pruchniewski, Jacob Crafoord, Suzanne Trudel, Chang-Ki Min, Darrell White, Adrian Alegre, Markus Hansson, Takashi Ikeda, Kazutaka Sunami, Eric Leip, Arthur Kudla, Gregory Finn, and Youngil Koh
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
14. Glasdegib plus intensive/nonintensive chemotherapy in untreated acute myeloid leukemia: BRIGHT AML 1019 Phase III trials
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Geoffrey Chan, Hervé Dombret, Barbara Sleight, Xiaoxi Zhang, Mikkael A. Sekeres, Timothy J Bell, Eric Leip, Christine DiRienzo, Naveed Shaik, Akil Merchant, Tetsuzo Tauchi, and Jorge E. Cortes
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Daunorubicin ,medicine.medical_treatment ,Azacitidine ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Clinical Protocols ,Pharmacokinetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Chemotherapy ,business.industry ,Phenylurea Compounds ,Myeloid leukemia ,General Medicine ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Research Design ,030220 oncology & carcinogenesis ,Cytarabine ,Benzimidazoles ,Female ,business ,medicine.drug - Abstract
Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179
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- 2019
15. MagnetisMM-5: An open-label, multicenter, randomized phase 3 study of elranatamab as monotherapy and in combination with daratumumab in patients with relapsed/refractory multiple myeloma
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Sebastian Grosicki, Jacob Crafoord, Youngil Koh, Darrel White, Ulf-Henrik Mellqvist, Eric Leip, Arthur Kudla, Gregory Finn, and Łukasz Pruchniewski
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Cancer Research ,Oncology - Abstract
TPS8074 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA)-expressing multiple myeloma (MM) cells and CD3-expressing T cells, with binding resulting in T cell-mediated cytotoxicity. Elranatamab has demonstrated antitumor activity and delayed tumor progression in preclinical studies, as well as promising efficacy and manageable safety in the ongoing phase 1 MagnetisMM-1 study in patients (pts) with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Methods: MagnetisMM-5 is an open-label, multicenter, randomized phase 3 study designed to evaluate the efficacy and safety of subcutaneous (SC) elranatamab monotherapy and SC elranatamab + SC daratumumab in pts with relapsed/refractory MM who have received prior therapy, including lenalidomide and a proteasome inhibitor (PI). The study consists of 2 parts. In part 1, a minimum of 20 pts will be enrolled to assess the safety of an elranatamab priming regimen and identify the recommended combination dose for SC elranatamab + SC daratumumab for part 2. The primary endpoint of part 1 is dose-limiting toxicities encompassing the elranatamab monotherapy priming duration (14 d) and the first cycle of SC elranatamab + SC daratumumab dosing (28 d). In part 2, ̃450 pts will be stratified by prior lines of therapy (1 vs 2–3 vs ≥4) and prior treatment with anti-CD38 therapy (yes vs no) and enrolled in a 1:1:1 ratio to receive SC elranatamab or SC elranatamab + SC daratumumab or SC daratumumab + oral pomalidomide + oral dexamethasone. The primary endpoint of part 2 is progression-free survival (PFS), according to International Myeloma Working Group (IMWG) response criteria and blinded independent review. Secondary endpoints include PFS and PFS on next-line treatment by investigator per IMWG, overall survival, objective response rate, duration of response, complete response (CR) rate, duration of CR, time to response, overall and sustained minimal residual disease negativity rates, safety, quality of life, immunogenicity, and PK. Key inclusion criteria are age ≥18 y, MM diagnosis with measurable disease according to IMWG criteria, ECOG performance status 0–2, and clinical laboratory values within specified ranges. For part 2, pts should have received ≥1 prior line of anti-myeloma therapy, including treatment with lenalidomide and a PI. Key exclusion criteria include smoldering MM, plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 wk of enrollment, primary refractory MM, active, uncontrolled bacterial, fungal, or viral infections, previous treatment with BCMA-targeted therapy, anti-CD38 therapy within 6 mo of the first dose of study treatment, and previous pomalidomide therapy. MagnestisMM-5 will include sites in 28 countries. Clinical trial information: NCT05020236.
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- 2022
16. Initial safety results for MagnetisMM-3: A phase 2 trial of elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM)
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Alexander M. Lesokhin, Bertrand Arnulf, Ruben Niesvizky, Mohamad Mohty, Nizar J. Bahlis, Michael H. Tomasson, Paula Rodríguez-Otero, Hang Quach, Noopur S. Raje, Shinsuke Iida, Marc-Steffen Raab, Akos Czibere, Sharon Sullivan, Eric Leip, Andrea Viqueira, and Xavier Leleu
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Cancer Research ,Oncology - Abstract
8006 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells. MagnetisMM-3 (NCT04649359) is an open-label, multicenter, non-randomized, phase 2 study to evaluate the safety and efficacy of elranatamab monotherapy in pts with R/R MM. Initial safety results are presented. Methods: MagnetisMM-3 enrolled pts who are refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Pts were assigned to 1 of 2 independent, parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed antibody-drug conjugates or CAR-T cells (Cohort B). Pts received subcutaneous elranatamab 76 mg QW on a 28-d cycle with a 2-step-up priming dose regimen administered during the first week. Dose modifications were permitted for toxicity. Treatment-emergent adverse events (TEAEs) were graded by CTCAE (v5.0), and cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by ASTCT criteria. Results: As of the data cutoff on Dec 31, 2021, 60 pts in Cohort A had received ≥1 dose of elranatamab; the last pt’s first dose was ̃2 months prior to the cutoff. Median age was 69.0 y (range, 44−89), 48.3% were male, 63.3% were white, 18.3% were Asian and 11.7% were Black/African American. At baseline, 60.0% of pts had an ECOG performance status 1−2 and pts had received a median of 5 (range, 2−12) prior therapies. Median duration of elranatamab treatment was 9.57 wks (range, 0.1−46.1); median relative dose intensity was 87.4% (range, 23.1−101.4). TEAEs were reported in 100% (Grade [G] 3/4, 75.0%) of pts. Most common (≥30%) hematologic TEAEs were neutropenia (36.7% [G3/4, 35.0%]), anemia (36.7% [G3/4, 30.0%]) and thrombocytopenia (30.0% [G3/4, 21.7%]). Among pts who received the 2-step-up priming regimen (n = 56), CRS and ICANS, respectively, were reported in 58.9% (G3/4, 0%) and 3.6% (G3/4: 0%); of those pts, 57.6% (n = 19/33) and 100% (n = 2/2) received tocilizumab and/or steroids. Most common (≥30%) non-hematologic TEAE, other than CRS/ICANS, was fatigue (31.7% [G3/4, 3.3%]). Infections were reported in 46.7% (G3/4: 18.3%) of pts; most frequently reported were upper respiratory tract infections (11.7% [G3/4: 0%]). Discontinuations due to adverse events were reported in 5.0% of pts. No pts permanently discontinued treatment due to CRS or ICANS. There were 10 deaths; causes were MM progression (n = 8), septic shock (n = 1) and unknown (n = 1). Data will be updated at the time of presentation to include ̃90 pts. Conclusions: Preliminary results of MagnetisMM-3 in pts with R/R MM and no prior BCMA-targeted treatment suggest that 76 mg QW elranatamab with a 2-step-up priming regimen is well tolerated, with no G ≥3 CRS or ICANS observed. Clinical trial information: NCT04649359.
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- 2022
17. Bosutinib (BOS) in newly diagnosed chronic myeloid leukemia (CML): Gastrointestinal (GI), liver, effusion, and renal safety characterization in the BFORE trial
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Jorge E. Cortes, Dragana Milojkovic, Carlo Gambacorti-Passerini, Valentin García-Gutierrez, Michael J. Mauro, Eric Leip, Simon Purcell, Andrea Viqueira, and Tim H. Brümmendorf
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Cancer Research ,Oncology - Abstract
7049 Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]
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- 2022
18. Efficacy and safety of bosutinib in later-line patients (pts) with chronic myeloid leukemia (CML): A sub-analysis from the phase 4 BYOND trial
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Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Thomas Ernst, Eric Leip, Simon Purcell, Andrea Viqueira, Francis J. Giles, Gianantonio Rosti, and Andreas Hochhaus
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Cancer Research ,Oncology - Abstract
e19055 Background: Bosutinib (BOS) is approved for pts with Philadelphia chromosome-positive CML resistant/intolerant to prior therapy and newly diagnosed pts in chronic phase. Methods: The BYOND trial (NCT02228382) evaluated the efficacy and safety of BOS in 163 pts with CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs; Gambacorti-Passerini et al, Blood, 2021). We report a sub-analysis of 48 pts treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance/intolerance to the last received TKI. This sub-analysis is based on the final Nov 23, 2020 database lock. Results: There were 18 and 30 pts resistant or intolerant to the last TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 mo (1.6–48.5) vs 28.3 mo (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant pts. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant pts. Overall, 61.1% vs 66.7% of resistant vs intolerant pts discontinued BOS, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% pts; 16.7% vs 6.7% discontinued BOS due to insufficient clinical response. Rates of CCyR/MMR are shown in the table. Among responders (resistant vs intolerant pts), median (range) time to CCyR was 5.1 mo (2.8–8.8) vs 3.0 mo (2.7–6.1); median (range) time to MMR was 5.8 mo (2.8–9.4) vs 3.2 mo (2.8–9.3). In resistant vs intolerant pts, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% pts; grade 3/4 TEAEs were reported by 72.2% vs 83.3% pts. Grade 3/4 TEAEs > 10% in resistant pts were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant pts were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Conclusions: This sub-analysis of resistant/intolerant pts without baseline CCyR or MMR shows BOS was active in heavily pretreated pts with resistance/intolerance to the last TKI. Despite a difference between resistant/intolerant pts, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports. Clinical trial information: NCT02228382. [Table: see text]
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- 2022
19. Long-term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome-positive leukemia resistant or intolerant to prior therapy
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Tim H. Brümmendorf, Hagop M. Kantarjian, Fiona An, Jorge E. Cortes, Carlo Gambacorti-Passerini, Eric Leip, Michael J. Mauro, Sonja Nick, Cortes, J, Kantarjian, H, Mauro, M, An, F, Nick, S, Leip, E, Gambacorti Passerini, C, and Brummendorf, T
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Adult ,Male ,medicine.medical_specialty ,Heart Diseases ,bosutinib ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,tyrosine kinase inhibitor ,chronic myeloid leukemia ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Nitriles ,Medicine ,Humans ,Adverse effect ,Aged ,Retrospective Studies ,Aniline Compounds ,business.industry ,Incidence ,Imatinib ,clinical trial ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,cardiovascular event ,Discontinuation ,Dasatinib ,Leukemia ,Nilotinib ,Effusion ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Hypertension ,Quinolines ,Female ,business ,Blast Crisis ,Bosutinib ,effusion event ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Introduction: Long-term follow-up (≥4years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after≥7years of follow-up in patients with Philadelphia chromosome–positive (Ph+) leukemia. Methods: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV). Results: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation. Conclusions: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+CML resistant or intolerant to prior therapy who were treated with bosutinib.
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- 2021
20. Efficacy and safety following bosutinib dose reduction in patients with Philadelphia chromosome‒positive leukemias
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Vamsi Kota, Rocco J. Crescenzo, Jeffrey H. Lipton, Carlo Gambacorti-Passerini, Jorge E. Cortes, Tim H. Brümmendorf, Dong-Wook Kim, Roxanne Ferdinand, Eric Leip, Fiona An, Kota, V, Brummendorf, T, Gambacorti Passerini, C, Lipton, J, Kim, D, An, F, Leip, E, Crescenzo, R, Ferdinand, R, and Cortes, J
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Dose modification ,Dasatinib ,Dose reduction ,Gastroenterology ,Young Adult ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,medicine ,Humans ,Philadelphia Chromosome ,Adverse effect ,Aged ,Retrospective Studies ,Dose Modification ,Aged, 80 and over ,Aniline Compounds ,Drug Tapering ,business.industry ,Chronic myeloid leukemia ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,Prognosis ,Pyrimidines ,Oncology ,Nilotinib ,Tolerability ,Drug Resistance, Neoplasm ,Imatinib Mesylate ,Quinolines ,Bosutinib ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph+ patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years’ follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4 maintained a dose of ≥500 mg/day. ClinicalTrials.gov: NCT00261846.
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- 2021
21. Efficacy and Safety of Bosutinib in Previously Treated Patients with Chronic Myeloid Leukemia: Final Results from the Byond Trial
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Thomas Ernst, Frank Giles, Gerald Luscan, Elisabetta Abruzzese, Carlo Gambacorti-Passerini, Simon Purcell, Andreas Hochhaus, Eric Leip, Kevin R. Kelly, Andrea Viqueira, Tim H. Brümmendorf, Vivian G. Oehler, Valentín García-Gutiérrez, and Henrik Hjorth-Hansen
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,medicine ,business ,Previously treated ,Bosutinib ,medicine.drug - Abstract
Introduction: Bosutinib is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and patients with newly diagnosed Ph+ chronic phase (CP) CML. The phase 4 BYOND trial (NCT02228382) further evaluated the efficacy and safety of bosutinib in patients with previously treated CML. We report the final results from BYOND. Methods: Patients with CML resistant/intolerant to previous tyrosine kinase inhibitor therapy received bosutinib 500 mg once daily. This final analysis was based on a November 23, 2020 database lock, after 3 years of follow-up. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML; 4 patients with accelerated phase CML and 3 with Ph−/BCR-ABL1+ CML were analyzed separately. At study completion (median follow-up, 47.8 months), 48.1% of patient with Ph+ CP CML were still receiving treatment, and 68.6% completed the study. Most common primary reason for treatment discontinuation was adverse events (AEs) (26.9% [n=42/156]). Median treatment duration was 40.9 months (range, 0.2−50.1) and median dose intensity 306.4 mg/day (range, 79.7−560.6). Dose interruptions due to AEs occurred in 76.3% of patients and dose reductions in 79.5% of patients. Dose reduction (without further reduction) to 400, 300, or 200 mg/day occurred in 35 (22.4%), 46 (29.5%), and 38 (24.4%) patients, respectively. In evaluable patients with Ph+ CP CML, 81.1% (95% CI: 73.7-87.2), 71.8% (95% CI: 63.9-78.9), 59.7% (95% CI: 51.4-67.7) and 48.3% (95% CI: 40.1−56.6) attained or maintained complete cytogenetic response, major molecular response (MMR), MR 4, and MR 4.5 respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib (Table 1). Among responders, the Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR 4 at 36 months were 87.2% (78.0−92.7) and 80.7% (69.4−88.1), respectively. No patients with Ph+ CP CML progressed to accelerated/blast phase on-treatment. At 48 months, the cumulative incidence of progression free-survival events was 5.1% (95% CI: 2.4-9.4) and the Kaplan-Meier overall survival rate 88.3% (95% CI: 81.8-92.6). There were 17 deaths; 2 were considered CML-related (off-treatment progression to AP/BP, n=1; cardiogenic shock, n=1) and none were considered to be treatment-related by the investigator. In the overall patient population (N=163), any grade treatment-emergent AEs (TEAEs) were reported by 99.4% of patients and grade 3/4 TEAEs were reported by 79.1% of patients (Table 2). Most common (≥10%) TEAEs leading to dose reduction were diarrhea (27.0%) and increased ALT (12.3%) and most common TEAEs leading to temporary dose interruption were diarrhea (30.7%), increased ALT (14.7%), vomiting (13.5%), increased AST (11.0%), and nausea (10.4%). AEs leading to treatment discontinuation in ≥2% of patients were increased ALT (4.9%) and AST (2.5%). Conclusions: After 3 years, bosutinib continued to show efficacy in previously treated patients with Ph+ CP CML. Long-term AEs were generally manageable and consistent with previous reports of bosutinib. These results confirm the use of bosutinib as a standard of care in previously treated patients with CML. Figure 1 Figure 1. Disclosures Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Brümmendorf: Bristol Myers: Research Funding; Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Kelly: Takeda: Consultancy; AstraZeneca: Consultancy; Sanofi-Aventis: Consultancy; Denovo Biopharma: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Berkley Lights: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company; Bayer: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Epizyme: Speakers Bureau; Pharmacyclics: Speakers Bureau; Karyopharm: Speakers Bureau; Gilead: Speakers Bureau. Oehler: OncLive: Honoraria; Takeda: Consultancy; Pfizer: Research Funding; BMS: Consultancy. Garcia-Gutiérrez: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Pfizer: Research Funding. Hjorth-Hansen: Pfizer: Research Funding; Novartis: Research Funding; AOP: Research Funding. Leip: Pfizer: Current Employment, Current equity holder in publicly-traded company. Purcell: Pfizer: Current Employment, Current equity holder in publicly-traded company. Luscan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira: Pfizer: Current Employment, Current equity holder in publicly-traded company. Giles: Novartis: Consultancy; Actutate Therapeutics: Current Employment; Epigene Therapeutics: Consultancy, Current equity holder in publicly-traded company. Hochhaus: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding.
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- 2021
22. Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results from the Bfore Trial
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Andreas Hochhaus, Simon Purcell, Philippe Rousselot, Philipp le Coutre, Carlo Gambacorti-Passerini, Andrea Viqueira, Jeffrey H. Lipton, Michael W. Deininger, Rafael Hurtado Monroy, Michael J. Mauro, Richard E. Clark, Charles Chuah, Tim H. Brümmendorf, Anne Yver, Valentín García-Gutiérrez, Eric Leip, Vamsi Kota, Jorge E. Cortes, and Dragana Milojkovic
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Internal medicine ,medicine ,business ,Bosutinib ,medicine.drug - Abstract
Introduction: BOS is approved for patients (pts) with Philadelphia chromosome-positive (Ph+) CML resistant/intolerant to prior therapy and pts with newly diagnosed Ph+ CP CML. Approval of first-line BOS was based on the primary results from the phase 3 BFORE trial, which showed superior efficacy vs imatinib (IMA) in the modified intent-to-treat (ITT) population (pop; Ph+ with e13a2/e14a2 transcripts) after ≥12 mo of follow-up. We report the final efficacy and safety results from the BFORE trial after 5 y of follow-up. Methods: In the open-label BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive BOS (n=268) or IMA (n=268; 3 untreated), both at 400 mg once daily. Efficacy was assessed in the ITT pop (all randomized pts). Long-term secondary endpoints included duration of response (DOR), on-treatment event-free survival (EFS) and overall survival (OS). Safety was assessed in the safety pop (all treated pts). This final analysis was based on an April 17, 2020 last pt last visit (June 12, 2020 database lock), 5 y (240 weeks) after the last enrolled pt. Results: At study completion in BOS and IMA arms, respectively, 59.7% and 57.4% were still on treatment, 86.6% and 86.2% completed 5 y on study. Median duration of treatment and time on study was 55.2 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 394 (39-583) vs 400 (189-765) mg/d. Cumulative major molecular response (MMR) rate by 60 mo was higher with BOS vs IMA (73.9% vs 64.6%), as was cumulative molecular response (MR)4 (58.2% vs 48.1%) and MR4.5 rate (47.4% vs 36.6%; Table). Among evaluable pts, more pts in the BOS arm achieved BCR-ABL1 ≤10% at 3 months (Table); cumulative MMR by 60 mo was higher in pts with transcripts ≤10% vs >10% in both treatment arms (BOS, HR 2.67 [95% CI, 1.90-3.75]; IMA, HR 3.12 [2.19-4.45]). Pts in the BOS arm achieved responses earlier than pts in the IMA arm; cumulative incidence function for MMR, MR4 and MR4.5 was higher with BOS vs IMA (HR [95% CI]: MMR 1.34 [1.10-1.64], MR4 1.34 [1.07-1.69], MR4.5 1.41 [1.09-1.83]). Among responders, duration of MMR was similar for BOS and IMA (Table). Superior MRs with BOS vs IMA were consistent across Sokal risk groups, with the greatest difference seen in pts with high Sokal risk (Table). On-treatment transformations to accelerated/blast phase (AP/BP) occurred in 6 (AP 3; BP 3) BOS- and 7 (AP 6; BP 1) IMA-treated pts. No transformation occurred after the 24-mo follow-up. In all, 18 BOS- vs 25 IMA-treated pts had EFS events. There were no differences in EFS between treatment arms; cumulative incidence of on treatment progression/death at 60 mo was 6.7% for BOS vs 9.3% for IMA (Table). The 60-mo OS rates were similar (94.5% and 94.6%; Table); 14 BOS- and 14 IMA-treated pts died during the study period: 3 and 4 were CML-related, 0 and 1 were due to adverse events (AEs) related to study treatment. The most common reasons for permanent discontinuation were AEs (25.0% vs 12.5%) and lack of efficacy (4.9% vs 16.2%). Treatment-emergent AEs (TEAEs) occurred in 98.9% of pts in each arm; most common (>30%) were diarrhea (75.0%), nausea (37.3%), thrombocytopenia (35.8%) and increased alanine aminotransferase (ALT; 33.6%) with BOS, and diarrhea (40.4%), nausea (42.3%) and muscle spasms (30.6%) with IMA. Most TEAEs occurred during the first year of treatment. Grade 3/4 TEAEs occurred in 73.5% of BOS- vs 57.0% of IMA-treated pts; most common (>5%) were increased ALT (20.9%) and lipase (13.4%), thrombocytopenia (14.2%), increased aspartate aminotransferase (10.4%), diarrhea (9.0%) and neutropenia (7.5%) with BOS, and neutropenia (13.6%), thrombocytopenia (6.0%), anemia (5.7%) and increased lipase (5.7%) with IMA. No individual AE led to discontinuation in >5% of pts. The most frequent AEs leading to permanent treatment discontinuation were increased ALT (4.9%) with BOS vs thrombocytopenia (1.5%) with IMA; 1.5% vs 1.1% of pts discontinued due to diarrhea. Conclusions: At 5 y, first-line BOS continued to show superior efficacy vs IMA; BOS-treated pts achieved earlier and deeper molecular response. An improvement in MR with BOS was demonstrated across Sokal risk groups, with the greatest benefit vs IMA observed in Sokal high-risk pts. Long-term AEs were generally manageable, and consistent with previous reports and the known safety profiles of both drugs. These results confirm the use of BOS as a standard of care in pts with newly diagnosed CP CML. Disclosures Brümmendorf: Takeda: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Merck: Consultancy; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding. Cortes:Astellas: Research Funding; Arog: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Immunogen: Research Funding; Telios: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis: Consultancy, Research Funding. Milojkovic:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Clark:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Ariad/Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria. Kota:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria. Lipton:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Rousselot:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Mauro:Sun Pharma/SPARC: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:MSD: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hurtado Monroy:Incyte: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Yver:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Deininger:Gilead Sciences: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Other; SPARC: Research Funding; DisperSol: Consultancy; Pfizer: Honoraria, Other, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galena: Consultancy, Honoraria, Other.
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- 2020
23. Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial
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Carlo Gambacorti-Passerini, Simon Purcell, Vamsi Kota, Tim H. Brümmendorf, Jorge E. Cortes, Philipp le Coutre, Pia Raanani, Eric Leip, Valentín García-Gutiérrez, Andrea Viqueira, and Henrik Hjorth-Hansen
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medicine.medical_specialty ,business.industry ,MedDRA ,Incidence (epidemiology) ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Discontinuation ,Internal medicine ,Medicine ,Risk factor ,business ,Adverse effect ,Bosutinib ,medicine.drug - Abstract
Introduction: Tyrosine kinase inhibitor therapy has been associated with cardiovascular (CV) events. BOS is approved for patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) CML and Ph+ CML resistant/intolerant to prior therapy. We analyzed cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) in pts with newly diagnosed CP CML receiving BOS or IMA after 5 yrs follow-up in BFORE. Methods: In the open-label, phase 3 BFORE trial (NCT02130557), 536 pts with newly diagnosed CP CML were randomized 1:1 to receive first-line 400 mg once-daily BOS (n=268) or IMA (n=268; 3 untreated). The current analysis included all pts who received ≥1 dose of study drug. TEAEs were monitored from first dose of study drug until 28 d after last dose; monitoring of non-serious adverse events (AE) ended at the start of a new cancer treatment. Prespecified MedDRA terms (cardiac, n=133; vascular, n=502) comprised clusters of investigator-assessed TEAEs (Table). Multivariable proportional subdistribution hazard models predicting time to first TEAE included treatment group; baseline demographic information; history of cardiac events, vascular events, hypertension, diabetes, hyperlipidemia, and tobacco use; as well as hypertension, cardiac (for vascular model) and vascular (for cardiac model) TEAEs. CI excluding 1 was considered predictive of outcome. This analysis was based on 17-Apr-20 last pt last visit (12-Jun-20 database lock), 5 y (240 wks) after last enrolled pt. Results: At study completion, 59.7% of BOS pts and 58.1% of IMA pts were still on treatment. Median duration of treatment was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39-583) vs 400.0 (189-765) mg/d. In the BOS vs IMA arm, 57.8% vs 56.2% of pts had ≥1 CV risk factor at baseline; 20.9% vs 17.7% had ≥3 risk factors, respectively. The most common risk factors were a history of hypertension (BOS, 34.0%; IMA, 30.6%), BMI >30 (BOS, 23.1%; IMA, 21.9%), age ≥65 y (BOS, 19.8%; IMA, 17.4%), and history of hyperlipidemia (BOS, 16.8%; IMA, 18.9%). Rates of cardiac, vascular and hypertension TEAEs; serious adverse events (AEs); AEs leading to treatment withdrawal and drug-related TEAEs (per investigator) were low in both arms (Table). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs were similar between arms (Table). Risk factors for cardiac TEAEs (HR; 95% CI) were age in years (1.04 [1.02-1.07]), race other than Asian or black compared to white ( Successful treatment rechallenge was achieved in the majority of pts with dose interruptions due to cardiac (BOS, 85.7%; IMA, 100%) and vascular (BOS, 100%; IMA, not applicable) TEAEs who were readministered study drug. No pts had dose interruptions due to hypertension TEAEs. Cardiac, vascular and hypertension TEAEs resolved in 57.7%, 75.0% and 35.7% of pts receiving BOS and 65.2%, 66.7% and 48.3% receiving IMA. Conclusions: In this final analysis of BFORE, the incidence of cardiac, vascular, and hypertension TEAEs in pts with newly diagnosed CP CML receiving BOS or IMA was low and was similar between treatment groups. These AEs infrequently led to treatment discontinuation. In addition to continued improved efficacy with BOS vs IMA after 5 yrs follow-up (Brümmendorf et al., ASH 2020), these safety results support the use of first-line BOS as a standard of care in pts with CP CML. Disclosures Cortes: Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Telios: Research Funding; Astellas: Research Funding; Sun Pharma: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Hjorth-Hansen:Pfizer: Honoraria, Research Funding; Austrian Orphan Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Garcia-Gutiérrez:Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding. Kota:Ariad: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Pfizer: Consultancy, Honoraria. Purcell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Viqueira:Pfizer: Current Employment, Current equity holder in publicly-traded company. Leip:Pfizer: Current Employment, Current equity holder in publicly-traded company. Brümmendorf:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding.
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- 2020
24. Outcomes before and after dose reduction in patients with newly diagnosed chronic myeloid leukemia receiving bosutinib or imatinib
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Michael W. Deininger, Jorge E. Cortes, Francisco Cervantes, Simon Purcell, Andrea Viqueira, Françoise Huguet, Eric Leip, Tim H. Brümmendorf, and Dragana Milojkovic
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Newly diagnosed ,Internal medicine ,Medicine ,Dose reduction ,In patient ,business ,Bosutinib ,medicine.drug - Abstract
7039 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia (CML), at a starting dose of 400 mg QD in newly diagnosed pts in chronic phase (CP). This analysis evaluated the impact dose reduction has on the outcomes of BOS and imatinib (IMA) in pts with CP CML. Methods: In the open-label BFORE trial, 536 pts with newly diagnosed CP CML were randomized to receive 400 mg QD BOS (N = 268) or IMA (N = 268; 3 untreated). Dose could be reduced to 300 mg QD for toxicity. Following sponsor approval, dose reduction to BOS 200 mg QD was permitted for 4 wks maximum; after this time, dose escalation or treatment discontinuation was required. Maintenance of response after dose reduction was defined as having a response > 6 mo after the first reduction. Database lock: June 12, 2020, 5 y after the last pt enrolled. Results: In the BOS arm, dose reduction to 300 (without further reduction) or 200 mg QD was seen in 82 (31%) and 33 (12%) pts, and median time to dose reduction was 85 and 205 d. In the IMA arm, 50 (19%) pts had a dose reduction to 300 mg QD, and median time to dose reduction was 92 d. Most common (≥2% of pts) treatment-emergent adverse events (TEAEs) leading to dose reduction were increased alanine aminotransferase (8%), thrombocytopenia (7%), diarrhea (7%), increased lipase (6%), increased aspartate aminotransferase (4%), nausea (4%), neutropenia (3%), rash (3%) and abdominal pain (2%) with BOS, and neutropenia (4%) with IMA. Of the pts who remained on 400 mg QD BOS (n = 153) or IMA (n = 214), respectively, 120 (78%) and 139 (65%) achieved major molecular response (MMR). Among pts who had a BOS dose reduction to 300 mg QD, 51/82 (62%) had MMR > 6 mo after dose reduction: 14 (17%) maintained MMR before and after dose reduction and 37 (45%) achieved MMR for the first time after dose reduction. Seven (9%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. In the IMA arm, 32/50 (64%) pts had MMR > 6 mo after dose reduction: 9 (18%) maintained MMR before and after dose reduction and 23 (46%) achieved MMR for the first time after dose reduction. One (2%) pt had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment and 1 (2%) pt lost a previously attained MMR after dose reduction. Among pts who had a BOS dose reduction to 200 mg QD, 12/33 (36%) had MMR > 6 mo after dose reduction: 7 (21%) maintained MMR before and after dose reduction and 5 (15%) achieved MMR for the first time after dose reduction. Six (18%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. Similar trends were seen for complete cytogenetic response. Conclusions: Management of TEAEs through BOS or IMA dose reduction enabled pts to continue treatment, with a substantial number of pts achieving MMR for the first time after dose reduction. Clinical trial information: NCT02130557.
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- 2021
25. The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia
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Andrea Viqueira, Lambert Busque, Carlo Gambacorti-Passerini, Michael W. Deininger, Leif Stenke, Eric Leip, Simon Purcell, Tim H. Brümmendorf, and Jorge E. Cortes
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Newly diagnosed ,Prior Therapy ,Internal medicine ,medicine ,In patient ,business ,Body mass index ,Bosutinib ,medicine.drug - Abstract
7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]
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- 2021
26. Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study
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Eric Leip, Dong-Wook Kim, Simon Purcell, Tim H. Brümmendorf, Arpad Batai, Andrea Viqueira, Yeow Tee Goh, Carlo Gambacorti-Passerini, Jocelyn M Leone, Jorge E. Cortes, Irina Dyagil, Katia B Pagnano, and Anna G. Turkina
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Newly diagnosed ,Philadelphia chromosome ,medicine.disease ,Prior Therapy ,Second line ,Internal medicine ,medicine ,business ,Bosutinib ,medicine.drug - Abstract
7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]
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- 2021
27. Long‐term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib
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Carlo Gambacorti-Passerini, Kay Noonan, Hanna Jean Khoury, Dong-Wook Kim, Jeffrey H. Lipton, Hagop M. Kantarjian, Jorge E. Cortes, Philippe Schafhausen, Eric Leip, Tim H. Brümmendorf, Ewa Matczak, Cortes, J, Khoury, H, Kantarjian, H, Lipton, J, Kim, D, Schafhausen, P, Matczak, E, Leip, E, Noonan, K, Brümmendorf, T, and GAMBACORTI PASSERINI, C
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Adult ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Nausea ,Dasatinib ,Antineoplastic Agents ,Pharmacology ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Humans ,Medicine ,Cumulative incidence ,Longitudinal Studies ,Adverse effect ,Research Articles ,Aged ,Aged, 80 and over ,Salvage Therapy ,Aniline Compounds ,business.industry ,Remission Induction ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,Survival Analysis ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,Nilotinib ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Quinolines ,medicine.symptom ,business ,Bosutinib ,Research Article ,medicine.drug - Abstract
American journal of hematology 91(12), 1206-1214 (2016). doi:10.1002/ajh.24536, Published by Wiley-Liss, New York, NY
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- 2016
28. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib
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H. Jean Khoury, Jean M. Aguiar, Carlo Gambacorti-Passerini, Svetoslav Dimitrov, Ewa Matczak, Jeffrey H. Lipton, Dmitri Pavlov, Mark Shapiro, Hagop M. Kantarjian, Jean-Bernard Durand, Kolette D. Fly, Jorge E. Cortes, Tim H. Brümmendorf, Michael J. Mauro, and Eric Leip
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medicine.medical_specialty ,Ejection fraction ,Performance status ,business.industry ,Phases of clinical research ,Imatinib ,Hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Imatinib mesylate ,030220 oncology & carcinogenesis ,Internal medicine ,Concomitant ,medicine ,business ,Intensive care medicine ,Adverse effect ,Bosutinib ,030215 immunology ,medicine.drug - Abstract
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
29. CML-277: Efficacy of Bosutinib in Imatinib-Resistant vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study
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Gail J. Roboz, Aude Charbonnier, Frank Castagnetti, Andreas Hochhaus, Thomas Ernst, B. Douglas Smith, Gianantonio Rosti, Frank Giles, Tim H. Brümmendorf, Carlo Gambacorti-Passerini, Andrea Viqueira, and Eric Leip
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Context (language use) ,Imatinib ,Hematology ,Philadelphia chromosome ,medicine.disease ,Dasatinib ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Imatinib mesylate ,Nilotinib ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adverse effect ,business ,Bosutinib ,medicine.drug - Abstract
Context Bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Objective To evaluate the efficacy of bosutinib in patients with Ph+ CP CML according to subgroups of resistance (imatinib vs. dasatinib/nilotinib) or intolerance to prior tyrosine kinase inhibitors (TKIs). Design BYOND ( NCT02228382 ) is an ongoing, phase 4, single-arm, open-label study. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Setting Multicenter study in Europe and North America. Patients Patients with CML resistant/intolerant to prior TKIs. Interventions Bosutinib 500 mg QD (starting dose). Main outcome measures Cumulative response rates. Results Of 156 patients with Ph+ CP CML who received bosutinib, 52 had resistance only to imatinib, 31 had resistance to dasatinib and/or nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration was 24.1, 8.9, and 25.3 months, and median dose intensity was 360, 431, and 292 mg/day. At the data cut-off, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment. The main reason for discontinuation was adverse events: 19.2%, 25.8%, and 28.8% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Corresponding discontinuations due to insufficient response occurred in 3.8%, 16.1%, and 1.4% of patients. No patient experienced on-treatment transformation to advanced phase CML. In patients without baseline complete cytogenetic response (CCyR), CCyR rates by 1 year were 65.0%, 50.0%, and 72.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. In patients without baseline major molecular response (MMR), cumulative MMR rates by 1 year were 55.6%, 28.6%, and 80.6% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Deaths occurred in 3, 3, and 4 imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Conclusions Response rates were similar between imatinib-resistant and TKI-intolerant patients. Despite the fact that dasatinib/nilotinib-resistant patients were more heavily pretreated and had a shorter treatment duration, responses were also seen in patients with resistance to these second-generation TKIs. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Study Sponsor Pfizer.
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- 2020
30. Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study
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Simon Purcell, Musa Yilmaz, Yeow Tee Goh, Andrea Viqueira, Tim H. Brümmendorf, Rebecca B. Klisovic, Carlo Gambacorti-Passerini, Jorge E. Cortes, and Eric Leip
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Newly diagnosed ,Prior Therapy ,Phase i ii ,Internal medicine ,Toxicity ,medicine ,In patient ,business ,Bosutinib ,medicine.drug - Abstract
7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (
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- 2020
31. Bosutinib in patients with chronic phase chronic myeloid leukemia intolerant to prior tyrosine kinase inhibitors: Analyses from the BYOND study
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Valentín García Gutiérrez, Thomas Ernst, Camille N. Abboud, Simon Purcell, Frank Giles, Andreas Hochhaus, Andrea Viqueira, Susanne Saussele, Eric Leip, and Carlo Gambacorti-Passerini
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Newly diagnosed ,Chronic phase chronic myeloid leukemia ,Philadelphia chromosome ,medicine.disease ,Prior Therapy ,Internal medicine ,medicine ,In patient ,business ,Tyrosine kinase ,Bosutinib ,medicine.drug - Abstract
7551 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and in newly diagnosed pts in chronic phase (CP). Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). We report findings in pts intolerant to all prior TKIs. Data are reported ≥1 y after the last enrolled pt (~85% TKI-intolerant pts had ≥2 y follow-up). Results: Of 163 pts who received BOS, 156 had Ph+ CP CML. 73 pts entered the study due to intolerance; 29, 26 and 18 had 1 (CP2L), 2 (CP3L) and 3 (CP4L) prior TKIs, respectively. After a median follow-up of 30.4 mo, median treatment duration across all 3 cohorts (CP2L, CP3L, CP4L, respectively) was 25.3 mo (29.2, 24.6, 17.6) and median dose intensity was 292.0 mg/d (304.5, 284.8, 272.1). Across CP CML cohorts (CP2L, CP3L, CP4L, respectively), 84.9% of patients (82.8%, 88.5%, 83.3%) had ≥1 dose reduction and 83.6% (79.3%, 84.6%, 88.9%) had ≥1 dose interruption due to adverse events (AEs). At the data cutoff, 53.4% (CP2L 65.5%, CP3L 42.3%, CP4L 50.0%) were still receiving BOS. The most common reason for discontinuation was AEs (28.8%). The most common ( > 40%) treatment-emergent AEs (TEAEs) were diarrhea (87.7%) and nausea (43.8%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.4%), increased alanine aminotransferase (19.2%) and increased lipase (12.3%). Most pts with a valid baseline assessment achieved major molecular responses (MMR) across therapy lines (Table). Deaths occurred in 4 pts (CP2L 1, CP3L 3, CP4L 0); none were related to BOS or CML. Overall survival rate (95% CI) at 2 y in TKI-intolerant pts was 97.2% (89.2–99.3); rates were 96.4% (77.2–99.5), 96.0% (74.8–99.4) and 100% (100–100) in CP2L, CP3L and CP4L pts, respectively. Conclusions: A long duration of treatment and high response rate were observed in TKI-intolerant pts treated with BOS. Despite being intolerant to all prior therapies, ≥50% of pts in the overall intolerant cohort remained on BOS treatment at the data cutoff and > 80% achieved/maintained MMR. These results further support BOS use in pts with Ph+ CP CML and intolerance to all prior TKIs. Clinical trial information: NCT02228382 . [Table: see text]
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- 2020
32. Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study
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B. Douglas Smith, Tim H Brümmendorf, Gail J. Roboz, Carlo Gambacorti-Passerini, Aude Charbonnier, Andrea Viquiera, Eric Leip, Frank Giles, Thomas Ernst, Andreas Hochhaus, and Gianantonio Rosti
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education ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,health care economics and organizations - Abstract
Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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- 2019
33. Efficacy and Safety of Bosutinib By Charlson Comorbidity Index in Previously Treated Patients with Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study
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Tim H. Brümmendorf, Bjørn Tore Gjertsen, Valentín García Gutiérrez, Gianantonio Rosti, Frank Giles, Eric Leip, Camille N. Abboud, Andrea Viqueira, Andreas Hochhaus, Carlo Gambacorti-Passerini, and Elisabetta Abruzzese
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Baseline data ,Increased alanine aminotransferase ,University hospital ,Biochemistry ,Discontinuation ,Family medicine ,Charlson comorbidity index ,medicine ,In patient ,Previously treated ,business ,Bosutinib ,medicine.drug - Abstract
Background: Bosutinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. The efficacy and safety of bosutinib by baseline comorbidities in patients with CML resistant/intolerant to prior TKIs were investigated. Methods: The phase 4 BYOND trial (NCT02228382) is further examining efficacy and safety of bosutinib (starting dose 500 mg/day) in patients with CML resistant/intolerant to prior TKIs. Comorbidities were analyzed using the Charlson Comorbidity Index (CCI), a validated measure of the influence of relevant comorbid conditions on mortality. Scores were derived from baseline data and patients grouped by CCI score 2-3, 4-5, and ≥6. This analysis was based on ≥1 year of follow-up and included patients with Ph+ CP CML. Results: 156 patients with Ph+ CP CML (n=42 [26.9%], 48 [30.8%], and 66 [42.3%] for CCI 2-3, 4-5, and ≥6) received bosutinib. Median treatment duration was 28.9, 23.9, and 20.1 months for CCI 2-3, 4-5, and ≥6; median dose intensity was 366.7, 385.3, and 291.5 mg/day. Across CCI groups, a substantial proportion of patients attained/maintained cytogenetic and molecular responses (Table). Grade 3/4 treatment-emergent adverse events (TEAEs) rates were 64.3%, 72.9%, and 80.3% for CCI 2-3, 4-5, and ≥6. Emerging grade 3/4 TEAEs differed between groups; diarrhea and increased alanine aminotransferase (ALT) were more common for CCI 2-3 (21.4% and 23.8%, respectively) and 4-5 (18.8% and 16.7%) and pleural effusion more common for CCI ≥6 (12.1%). For CCI 2-3, 4-5, and ≥6, 19.0%, 20.8%, and 31.8% of patients discontinued treatment due to AEs and 2.4%, 2.1%, and 9.1% due to insufficient response. Most common AEs leading to discontinuation in the respective groups were increased ALT and aspartate aminotransferase (7.1% each), increased ALT (8.3%), and pleural effusion (3.0%). 10 deaths occurred (n=0 [0%], 1 [2.1%], and 9 [13.6%] for CCI 2-3, 4-5, and ≥6), 8 due to AEs (none bosutinib-related), 1 CML-related, and 1 of unknown cause. No on-treatment transformations to advanced CML occurred. Conclusions: Across CCI groups, a majority of patients with Ph+ CP CML achieved/maintained cytogenetic and molecular responses, and only 1 CML-related death was reported. Patients with CCI ≥6 showed a trend toward higher rates of TEAEs, discontinuations due to AEs, and death. Results demonstrate efficacy of bosutinib across CCI scores, including patients with important comorbidities. However, CCI stratification may enable identification of patients at higher risk of developing TEAEs who require more careful monitoring. Disclosures Gambacorti-Passerini: Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Gjertsen:Astellas: Consultancy; The Norwegian Cancer Society: Research Funding; BerGenBio: Consultancy; ERA PerMed: Research Funding; ACTII AS: Equity Ownership; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy; Haukeland University Hospital / University of Bergen: Employment; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding; EU Horizon 2020: Research Funding; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Giles:Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy; Actuate Therapeutics Inc: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding.
- Published
- 2019
34. Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study
- Author
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Philipp le Coutre, Gianantonio Rosti, Justin M. Watts, Eric Leip, Jorge E. Cortes, Guillermo Ortí, Bjørn Tore Gjertsen, Frank Giles, Carlo Gambacorti-Passerini, Andrea Viqueira, and Andreas Hochhaus
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Drug intolerance ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Discontinuation ,Dasatinib ,Imatinib mesylate ,Nilotinib ,Internal medicine ,Medicine ,business ,Adverse effect ,Bosutinib ,health care economics and organizations ,medicine.drug - Abstract
Background: Some patients receiving a tyrosine kinase inhibitor (TKI) for chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) experience drug intolerance and require switching to an alternative TKI. Bosutinib, a TKI approved for newly diagnosed CP Ph+ CML and Ph+ CML resistant/intolerant to prior therapy, has a distinct adverse event (AE) profile vs other TKIs used to treat Ph+ CML. Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients with Ph+ CP CML (n=156) previously treated with imatinib, dasatinib, and/or nilotinib received bosutinib (starting dose 500 mg once daily). Cross-intolerance (AEs leading to permanent discontinuation of both prior TKI and bosutinib), recurrent AEs (grades 1/2 or 3/4), and bosutinib dose modifications due to recurrent AEs were assessed across AEs and AE clusters. This analysis was based on ≥1 year after the last enrolled patient (median treatment duration 23.7 months [range 0.2-42.2]). Results: Of 141, 95, and 79 patients who received prior imatinib, dasatinib, or nilotinib, respectively, 63 (45%), 70 (74%), and 60 (76%) were intolerant and discontinued treatment due to an AE as the primary reason. 1 (2%) imatinib-intolerant and 5 (7%) dasatinib-intolerant patients had cross-intolerance with bosutinib; no cross-intolerance with bosutinib was reported for the 60 nilotinib-intolerant patients (Table). 15 patients discontinued >1 TKI due to the same AE. Of these, only 1 with prior imatinib and dasatinib intolerance due to anemia (below), was cross-intolerant to bosutinib. No deaths occurred due to cross-intolerance to bosutinib. Imatinib-intolerant: The most common cause of imatinib intolerance was musculoskeletal pain in 19 patients. Of these, 9 patients experienced grade 1/2 recurrence and 1 had a grade 3/4 AE. There was no cross-intolerance with bosutinib due to musculoskeletal pain. 6 patients were intolerant due to edema, which recurred as grade 1/2 in 3 bosutinib-treated patients. In 2 patients with intolerance due to diarrhea, both had grade 1/2 diarrhea with bosutinib. 2 patients were imatinib-intolerant due to neutropenia or thrombocytopenia (n=1 each) and experienced grade 3/4 recurrence with bosutinib. 1 patient was cross-intolerant to bosutinib due to anemia. Dasatinib-intolerant: The most common reason for prior dasatinib intolerance was pleural effusion. Of 36 patients, 10 (28%) had recurrence of grade 1/2 AE and 4 (11%) had grade 3/4 AE with bosutinib that caused dose delay and reduction in 6 (17%) and 4 (11%) patients, respectively. 1 patient had cross-intolerance with bosutinib due to pleural effusion. Of 8 patients dasatinib-intolerant due to dyspnea, 1 had cross-intolerance with bosutinib (this patient also developed pleural effusion with dasatinib). Of 2 patients with dasatinib intolerance due to pulmonary hypertension, 1 had grade 1/2 and 1 had grade 3/4 recurrence with bosutinib, leading to cross-intolerance in 1 patient. 2 other dasatinib-intolerant patients experienced cross-intolerance due to anemia and nausea (n=1 each). Grade 3/4 recurrence of thrombocytopenia was experienced in 1 of 3 patients with prior dasatinib-intolerance. 1 patient with dasatinib intolerance due to diarrhea had grade 3/4 diarrhea with bosutinib that was managed with dose delay/reduction. Nilotinib-intolerant: 6 patients discontinued nilotinib due to peripheral ischemia, of whom 1 experienced grade 3/4 recurrence with bosutinib. None of the 4 patients with nilotinib intolerance due to acute coronary syndrome had recurrence with bosutinib. Of 3 patients with prior intolerance due to pancreatitis, 1 had grade 3/4 recurrence with bosutinib. 2 patients had recurrent diarrhea with bosutinib, both grade 1/2. There were no bosutinib dose reductions, delays, or recurrence of AEs in patients with prior nilotinib intolerance due to rash, hematologic AEs, hepatotoxicity, or metabolic disorders. Conclusions: Incidence of cross-intolerance, dose delay, or dose reduction with bosutinib in patients intolerant to prior TKIs was low. Despite recurrence of certain same grade 1/2 or grade 3/4 AEs that caused prior TKI intolerance, these were manageable and patients were able to remain on bosutinib. These findings support the use of bosutinib in patients with CP Ph+ CML intolerant to prior TKI treatment. Disclosures Gjertsen: Haukeland University Hospital / University of Bergen: Employment; ERA PerMed: Research Funding; BerGenBio: Consultancy; Astellas: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; ACTII AS: Equity Ownership; Seattle Genetics: Consultancy; Research Council of Norway: Research Funding; EU Horizon 2020: Research Funding; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding. Hochhaus:Pfizer: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Watts:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ortí:Bristol-Myers Squibb: Consultancy, Other: Travel Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Travel Expenses, Speakers Bureau. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. Cortes:Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy.
- Published
- 2019
35. Cardiac, Vascular and Hypertension Safety of Bosutinib vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia in the BFORE Trial
- Author
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Richard E. Clark, Carlo Gambacorti-Passerini, Michael W. Deininger, Vamsi Kota, Jorge E. Cortes, Eric Leip, Andrea Viqueira, and Tim H. Brümmendorf
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,Newly diagnosed ,Internal medicine ,medicine ,business ,Bosutinib ,medicine.drug - Published
- 2019
36. PF415 EFFICACY AND SAFETY FOLLOWING DOSE REDUCTION OF BOSUTINIB IN PREVIOUSLY TREATED PATIENTS WITH CHRONIC MYELOID LEUKEMIA: ANALYSIS OF THE PHASE 4 BYOND TRIAL
- Author
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Andrea Viqueira, Henrik Hjorth-Hansen, T H Brümmendorf, Gail J. Roboz, Nathalie Bardy-Bouxin, J.L. Steegmann, Francis J. Giles, J. E. Cortes, Philippe Rousselot, C. Gambacorti-Passerini, J.M. Leone, A. Hochhaus, Eric Leip, P. Le Coutre, Leif Stenke, and Francisco Cervantes
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Myeloid leukemia ,Dose reduction ,Hematology ,business ,Previously treated ,Bosutinib ,medicine.drug - Published
- 2019
37. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial
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Michael W. Deininger, Allison Jeynes-Ellis, Carlo Gambacorti-Passerini, Valentín García-Gutiérrez, Jorge E. Cortes, Dragana Milojkovic, Laurence Reilly, Charles Chuah, Tim H. Brümmendorf, Nathalie Bardy-Bouxin, Dong-Wook Kim, Nataliia Glushko, Irina Dyagil, Andreas Hochhaus, P. le Coutre, Michael J. Mauro, Eric Leip, Cortes, J, Gambacorti Passerini, C, Deininger, M, Mauro, M, Chuah, C, Kim, D, Dyagil, I, Glushko, N, Milojkovic, D, Le Coutre, P, Garcia-Gutierrez, V, Reilly, L, Jeynes-Ellis, A, Leip, E, Bardy-Bouxin, N, Hochhaus, A, and Brümmendorf, T
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Time Factors ,DNA Mutational Analysis ,Dasatinib ,Fusion Proteins, bcr-abl ,Pharmacology ,Gastroenterology ,0302 clinical medicine ,hemic and lymphatic diseases ,Cumulative incidence ,Philadelphia Chromosome ,Aged, 80 and over ,education.field_of_study ,Aniline Compounds ,Hazard ratio ,Myeloid leukemia ,ORIGINAL REPORTS ,Middle Aged ,3. Good health ,Leukemia ,Phenotype ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cytogenetic Analysis ,Disease Progression ,Imatinib Mesylate ,Quinolines ,Female ,Bosutinib ,Algorithms ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Clinical Decision-Making ,Population ,Antineoplastic Agents ,Philadelphia chromosome ,Decision Support Techniques ,03 medical and health sciences ,Young Adult ,Predictive Value of Tests ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Nitriles ,Hematologic Malignancy ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,education ,Protein Kinase Inhibitors ,Aged ,business.industry ,Patient Selection ,Imatinib ,medicine.disease ,030104 developmental biology ,Mutation ,business - Abstract
Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome–positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome–positive with typical (e13a2/e14a2) transcripts (bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome–negative–/ BCR-ABL1–positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population. Results The major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with bosutinib. Cardiac and vascular toxicities were uncommon. Conclusion Patients who received bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.
- Published
- 2017
38. Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors
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Tim H. Brümmendorf, Kathleen Turnbull, Eric Leip, Ewa Matczak, Hanna Jean Khoury, Nathalie Bardy-Bouxin, Mark Shapiro, Carlo Gambacorti-Passerini, Hagop M. Kantarjian, Jorge E. Cortes, Dong-Wook Kim, Anna G. Turkina, GAMBACORTI PASSERINI, C, Kantarjian, H, Kim, D, Khoury, H, Turkina, A, Brümmendorf, T, Matczak, E, Bardy Bouxin, N, Shapiro, M, Turnbull, K, Leip, E, and Cortes, J
- Subjects
Male ,Quinoline ,Gastroenterology ,Piperazines ,Blast Crisi ,Antineoplastic Agent ,0302 clinical medicine ,Aged, 80 and over ,Aniline Compounds ,Hematology ,Myeloid leukemia ,Aniline Compound ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,3. Good health ,Leukemia ,Treatment Outcome ,030220 oncology & carcinogenesis ,Benzamides ,Toxicity ,Imatinib Mesylate ,Quinolines ,Female ,Survival Analysi ,Nitrile ,Bosutinib ,Human ,Research Article ,medicine.drug ,Adult ,Diarrhea ,medicine.medical_specialty ,Adolescent ,Fever ,Protein Kinase Inhibitor ,Antineoplastic Agents ,Follow-Up Studie ,03 medical and health sciences ,Benzamide ,Internal medicine ,Nitriles ,medicine ,Humans ,Piperazine ,Protein Kinase Inhibitors ,Survival analysis ,Aged ,business.industry ,Imatinib ,Pneumonia ,Original Articles ,medicine.disease ,Survival Analysis ,Surgery ,Pyrimidines ,Imatinib mesylate ,Pyrimidine ,Drug Resistance, Neoplasm ,Blast Crisis ,business ,Follow-Up Studies ,030215 immunology - Abstract
Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
- Published
- 2015
39. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study
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Philippe Schafhausen, Kay Noonan, H. Jean Khoury, Tim H. Brümmendorf, Jeffrey H. Lipton, Rocco J. Crescenzo, Carlo Gambacorti-Passerini, Liza DeAnnuntis, Mark Shapiro, Nathalie Bardy-Bouxin, Eric Leip, Hagop M. Kantarjian, Jorge E. Cortes, Dong-Wook Kim, Gambacorti-Passerini, C, Cortes, J, Lipton, J, Kantarjian, H, Kim, D, Schafhausen, P, Crescenzo, R, Bardy-Bouxin, N, Shapiro, M, Noonan, K, Leip, E, Deannuntis, L, Brümmendorf, T, and Khoury, H
- Subjects
Adult ,medicine.medical_specialty ,Myeloid ,Adolescent ,Chronic Myeloid Leukemia ,Chronic Myelogenous Leukemia, Bosutinib, Second-line therapy, tyrosine kinase inhibitor ,Antineoplastic Agents ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,MED/15 - MALATTIE DEL SANGUE ,Median follow-up ,Internal medicine ,Nitriles ,medicine ,Humans ,Cumulative incidence ,Survival analysis ,Aged ,Aniline Compounds ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Peptide Fragments ,Leukemia ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Quinolines ,business ,Bosutinib ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
- Published
- 2017
40. Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias
- Author
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Ewa Matczak, Moshe Talpaz, Elly Barry, H. Jean Khoury, Eric Leip, Jeffrey H. Lipton, Amit Lahoti, Carlo Gambacorti-Passerini, Dong-Wook Kim, Hagop M. Kantarjian, Jorge E. Cortes, Tim H. Brümmendorf, Cortes, J, Gambacorti Passerini, C, Dong Wook, K, Kantarjian, H, Lipton, J, Lahoti, A, Talpaz, M, Matczak, E, Barry, E, Leip, E, Brümmendorf, T, and Khoury, H
- Subjects
Male ,Cancer Research ,Tyrosine kinase inhibitor ,Kidney Function Tests ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Philadelphia Chromosome ,Aged, 80 and over ,Clinical Trials as Topic ,Aniline Compounds ,Leukemia ,Hematology ,Philadelphia Chromosome Positive ,Chronic myeloid leukemia ,Middle Aged ,Oncology ,Creatinine ,030220 oncology & carcinogenesis ,Quinolines ,Female ,Kidney Diseases ,Bosutinib ,Glomerular Filtration Rate ,medicine.drug ,Adult ,Adverse event ,medicine.medical_specialty ,Adolescent ,Renal function ,Antineoplastic Agents ,Young Adult ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Humans ,In patient ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Imatinib ,Patient Outcome Assessment ,chemistry ,Immunology ,Renal toxicity ,business ,030215 immunology - Abstract
Clinical lymphoma, myeloma & leukemia 17(10), 684-695.e6 (2017). doi:10.1016/j.clml.2017.06.001, Published by Elsevier, Amsterdam [u.a.]
- Published
- 2017
41. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance
- Author
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Sarit Assouline, Dong-Wook Kim, Vikram Mathews, Jie Jin, Zhi Xiang Shen, Edo Vellenga, H. Jean Khoury, Ricardo Pasquini, Andrey Zaritskey, Hagop M. Kantarjian, Simon Durrant, Tim H. Brümmendorf, Jorge E. Cortes, Anna G. Turkina, Francisco Cervantes, Carlo Gambacorti-Passerini, Kathleen Turnbull, Eric Leip, Tamas Masszi, Virginia Kelly, Nadine Besson, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), GAMBACORTI PASSERINI, C, Brümmendorf, T, Kim, D, Turkina, A, Masszi, T, Assouline, S, Durrant, S, Kantarjian, H, Khoury, H, Zaritskey, A, Shen, Z, Jin, J, Vellenga, E, Pasquini, R, Mathews, V, Cervantes, F, Besson, N, Turnbull, K, Leip, E, Kelly, V, and Cortes, J
- Subjects
Male ,DIAGNOSED CHRONIC-PHASE ,NILOTINIB ,DURABLE CYTOGENETIC RESPONSES ,Gastroenterology ,Piperazines ,hemic and lymphatic diseases ,Aged, 80 and over ,DASATINIB ,Hematology ,Aniline Compounds ,CHRONIC MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,Middle Aged ,Dasatinib ,Treatment Outcome ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Quinolines ,Female ,TRIAL ,Bosutinib ,Complete Hematologic Response ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,ABL ,INHIBITION ,Antineoplastic Agents ,chronic myeloid leukemia CML ,Disease-Free Survival ,Young Adult ,Internal medicine ,Nitriles ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Imatinib ,Original Articles ,medicine.disease ,THERAPY FAILURE ,Surgery ,Pyrimidines ,Nilotinib ,Drug Resistance, Neoplasm ,SKI-606 ,business ,Chronic myelogenous leukemia ,Follow-Up Studies - Abstract
Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. http://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00261846","term_id":"NCT00261846"}}NCT00261846. Am. J. Hematol. 89:732–742, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.
- Published
- 2014
42. Primary Results of the Phase 4 BYOND Study of Bosutinib for Pretreated Chronic Phase (CP) Chronic Myeloid Leukemia (CML)
- Author
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Justin M. Watts, Camille N. Abboud, B. Douglas Smith, Jocelyn M Leone, Andreas Hochhaus, Gianantonio Rosti, Frank Giles, Susanne Saussele, Ulla Strömberg, Bjørn Tore Gjertsen, Andrea Viqueira, Carlo Gambacorti-Passerini, Pilar Giraldo-Castellano, Nathalie Bardy-Bouxin, Tim H. Brümmendorf, and Eric Leip
- Subjects
Cancer Research ,Primary (chemistry) ,Oncology ,business.industry ,Phase (matter) ,Cancer research ,medicine ,Myeloid leukemia ,Hematology ,business ,Bosutinib ,medicine.drug - Published
- 2019
43. PS1176 PRIMARY RESULTS OF THE PHASE 4 BYOND STUDY OF BOSUTINIB FOR PRETREATED CHRONIC PHASE CHRONIC MYELOID LEUKEMIA
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F. Giles, C. Gambacorti-Passerini, Eric Leip, U. Strömberg, B.D. Smith, A. Hochhaus, C. Abboud, S. Saussele, B.T. Gjertsen, P. Giraldo-Castellano, Tim H. Brümmendorf, Andrea Viqueira, J.M. Leone, G. Rosti, J. Watts, and N. Bardy-Bouxin
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business.industry ,Phase (matter) ,Cancer research ,Medicine ,Hematology ,Chronic phase chronic myeloid leukemia ,business ,Bosutinib ,medicine.drug - Published
- 2019
44. PF413 CARDIAC, VASCULAR, AND HYPERTENSION SAFETY OF BOSUTINIB VS IMATINIB FOR NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA IN THE BFORE TRIAL
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C. Gambacorti-Passerini, Eric Leip, Andrea Viqueira, M. Deininger, Vamsi Kota, R. Clark, J. E. Cortes, and Tim H. Brümmendorf
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Myeloid leukemia ,Imatinib ,Hematology ,Newly diagnosed ,business ,Bosutinib ,medicine.drug - Published
- 2019
45. Cardiac, vascular, and hypertension safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the BFORE trial
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Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Michael W. Deininger, Eric Leip, Vamsi Kota, Jorge E. Cortes, Richard E. Clark, and Andrea Viqueira
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Myeloid leukemia ,Imatinib ,Newly diagnosed ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,business ,Adverse effect ,Bosutinib ,030215 immunology ,medicine.drug - Abstract
7051 Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients (pts) who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/d in the phase 3 BFORE trial were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure-adjusted TEAE rate was defined as the number of pts with TEAEs / total pt-yr (pt-yr = sum of total time to first TEAE for pts with TEAEs and treatment duration for pts without TEAEs). Results: After ≥36 mo follow-up, 65% vs 62% of pts in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals and drug-related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%) and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%) and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3% and 4% vs 1%, 0.4% and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of pts in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs, respectively, were 0.04, 0.03 and 0.04 vs 0.03, 0.01 and 0.04 (grade 3/4/5 only: 0.01, 0.01 and 0.02 vs 0.01, 0.002 and 0.02) for bosutinib vs imatinib. Conclusions: Cardiac, vascular and hypertension TEAE rates were low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. Clinical trial information: NCT02130557. [Table: see text]
- Published
- 2019
46. Bosutinib or Imatinib in Older Vs Younger Patients with Newly Diagnosed Chronic Myeloid Leukemia in the Phase 3 BFORE Trial
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Tim H. Brümmendorf, Michael W. Deininger, Dragana Milojkovic, Sonja Nick, Vamsi Kota, Jorge E. Cortes, Valentín García Gutiérrez, Andreas Hochhaus, Eric Leip, Jeffrey H. Lipton, and Carlo Gambacorti-Passerini
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Hazard ratio ,Imatinib ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Discontinuation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Clinical endpoint ,Medicine ,business ,Adverse effect ,Bosutinib ,medicine.drug - Abstract
Introduction: Bosutinib is approved for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) and CML resistant or intolerant to prior therapy. Efficacy and safety of first-line bosutinib and imatinib were assessed in older vs younger patients in the ongoing phase 3 BFORE trial (NCT02130557). Methods: In all, 536 patients were randomized 1:1 to receive bosutinib or imatinib (400 mg once daily). We compared outcomes in patients aged ≥65 years (older group) vs Results: In the bosutinib arm (n=268), 53 were older and 215 were younger patients. In the imatinib arm (n=268; 3 untreated), 48 (2 untreated) were older and 220 (1 untreated) were younger patients. Sokal risk scores were balanced between treatment arms but higher in the overall older (8.9% low, 70.3% intermediate, 20.8% high) vs younger (44.1% low, 34.7% intermediate, 21.1% high) populations, reflecting that age is part of the score. Bosutinib was discontinued in 32.1% of older and 28.4% of younger patients; the most common primary reason was treatment-related adverse events (AEs; 18.9% and 15.3%, respectively). Imatinib was discontinued in 32.6% of older and 33.8% of younger patients, most frequently due to suboptimal response or treatment failure (13.0% and 13.2%, respectively). The percentage of patients who discontinued treatment due to treatment-emergent AEs (TEAEs) was similar in the older vs younger group in both arms (bosutinib: 22.6% vs 19.1%; imatinib: 8.7% vs 12.3%). In older vs younger patients, median (range) duration of treatment was similar: 24.8 months (0.3-33.3) vs 24.9 months (0.3-33.5) for bosutinib and 25.6 months (2.9-33.1) vs 24.5 months (0.7-33.4) for imatinib. Median relative dose intensity was slightly lower in older vs younger patients in the bosutinib arm (92.8% vs 99.3%) but was 100% in both age groups in the imatinib arm. The difference in rates of major molecular response (MMR) at 12 months (primary endpoint) with bosutinib vs imatinib was consistent across age groups (older: 43.4% vs 35.4%; younger: 47.4% vs 36.4%; P=0.7879 for test of interaction), as was the difference in rates of CCyR by 12 months (older: 68.8% vs 69.0%; younger: 79.3% vs 65.8%; P=0.1689). MR rates at 24 months (and MR1 at 3 months) were generally similar in older vs younger patients within each arm and higher with bosutinib than with imatinib (Table 1). Time to achieve MMR on bosutinib was not different in older vs younger patients (hazard ratio: 1.227; P=0.2380, after adjustment for baseline and time-dependent covariates in a multivariable proportional subdistribution hazards model). Rates of common TEAEs in each treatment arm were similar ( Conclusions: In the phase 3 BFORE trial, bosutinib showed clinical activity in older and younger patients with newly diagnosed CP CML. Difference in rates of MMR at 12 months for bosutinib vs imatinib was consistent in older and younger patients. MR rates at 24 months were similar in older and younger patients and higher with bosutinib than with imatinib. Although the incidence of grade 3/4 TEAEs, serious TEAEs, and dose modifications due to TEAEs were higher in older vs younger bosutinib-treated patients, treatment discontinuation rates were similar between age groups, suggesting that, regardless of patient age, TEAEs were manageable with bosutinib. Disclosures Deininger: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Kota:Pfizer: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Lipton:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Hochhaus:Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Cortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Brummendorf:Merck: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding.
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- 2018
47. Efficacy and Safety Following Dose Reduction of Bosutinib or Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia: Analysis of the Phase 3 BFORE Trial
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Jeffrey H. Lipton, Andrea Viqueira, Eric Leip, Michael W. Deininger, Vamsi Kota, Jorge E. Cortes, Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Roxanne Ferdinand, and Andreas Hochhaus
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Discontinuation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Imatinib mesylate ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Dose Reduced ,Adverse effect ,Bosutinib ,medicine.drug - Abstract
Introduction: Bosutinib, an oral dual Src/Abl tyrosine kinase inhibitor (TKI) is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), at a starting dose of 400 once daily (QD) in newly diagnosed patients in chronic phase (CP). Approval of first-line bosutinib was based on results from the phase 3 BFORE trial, which showed improved efficacy outcomes with bosutinib vs imatinib in this patient population. This analysis evaluated efficacy and safety of bosutinib and imatinib following dose reductions in adult patients with newly diagnosed CP CML. Methods: This retrospective analysis included data (≥24-month follow-up) from the ongoing, open-label, phase 3 BFORE trial (NCT02130557). In all, 536 patients were randomized 1:1 to bosutinib or imatinib at a starting dose of 400 mg QD. Doses could be reduced in 100 mg decrements for toxicity; dose reductions to Results: Of the 268 patients in the bosutinib arm, 80 dose-reduced to 300 mg only and 23 dose-reduced to 200 mg. The median (range) overall duration of bosutinib treatment for patients dose reduced to 300 mg was 24.3 months (1.4-33.5) and to 200 mg was 8.3 months (1.0-32.9) vs. 25.1 months (range: 0.26-33.2) for patients who remained on the 400 mg starting dose. Median (range) time to bosutinib dose reduction to 300 mg was 83 days (18-793) and to 200 mg was 121 days (29-882); respective median (range) duration on reduced dose was 138.5 days (1-957) and 28 days (3-463). Of the 268 (3 untreated) patients in the imatinib arm, 44 dose-reduced to 300 mg. The median duration of imatinib treatment for patients dose reduced to 300 mg was 22.4 months (range: 1.2-33.0) vs. 24.8 months (range: 0.7-33.4) for patients who remained on 400 mg. Median time to imatinib dose reduction to 300 mg was 85.0 days (range: 15-687); median duration on reduced dose was 99.0 days (range: 2-787). TEAEs leading to dose reduction in ≥10 patients were alanine aminotransferase increased and/or aspartate aminotransferase increased (n=21), thrombocytopenia (n=19), lipase increased (n=15) and diarrhea (n=11) with bosutinib, and neutropenia (n=11) with imatinib. The most common reason for treatment discontinuation in patients who dose-reduced was a TEAE related to bosutinib (300 mg: 22.5%; 200 mg: 52.2%) or imatinib (300 mg: 27.3%). Among patients who dose-reduced to 300 mg, 16 (20%) had a major molecular response (MMR) with bosutinib before and after reduction; an additional 36 (45%) achieved MMR for the first time after dose reduction. In the imatinib arm, 7 (15.9%) had an MMR before and after reduction; an additional 22 (50%) achieved MMR for the first time after dose reduction (Table 1). 1 (1.3%) patient lost a previously attained MMR following bosutinib dose reduction to 300 mg. Among patients who dose-reduced to 200 mg bosutinib, 4 (17.4%) had an MMR before and after reduction, and an additional 4 (17.4%) achieved MMR for the first time after dose reduction. Similar trends were seen for complete cytogenetic response (CCyR) before and after dose reduction (Table 1). Among patients who remained on 400 mg, 123/165 (74.5%) had a MMR with bosutinib; 131/152 (86.2%) achieved CCyR. In the imatinib arm, 130/219 (59.4%) had a MMR and 159/198 (80.3%) achieved CCyR. The majority of TEAEs decreased in incidence with dose reduction (Table 2). Following bosutinib dose reduction to 300 mg or to 200 mg decreases >10% were seen in the incidence of diarrhea and nausea; with a decrease for rash following dose reduction to bosutinib 200 mg. Decreases (>10%) were noted for nausea following dose reduction to 300 mg imatinib. Conclusions: Management of TEAEs through bosutinib dose reduction to 300 mg or 200 mg improved tolerability in patients with newly diagnosed CP CML. These reductions in TEAEs enabled patients to continue bosutinib treatment, with a substantial number of patients achieving MMR and CCyR for the first time after dose reduction. Findings were similar for patients who dose-reduced to 300 mg imatinib. Disclosures Brummendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kota:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Ferdinand:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.
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- 2018
48. An Indirect Comparison between Bosutinib, Nilotinib and Dasatinib in First-Line Chronic Phase Chronic Myeloid Leukemia
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Carla Mamolo, Eric Leip, Andrea Viqueira, Bart Heeg, Rocco J. Crescenzo, B. Muresan, and Joseph C. Cappelleri
- Subjects
education.field_of_study ,medicine.medical_specialty ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,Biochemistry ,Confidence interval ,law.invention ,Clinical research ,Randomized controlled trial ,Nilotinib ,law ,Sample size determination ,Statistical significance ,Internal medicine ,Medicine ,business ,education ,Bosutinib ,medicine.drug - Abstract
Introduction Several randomized controlled trials (RCTs) compare second generation tyrosine kinase inhibitors (TKIs) with imatinib (IM) for the first-line (1L) treatment of chronic phase chronic myeloid leukemia (CP-CML). However, an examination indicated cross-trial heterogeneity in terms of disease and patient characteristics (baseline risk score, age, trial region, and post-baseline IM dose escalation) and outcomes reported (type and time of evaluation). For this reason, a matching adjusted indirect treatment comparison (MAIC) can be used to assess comparative efficacy. The objective of this study was to compare the efficacy of bosutinib (BOS) with nilotinib (NIL) and dasatinib (DAS) in 1L CP-CML via unanchored MAICs. Methods As well as heterogeneity in baseline characteristics, differences in the amount of IM dose escalations in earlier clinical pivotal trials (ENESTnd: 15.9% at 12 months; DASISION 20% at 24 months) relative to more recent ones (BFORE: 27.5% and 30.9% at 12 and 24 months, respectively) were observed. Because differences in IM dose-escalation regimens are trial design matters, they cannot be adjusted for using anchored MAICs. Therefore, an unanchored MAIC (which dismisses the common comparator arm, in this case IM) was used. Unanchored MAICs comparing BOS with NIL and DAS were performed to match the summary statistics in the BFORE trial to the reported summary statistics in the ENESTnd (NIL) and the DASISION (DAS) trials. Outcomes assessed included major molecular response (MMR) at 12 months and at any time after 12 months, complete cytogenetic response (CCyR) by 12 months, and deep molecular response (MR4) at 12 months. Statistical significance was assessed based on confidence intervals (CI; significant when CI excludes 1). The sample size of the matching-adjusted BOS population was estimated using the effective sample size (ESS). No adjustments for multiple comparisons were made. Results The MAICs showed an MMR at 12 months of 49.32% (vs 47.13% before the MAIC, N=244, ESS=186) for BOS vs 44% for NIL (OR 1.24, 95% CI [0.87-1.77], N=282) and an MMR at any time of 58.09% (vs 57.79% before MAIC, N=244, ESS=142) for BOS vs 57% for NIL (OR 1.05, 95% CI [0.72-1.5], N=282), and 58.52% (vs 58.16% before MAIC, N=239, ESS=192) for BOS vs 52% for DAS (OR 1.3, 95% CI [0.9-1.88], N=259). BOS had a CCyR by 12 months of 82.59% (vs 82.38% before MAIC, N=244) vs 80% for NIL (OR 1.19, 95% CI [0.75-1.87], N=282, ESS=195) and 80.47% (vs 82.01% before MAIC, N=239, ESS=185) vs 83% for DAS (OR 0.84, 95% CI [0.53-1.35], N=259). MR4 at 12 months was 20.34% (vs 20.49% before MAIC, N=244, ESS=185) for BOS vs 12% for NIL (OR 1.87, 95% CI [1.15-3.05], N=282). MMR and MR4 at month 12 were not reported for DAS. Discussion The general MAIC limitations (impact of having access to only marginal covariate distribution, choice of scale for indirect comparisons, choice of target population and sampling variation in the target population) apply to our analyses as well. Nevertheless, indirect comparisons using unanchored MAICs were conducted because cross-trial heterogeneity in patient baseline characteristics could bias the results of a naïve comparison and increases in IM dose escalation over time could bias the results of an anchored MAIC. The unanchored MAICs indicated that BOS was numerically higher than NIL for all response rates examined, however, except for MR4, none were statistically significant. BOS had a numerically higher MMR at any time and a numerically lower CCyR by 12 months compared with DAS, however, neither were statistically significant. BOS therefore seems to be an equally effective TKI as NIL and DAS in the 1L CP-CML setting. These findings, based on statistical methods, should be confirmed by clinical research. Disclosures Muresan: Ingress-health Nederland BV: Employment. Mamolo:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Crescenzo:Pfizer: Employment. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding.
- Published
- 2018
49. Efficacy and safety of bosutinib vs imatinib in Indian and non-Indian patients with newly diagnosed chronic phase chronic myeloid leukemia: Subgroup analysis from the BELA trial
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Hemant Malhotra, M. V. Ramanan, Eric Leip, Rocco J. Crescenzo, A. Maru, Jorge E. Cortes, Navin Khattry, and Carlo Gambacorti-Passerini
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Oncology ,medicine.medical_specialty ,business.industry ,Subgroup analysis ,Imatinib ,Hematology ,Newly diagnosed ,Chronic phase chronic myeloid leukemia ,Internal medicine ,medicine ,business ,Bosutinib ,medicine.drug - Published
- 2018
50. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib
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Jorge E, Cortes, H, Jean Khoury, Hagop, Kantarjian, Tim H, Brümmendorf, Michael J, Mauro, Ewa, Matczak, Dmitri, Pavlov, Jean M, Aguiar, Kolette D, Fly, Svetoslav, Dimitrov, Eric, Leip, Mark, Shapiro, Jeff H, Lipton, Jean-Bernard, Durand, Carlo, Gambacorti-Passerini, Cortes, J, Jean Khoury, H, Kantarjian, H, Brümmendorf, T, Mauro, M, Matczak, E, Pavlov, D, Aguiar, J, Fly, K, Dimitrov, S, Leip, E, Shapiro, M, Lipton, J, Durand, J, and GAMBACORTI PASSERINI, C
- Subjects
Adult ,Aged, 80 and over ,Male ,Aniline Compounds ,Adolescent ,Hypercholesterolemia ,Age Factors ,Hyperlipidemias ,Middle Aged ,Cardiotoxicity ,Article ,Young Adult ,Risk Factors ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Nitriles ,Imatinib Mesylate ,Quinolines ,Humans ,Female ,Vascular Diseases ,Protein Kinase Inhibitors ,Hematology, TKI , Ph+ leukemia ,Aged ,Retrospective Studies - Abstract
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
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