JNJ-74856665(二氢酸脱氢酶抑制剂)单独或联合用于AML或MDS患者的1期临床试验。

IF 3.8 2区 医学 Q1 HEMATOLOGY
Emma Searle, Thomas Cluzeau, Jenny O'Nions, Christian Recher, Emmanuel Gyan, Daniel Morillo, Jordi Esteve, Austin Kulasekararaj, Emmanuel Raffoux, Harriet S. Walter, Arnaud Pigneux, David Valcárcel, Nikki Daskalakis, Jacqueline Bussolari, E. Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo, Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy, Wim van Dijck, Ana Alfonso Piérola
{"title":"JNJ-74856665(二氢酸脱氢酶抑制剂)单独或联合用于AML或MDS患者的1期临床试验。","authors":"Emma Searle,&nbsp;Thomas Cluzeau,&nbsp;Jenny O'Nions,&nbsp;Christian Recher,&nbsp;Emmanuel Gyan,&nbsp;Daniel Morillo,&nbsp;Jordi Esteve,&nbsp;Austin Kulasekararaj,&nbsp;Emmanuel Raffoux,&nbsp;Harriet S. Walter,&nbsp;Arnaud Pigneux,&nbsp;David Valcárcel,&nbsp;Nikki Daskalakis,&nbsp;Jacqueline Bussolari,&nbsp;E. Christine Pietsch,&nbsp;Scott Kuduk,&nbsp;Tammy Bush,&nbsp;Xiaochun Zhang,&nbsp;Ulrike Philippar,&nbsp;Adetokunbo Oluwasanjo,&nbsp;Kathryn Bradford,&nbsp;Jonathan Miller,&nbsp;Charlotte Van Bogaert,&nbsp;Martin Curtis,&nbsp;Shih-Yu Chang,&nbsp;Christina Guttke,&nbsp;Stan Gaj,&nbsp;Rachel Pearson,&nbsp;Joseph Murphy,&nbsp;Wim van Dijck,&nbsp;Ana Alfonso Piérola","doi":"10.1111/bjh.20224","DOIUrl":null,"url":null,"abstract":"<p>JNJ-74856665 is an orally bioavailable, potent and selective dihydroorotate dehydrogenase inhibitor (DHODHi) designed to induce myeloid differentiation and eliminate undifferentiated leukaemia blasts and stem cells.<span><sup>1, 2</sup></span> JNJ-74856665 binding to DHODH promotes myeloblast differentiation, cell cycle arrest and apoptosis. Herein, we detail preclinical studies and a first-in-human, open-label, dose-escalation, dose-expansion, phase 1 study of JNJ-74856665, administered alone or in combination with azacitidine (AZA) or venetoclax (VEN) (Figure S1).</p><p>Primary clinical trial objectives were to determine maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D[s]) and to evaluate safety and tolerability. Eligible patients (i.e. ≥18 years old with newly diagnosed acute myeloid leukaemia [AML]/myelodysplastic syndromes (MDS),<span><sup>3</sup></span> relapsed/refractory [R/R] AML,<span><sup>4</sup></span> R/R MDS<span><sup>4, 5</sup></span> or R/R chronic myelomonocytic leukaemia group 2<span><sup>4</sup></span> [CMML-2; Table S1]) were enrolled into one of two JNJ-74856665 monotherapy arms (mono-R/R or mono-LR) or one of two combination arms (JNJ+AZA or JNJ+VEN). Detailed methods and results for both the preclinical and clinical studies are in the Supporting Information.</p><p>Clinical trial enrolment included 153 patients (218 screened): 84 in mono-R/R, 35 in JNJ+AZA, 29 in JNJ+VEN and 5 in mono-LR (Table 1; Tables S3–S5; Figure S6). At data cut-off, 46 patients remained on study (26 on treatment). Median (range) duration of JNJ-74856665 treatment was 52 (3–442) days, and number of treatment cycles was 3 (range, 1–22) for mono-R/R, 7 (2–15) for mono-LR, 2 (1–13) for JNJ+AZA and 2 (1–7) for JNJ+VEN.</p><p>Dose escalation was stopped based on limited clinical activity after reviewing available safety, pharmacokinetic/pharmacodynamic and efficacy data. MTD was not reached, and RP2D was not established.</p><p>Most (97.4%) patients experienced ≥1 treatment-emergent adverse event (TEAE), 64.7% of which were considered JNJ-74856665 related by investigators (Table S6). The most common TEAEs were stomatitis (48.8%; all JNJ-74856665 related), diarrhoea (32.1%; 17.9% JNJ-74856665 related), anaemia (31%) and asthenia (25%) in the mono-R/R arm; mouth ulceration (40%) in the mono-LR arm; thrombocytopenia and vomiting (42.9% each), diarrhoea (37.1%), nausea (34.3%), anaemia and constipation (31.4% each) and stomatitis (20.0%; 17.1% JNJ-74856665 related) with JNJ+AZA; and diarrhoea (27.6%), neutropenia (27.6%) and stomatitis (13.8%) with JNJ+VEN. TEAEs in ≥10% of patients are in Table 2. In the mono-R/R, JNJ+AZA and JNJ+VEN arms, 82.1%, 94.3% and 86.2% of patients, respectively, experienced Grade ≥3 TEAEs (JNJ-74856665 related in 34.5%, 31.4% and 27.6% of patients) (Table S6). Furthermore, 72.6%, 71.4% and 75.9% of patients, respectively, experienced SAEs (JNJ-74856665 related in 19.0%, 17.1% and 13.8%) (Table S7).</p><p>DLTs (Table S8) due to mucositis occurred in 14.3% of patients in the mono-R/R arm (stomatitis, 13.1%; anal inflammation, 1.2%; and vulvovaginal inflammation, 1.2%). With JNJ+AZA, 11.4% of patients experienced DLTs, most commonly maculopapular rash (5.7%). With JNJ+VEN, 13.8% of patients experienced DLTs, including stomatitis (10.3%). No DLTs occurred in the mono-LR arm. Mucositis and diarrhoea of any grade were considered AEs of special interest. Overall, 33.3% of patients experienced ≥1 JNJ-74856665-related TEAE of mucositis (DLTs, 9.2%), which included anal inflammation, glossitis, mucosal inflammation, pharyngeal inflammation, stomatitis and vulvovaginal inflammation (Table S9). Median (range) mucositis onset across treatment arms was 23 (1–358) days, and most events were Grade 2 (45.1%) or 3 (33.3%). Grade ≥2 mucositis was observed in 60.0%, 30.4% and 13.6% of patients treated with &gt;5, 2.6–5 and &lt;2.6 mg JNJ-74856665, respectively (Table S10). Overall, 17.6% of patients experienced JNJ-74856665-related diarrhoea (no DLTs). Median (range) diarrhoea onset across treatment arms was 35.5 (1–132) days, and most events were Grade ≤2 (88.9%).</p><p>ORR for the mono-R/R arm was 4.8% (4/84; Figure S7). For AML, ORR was 1.5% (1/66; best overall response [bOR] of complete response with incomplete haematological recovery [CRi])—2 (3%) additional patients achieved a bOR of morphologic leukaemia-free state (MLFS) and 3 (4.5%) achieved a bOR of stable disease (SD). For MDS, ORR was 16.7% (3/18; all bOR of marrow CR [mCR])—3 (16.7%) additional patients had a bOR of SD. In the mono-LR arm, ORR was 20% (1/5; bOR of mCR)—an additional patient (20%) had a bOR of SD. With JNJ+AZA, ORR was 8.6% (3/35) (AML, 10% [2/20 (both bOR of CRi) plus 2 MLFS and 4 SD]; MDS, 7.1% [1/14 (bOR of mCR) plus 1 SD]; CMML-2, 0% [0/1]). With JNJ+VEN, ORR was 3.4% (1/29) (AML, 4.2% [1/24 (bOR of CR without minimal residual disease or minimal residual disease-negative)] plus 1 SD; MDS, 0% [0/5]).</p><p>Increased plasma DHO concentrations were observed following JNJ-74856665 treatment across treatment arms and disease states (Figure S8). Trends towards lower fold change in DHO concentrations were observed with JNJ-74856665 combination therapy versus monotherapy, and towards higher concentrations of DHO in patients with versus without stomatitis (any grade).</p><p>Clinical development of JNJ-74856665 was driven by single-agent, preclinical activity showing significant dose-dependent increase in survival and tumour growth inhibition in xenograft models at doses of 0.062–0.25 mg/kg, and significant increased life span occurred with JNJ-74856665, JNJ+AZA and JNJ+VEN, and with JNJ+AZA versus AZA or VEN alone. Biological activity of JNJ-74856665 starting at the lowest administered dose (0.3 mg daily) was confirmed in the phase 1 study. Most frequent toxicity with JNJ-74856665 was mucositis at all dose levels in a dose-dependent manner. Planned drug holidays helped reduce incidence and mitigate severity of stomatitis but also may have affected efficacy. Limited clinical activity was observed, and dose escalation was extensively constrained by dose-dependent toxicity, particularly mucositis, leading to early enrolment stop. In a responder analysis (Supporting Information), responses were seen across treatment arms; however, a common predictor of response was not identified among the limited number of responders, and no additive or synergistic effects of combination therapy were observed clinically. DHO plasma concentrations increased after treatment, providing evidence of target engagement. Whether full, uninterrupted inhibition of DHODH led to improved outcomes in patients with AML and MDS is unknown. While efficacy was limited, observed target engagement and transient limited responses support the potential for clinical activity with DHODHi, as monotherapy or in combination with other agents. Approaches to minimise dose interruptions, mitigate mucositis and identify predictor-of-response biomarkers could aid further development of DHODHi in these populations.</p><p>All authors participated in the research. Kathryn Bradford (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) conceived and designed the research study. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter, Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Ulrike Philippar (preclinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Ana Alfonso Piérola supervised the research. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter and Emmanuel Gyan acquired the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Stan Gaj (preclinical study; clinical study biomarker data), E. Christine Pietsch (preclinical study), Xiaochun Zhang (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) analysed and interpreted the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Rachel Pearson (statistician, clinical study) wrote the manuscript, and all authors critically reviewed and/or revised the manuscript.</p><p>Emma Searle reports consulting fees from Sanofi, BMS, Johnson &amp; Johnson, Syndax, Cellcentric, Sumitomo, Beigene &amp; Pfizer; meeting and/or travel support from Johnson &amp; Johnson, Abbvie, Beigene, and Menarini Stemline; payment or honoraria from Astellas, Jazz Pharma, Johnson &amp; Johnson, Abbvie &amp; Pfizer; participation on a data safety monitoring board or advisory board for Dark Blue Therapeutics, Sanofi, BMS, Johnson &amp;Johnson, Syndax, Pfizer and Sumitomo; and leadership or fiduciary role (unpaid) with British Society of Haematology Research and Grants (Committee Chair) and ECMC Haematology Network Group (Deputy Chair). Thomas Cluzeau reports consulting fees from Abbvie, Jazz Pharma, Novartis, Agios, Servier, BluePrint and BMS; payment or honoraria from Novartis, Astellas, BMS, Jazz Pharma, Servier, and Incyte; meeting and/or travel support from Pfizer, BMS, Novartis, Abbvie, Servier, Gilead; and participation on a data safety monitoring board or advisory board for BMS, Novartis and KEROS. Jenny O'Nions reports payment or honoraria from Jazz and Astellas; meeting and/or travel support from Janssen, Abbvie, Servier and Jazz; and participation on a data safety monitoring board or advisory board for Abbvie. Christian Recher reports grants or contracts from Abbvie, Astellas, BMS, Jazz Pharma and Iqvia; payment or honoraria from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; meeting and/or travel support from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; and participation on a data safety monitoring board or advisory board for Abbvie, Astellas, BMS, Jazz Pharma, Novartis, Servier and Takeda. Emmanuel Gyan reports grants or contracts from Novartis; consulting fees from Janssen, Sanofi, Abbvie and Incyte; payment or honoraria from Gilead and Roche; meeting and/or travel support from Roche; and receipt of equipment, materials, drugs, medical writing, gifts or other services from BMS and Sandoz. Daniel Morillo reports payment or honoraria from Abbvie and GSK; and meeting and/or travel support from Roche, Janssen and Kite. Jordi Esteve reports grants or contracts (to CETLAM cooperative group) from Jazz and Pfizer; payment or honoraria from Abbvie and Jazz; and meeting and/or travel support from Abbvie. Austin Kulasekararaj reports consulting fees from Novartis, SOBI, Alexion/AstraZeneca, Novartis and Roche; payment or honoraria from Celgene/BMS, Novartis, SOBI, Alexion/AstraZeneca, Roche, Samsung, and Amgen; meeting and/or travel support from SOBI and Alexion/AstraZeneca; and participation on a data safety monitoring board or advisory board for Agious, Roche and Biocryst. Emmanuel Raffoux reports consulting fees from Servier and BMS; and payment or honoraria from Servier, BMS and Astellas. Harriet Walter reports research funding paid by Janssen to institutions; medical education grant from Pfizer and research funding from Isogenica and Gilead; payment or honoraria from Abbvie; and participation on a data safety monitoring board or advisory board for Beigene, Eli Lilly and Genmab. Arnaud Pigneux has nothing to report. David Valcárcel reports consulting fees from Amgen, BMS/Celgene, Kite/Gilead, Novartis, SOBI, Astellas, Jazz, MSD and Sanofi; payment or honoraria from Amgen, BMS/Celgene, Grifols, Jazz, MSD, Pfizer, SOBI, Astellas, GEBRO, Janssen, Kite/Gilead, Novartis, Sanofi and Agios; meeting and/or travel support from BMS/Celgene, Jazz, SOBI, Novartis and Sanofi; and participation on a data safety monitoring board or advisory board for Novartis, SOBI, BMS/Celgene, Jazz, Servier, Amgen and Grifols. Nikki Daskalakis, Jacqueline Bussolari, E. Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo (at time of study conduct), Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy and Wim van Dijck are employees of Janssen and may hold company stock in the company. E. Christine Pietsch and Christina Guttke also report patents planned, issued or pending, and Ulrike Philippar also reports a leadership or fiduciary role with J&amp;J Belgium (Board of Directors). Ana Alfonso Piérola reports grants or contracts from AstraZeneca; consulting fees from Jazz Pharmaceuticals and Astellas; payment or honoraria from Novartis, BMS, Jazz Pharmaceuticals, Astellas and Abbvie; and meeting and/or travel support from Kite, BMS and Novartis.</p>","PeriodicalId":135,"journal":{"name":"British Journal of Haematology","volume":"207 2","pages":"624-630"},"PeriodicalIF":3.8000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.20224","citationCount":"0","resultStr":"{\"title\":\"A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS\",\"authors\":\"Emma Searle,&nbsp;Thomas Cluzeau,&nbsp;Jenny O'Nions,&nbsp;Christian Recher,&nbsp;Emmanuel Gyan,&nbsp;Daniel Morillo,&nbsp;Jordi Esteve,&nbsp;Austin Kulasekararaj,&nbsp;Emmanuel Raffoux,&nbsp;Harriet S. Walter,&nbsp;Arnaud Pigneux,&nbsp;David Valcárcel,&nbsp;Nikki Daskalakis,&nbsp;Jacqueline Bussolari,&nbsp;E. Christine Pietsch,&nbsp;Scott Kuduk,&nbsp;Tammy Bush,&nbsp;Xiaochun Zhang,&nbsp;Ulrike Philippar,&nbsp;Adetokunbo Oluwasanjo,&nbsp;Kathryn Bradford,&nbsp;Jonathan Miller,&nbsp;Charlotte Van Bogaert,&nbsp;Martin Curtis,&nbsp;Shih-Yu Chang,&nbsp;Christina Guttke,&nbsp;Stan Gaj,&nbsp;Rachel Pearson,&nbsp;Joseph Murphy,&nbsp;Wim van Dijck,&nbsp;Ana Alfonso Piérola\",\"doi\":\"10.1111/bjh.20224\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>JNJ-74856665 is an orally bioavailable, potent and selective dihydroorotate dehydrogenase inhibitor (DHODHi) designed to induce myeloid differentiation and eliminate undifferentiated leukaemia blasts and stem cells.<span><sup>1, 2</sup></span> JNJ-74856665 binding to DHODH promotes myeloblast differentiation, cell cycle arrest and apoptosis. Herein, we detail preclinical studies and a first-in-human, open-label, dose-escalation, dose-expansion, phase 1 study of JNJ-74856665, administered alone or in combination with azacitidine (AZA) or venetoclax (VEN) (Figure S1).</p><p>Primary clinical trial objectives were to determine maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D[s]) and to evaluate safety and tolerability. Eligible patients (i.e. ≥18 years old with newly diagnosed acute myeloid leukaemia [AML]/myelodysplastic syndromes (MDS),<span><sup>3</sup></span> relapsed/refractory [R/R] AML,<span><sup>4</sup></span> R/R MDS<span><sup>4, 5</sup></span> or R/R chronic myelomonocytic leukaemia group 2<span><sup>4</sup></span> [CMML-2; Table S1]) were enrolled into one of two JNJ-74856665 monotherapy arms (mono-R/R or mono-LR) or one of two combination arms (JNJ+AZA or JNJ+VEN). Detailed methods and results for both the preclinical and clinical studies are in the Supporting Information.</p><p>Clinical trial enrolment included 153 patients (218 screened): 84 in mono-R/R, 35 in JNJ+AZA, 29 in JNJ+VEN and 5 in mono-LR (Table 1; Tables S3–S5; Figure S6). At data cut-off, 46 patients remained on study (26 on treatment). Median (range) duration of JNJ-74856665 treatment was 52 (3–442) days, and number of treatment cycles was 3 (range, 1–22) for mono-R/R, 7 (2–15) for mono-LR, 2 (1–13) for JNJ+AZA and 2 (1–7) for JNJ+VEN.</p><p>Dose escalation was stopped based on limited clinical activity after reviewing available safety, pharmacokinetic/pharmacodynamic and efficacy data. MTD was not reached, and RP2D was not established.</p><p>Most (97.4%) patients experienced ≥1 treatment-emergent adverse event (TEAE), 64.7% of which were considered JNJ-74856665 related by investigators (Table S6). The most common TEAEs were stomatitis (48.8%; all JNJ-74856665 related), diarrhoea (32.1%; 17.9% JNJ-74856665 related), anaemia (31%) and asthenia (25%) in the mono-R/R arm; mouth ulceration (40%) in the mono-LR arm; thrombocytopenia and vomiting (42.9% each), diarrhoea (37.1%), nausea (34.3%), anaemia and constipation (31.4% each) and stomatitis (20.0%; 17.1% JNJ-74856665 related) with JNJ+AZA; and diarrhoea (27.6%), neutropenia (27.6%) and stomatitis (13.8%) with JNJ+VEN. TEAEs in ≥10% of patients are in Table 2. In the mono-R/R, JNJ+AZA and JNJ+VEN arms, 82.1%, 94.3% and 86.2% of patients, respectively, experienced Grade ≥3 TEAEs (JNJ-74856665 related in 34.5%, 31.4% and 27.6% of patients) (Table S6). Furthermore, 72.6%, 71.4% and 75.9% of patients, respectively, experienced SAEs (JNJ-74856665 related in 19.0%, 17.1% and 13.8%) (Table S7).</p><p>DLTs (Table S8) due to mucositis occurred in 14.3% of patients in the mono-R/R arm (stomatitis, 13.1%; anal inflammation, 1.2%; and vulvovaginal inflammation, 1.2%). With JNJ+AZA, 11.4% of patients experienced DLTs, most commonly maculopapular rash (5.7%). With JNJ+VEN, 13.8% of patients experienced DLTs, including stomatitis (10.3%). No DLTs occurred in the mono-LR arm. Mucositis and diarrhoea of any grade were considered AEs of special interest. Overall, 33.3% of patients experienced ≥1 JNJ-74856665-related TEAE of mucositis (DLTs, 9.2%), which included anal inflammation, glossitis, mucosal inflammation, pharyngeal inflammation, stomatitis and vulvovaginal inflammation (Table S9). Median (range) mucositis onset across treatment arms was 23 (1–358) days, and most events were Grade 2 (45.1%) or 3 (33.3%). Grade ≥2 mucositis was observed in 60.0%, 30.4% and 13.6% of patients treated with &gt;5, 2.6–5 and &lt;2.6 mg JNJ-74856665, respectively (Table S10). Overall, 17.6% of patients experienced JNJ-74856665-related diarrhoea (no DLTs). Median (range) diarrhoea onset across treatment arms was 35.5 (1–132) days, and most events were Grade ≤2 (88.9%).</p><p>ORR for the mono-R/R arm was 4.8% (4/84; Figure S7). For AML, ORR was 1.5% (1/66; best overall response [bOR] of complete response with incomplete haematological recovery [CRi])—2 (3%) additional patients achieved a bOR of morphologic leukaemia-free state (MLFS) and 3 (4.5%) achieved a bOR of stable disease (SD). For MDS, ORR was 16.7% (3/18; all bOR of marrow CR [mCR])—3 (16.7%) additional patients had a bOR of SD. In the mono-LR arm, ORR was 20% (1/5; bOR of mCR)—an additional patient (20%) had a bOR of SD. With JNJ+AZA, ORR was 8.6% (3/35) (AML, 10% [2/20 (both bOR of CRi) plus 2 MLFS and 4 SD]; MDS, 7.1% [1/14 (bOR of mCR) plus 1 SD]; CMML-2, 0% [0/1]). With JNJ+VEN, ORR was 3.4% (1/29) (AML, 4.2% [1/24 (bOR of CR without minimal residual disease or minimal residual disease-negative)] plus 1 SD; MDS, 0% [0/5]).</p><p>Increased plasma DHO concentrations were observed following JNJ-74856665 treatment across treatment arms and disease states (Figure S8). Trends towards lower fold change in DHO concentrations were observed with JNJ-74856665 combination therapy versus monotherapy, and towards higher concentrations of DHO in patients with versus without stomatitis (any grade).</p><p>Clinical development of JNJ-74856665 was driven by single-agent, preclinical activity showing significant dose-dependent increase in survival and tumour growth inhibition in xenograft models at doses of 0.062–0.25 mg/kg, and significant increased life span occurred with JNJ-74856665, JNJ+AZA and JNJ+VEN, and with JNJ+AZA versus AZA or VEN alone. Biological activity of JNJ-74856665 starting at the lowest administered dose (0.3 mg daily) was confirmed in the phase 1 study. Most frequent toxicity with JNJ-74856665 was mucositis at all dose levels in a dose-dependent manner. Planned drug holidays helped reduce incidence and mitigate severity of stomatitis but also may have affected efficacy. Limited clinical activity was observed, and dose escalation was extensively constrained by dose-dependent toxicity, particularly mucositis, leading to early enrolment stop. In a responder analysis (Supporting Information), responses were seen across treatment arms; however, a common predictor of response was not identified among the limited number of responders, and no additive or synergistic effects of combination therapy were observed clinically. DHO plasma concentrations increased after treatment, providing evidence of target engagement. Whether full, uninterrupted inhibition of DHODH led to improved outcomes in patients with AML and MDS is unknown. While efficacy was limited, observed target engagement and transient limited responses support the potential for clinical activity with DHODHi, as monotherapy or in combination with other agents. Approaches to minimise dose interruptions, mitigate mucositis and identify predictor-of-response biomarkers could aid further development of DHODHi in these populations.</p><p>All authors participated in the research. Kathryn Bradford (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) conceived and designed the research study. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter, Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Ulrike Philippar (preclinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Ana Alfonso Piérola supervised the research. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter and Emmanuel Gyan acquired the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Stan Gaj (preclinical study; clinical study biomarker data), E. Christine Pietsch (preclinical study), Xiaochun Zhang (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) analysed and interpreted the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Rachel Pearson (statistician, clinical study) wrote the manuscript, and all authors critically reviewed and/or revised the manuscript.</p><p>Emma Searle reports consulting fees from Sanofi, BMS, Johnson &amp; Johnson, Syndax, Cellcentric, Sumitomo, Beigene &amp; Pfizer; meeting and/or travel support from Johnson &amp; Johnson, Abbvie, Beigene, and Menarini Stemline; payment or honoraria from Astellas, Jazz Pharma, Johnson &amp; Johnson, Abbvie &amp; Pfizer; participation on a data safety monitoring board or advisory board for Dark Blue Therapeutics, Sanofi, BMS, Johnson &amp;Johnson, Syndax, Pfizer and Sumitomo; and leadership or fiduciary role (unpaid) with British Society of Haematology Research and Grants (Committee Chair) and ECMC Haematology Network Group (Deputy Chair). Thomas Cluzeau reports consulting fees from Abbvie, Jazz Pharma, Novartis, Agios, Servier, BluePrint and BMS; payment or honoraria from Novartis, Astellas, BMS, Jazz Pharma, Servier, and Incyte; meeting and/or travel support from Pfizer, BMS, Novartis, Abbvie, Servier, Gilead; and participation on a data safety monitoring board or advisory board for BMS, Novartis and KEROS. Jenny O'Nions reports payment or honoraria from Jazz and Astellas; meeting and/or travel support from Janssen, Abbvie, Servier and Jazz; and participation on a data safety monitoring board or advisory board for Abbvie. Christian Recher reports grants or contracts from Abbvie, Astellas, BMS, Jazz Pharma and Iqvia; payment or honoraria from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; meeting and/or travel support from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; and participation on a data safety monitoring board or advisory board for Abbvie, Astellas, BMS, Jazz Pharma, Novartis, Servier and Takeda. Emmanuel Gyan reports grants or contracts from Novartis; consulting fees from Janssen, Sanofi, Abbvie and Incyte; payment or honoraria from Gilead and Roche; meeting and/or travel support from Roche; and receipt of equipment, materials, drugs, medical writing, gifts or other services from BMS and Sandoz. Daniel Morillo reports payment or honoraria from Abbvie and GSK; and meeting and/or travel support from Roche, Janssen and Kite. Jordi Esteve reports grants or contracts (to CETLAM cooperative group) from Jazz and Pfizer; payment or honoraria from Abbvie and Jazz; and meeting and/or travel support from Abbvie. Austin Kulasekararaj reports consulting fees from Novartis, SOBI, Alexion/AstraZeneca, Novartis and Roche; payment or honoraria from Celgene/BMS, Novartis, SOBI, Alexion/AstraZeneca, Roche, Samsung, and Amgen; meeting and/or travel support from SOBI and Alexion/AstraZeneca; and participation on a data safety monitoring board or advisory board for Agious, Roche and Biocryst. Emmanuel Raffoux reports consulting fees from Servier and BMS; and payment or honoraria from Servier, BMS and Astellas. Harriet Walter reports research funding paid by Janssen to institutions; medical education grant from Pfizer and research funding from Isogenica and Gilead; payment or honoraria from Abbvie; and participation on a data safety monitoring board or advisory board for Beigene, Eli Lilly and Genmab. Arnaud Pigneux has nothing to report. David Valcárcel reports consulting fees from Amgen, BMS/Celgene, Kite/Gilead, Novartis, SOBI, Astellas, Jazz, MSD and Sanofi; payment or honoraria from Amgen, BMS/Celgene, Grifols, Jazz, MSD, Pfizer, SOBI, Astellas, GEBRO, Janssen, Kite/Gilead, Novartis, Sanofi and Agios; meeting and/or travel support from BMS/Celgene, Jazz, SOBI, Novartis and Sanofi; and participation on a data safety monitoring board or advisory board for Novartis, SOBI, BMS/Celgene, Jazz, Servier, Amgen and Grifols. Nikki Daskalakis, Jacqueline Bussolari, E. Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo (at time of study conduct), Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy and Wim van Dijck are employees of Janssen and may hold company stock in the company. E. Christine Pietsch and Christina Guttke also report patents planned, issued or pending, and Ulrike Philippar also reports a leadership or fiduciary role with J&amp;J Belgium (Board of Directors). Ana Alfonso Piérola reports grants or contracts from AstraZeneca; consulting fees from Jazz Pharmaceuticals and Astellas; payment or honoraria from Novartis, BMS, Jazz Pharmaceuticals, Astellas and Abbvie; and meeting and/or travel support from Kite, BMS and Novartis.</p>\",\"PeriodicalId\":135,\"journal\":{\"name\":\"British Journal of Haematology\",\"volume\":\"207 2\",\"pages\":\"624-630\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.20224\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Haematology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bjh.20224\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Haematology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bjh.20224","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

Christian Recher报告了来自艾伯维(Abbvie)、安斯泰来(Astellas)、BMS、Jazz Pharma和Iqvia的赠款或合同;来自艾伯维、安斯泰来、BMS、Jazz Pharma、诺华和施维雅的付款或酬金;来自艾伯维、安斯泰来、BMS、Jazz Pharma、诺华和施维雅的会议和/或差旅支持;并参与艾伯维、安斯泰来、BMS、Jazz Pharma、诺华、施维雅和武田的数据安全监测委员会或顾问委员会。伊曼纽尔·吉安报道诺华的拨款或合同;杨森、赛诺菲、艾伯维和Incyte的咨询费;来自吉利德和罗氏的报酬或酬金;罗氏公司的会议和/或差旅支持;以及接收BMS和山德士提供的设备、材料、药品、医疗文书、礼品或其他服务。Daniel Morillo报道了来自艾伯维和葛兰素史克的报酬或酬金;罗氏、杨森和凯特的会议和/或差旅支持。Jordi Esteve报告来自Jazz和Pfizer的赠款或合同(给CETLAM合作小组);艾伯维和爵士的报酬或酬金;艾伯维提供的会议和/或差旅支持。Austin Kulasekararaj报告了诺华、SOBI、Alexion/AstraZeneca、诺华和罗氏的咨询费;来自Celgene/BMS、Novartis、SOBI、Alexion/AstraZeneca、Roche、Samsung和Amgen的付款或酬金;来自SOBI和Alexion/AstraZeneca的会议和/或差旅支持;并参与Agious、Roche和Biocryst的数据安全监测委员会或顾问委员会。Emmanuel Raffoux报告了施维雅和BMS的咨询费;以及施维雅、BMS和安斯泰来的付款或酬金。哈里特·沃尔特报道了杨森向机构支付的研究经费;辉瑞(Pfizer)的医学教育资助以及Isogenica和Gilead的研究资助;艾伯维的报酬或酬金;并参与百济神州、礼来和Genmab的数据安全监测委员会或顾问委员会。Arnaud Pigneux没有什么可报道的。David Valcárcel报告了安进、BMS/Celgene、Kite/Gilead、诺华、SOBI、安斯泰来、Jazz、默沙东和赛诺菲的咨询费;来自安进、BMS/Celgene、Grifols、Jazz、默沙东、辉瑞、SOBI、安斯泰来、GEBRO、杨森、Kite/Gilead、诺华、赛诺菲和Agios的付款或酬金;BMS/Celgene、Jazz、SOBI、诺华和赛诺菲的会议和/或差旅支持;并参与Novartis、SOBI、BMS/Celgene、Jazz、Servier、Amgen和Grifols的数据安全监测委员会或顾问委员会。Nikki Daskalakis, Jacqueline Bussolari, E. Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo(研究进行时),Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy和Wim Van Dijck是杨森的员工,可能持有该公司的股票。E. Christine Pietsch和Christina Guttke也负责计划、发布或待批的专利,Ulrike Philippar还负责J&amp;J Belgium(董事会)的领导或受托人角色。Ana Alfonso pisamoora报道阿斯利康的拨款或合同;Jazz Pharmaceuticals和Astellas的咨询费;来自诺华、BMS、Jazz Pharmaceuticals、Astellas和Abbvie的付款或酬金;Kite、BMS和诺华的会议和/或旅行支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS

JNJ-74856665 is an orally bioavailable, potent and selective dihydroorotate dehydrogenase inhibitor (DHODHi) designed to induce myeloid differentiation and eliminate undifferentiated leukaemia blasts and stem cells.1, 2 JNJ-74856665 binding to DHODH promotes myeloblast differentiation, cell cycle arrest and apoptosis. Herein, we detail preclinical studies and a first-in-human, open-label, dose-escalation, dose-expansion, phase 1 study of JNJ-74856665, administered alone or in combination with azacitidine (AZA) or venetoclax (VEN) (Figure S1).

Primary clinical trial objectives were to determine maximum tolerated dose (MTD) and recommended phase 2 dose(s) (RP2D[s]) and to evaluate safety and tolerability. Eligible patients (i.e. ≥18 years old with newly diagnosed acute myeloid leukaemia [AML]/myelodysplastic syndromes (MDS),3 relapsed/refractory [R/R] AML,4 R/R MDS4, 5 or R/R chronic myelomonocytic leukaemia group 24 [CMML-2; Table S1]) were enrolled into one of two JNJ-74856665 monotherapy arms (mono-R/R or mono-LR) or one of two combination arms (JNJ+AZA or JNJ+VEN). Detailed methods and results for both the preclinical and clinical studies are in the Supporting Information.

Clinical trial enrolment included 153 patients (218 screened): 84 in mono-R/R, 35 in JNJ+AZA, 29 in JNJ+VEN and 5 in mono-LR (Table 1; Tables S3–S5; Figure S6). At data cut-off, 46 patients remained on study (26 on treatment). Median (range) duration of JNJ-74856665 treatment was 52 (3–442) days, and number of treatment cycles was 3 (range, 1–22) for mono-R/R, 7 (2–15) for mono-LR, 2 (1–13) for JNJ+AZA and 2 (1–7) for JNJ+VEN.

Dose escalation was stopped based on limited clinical activity after reviewing available safety, pharmacokinetic/pharmacodynamic and efficacy data. MTD was not reached, and RP2D was not established.

Most (97.4%) patients experienced ≥1 treatment-emergent adverse event (TEAE), 64.7% of which were considered JNJ-74856665 related by investigators (Table S6). The most common TEAEs were stomatitis (48.8%; all JNJ-74856665 related), diarrhoea (32.1%; 17.9% JNJ-74856665 related), anaemia (31%) and asthenia (25%) in the mono-R/R arm; mouth ulceration (40%) in the mono-LR arm; thrombocytopenia and vomiting (42.9% each), diarrhoea (37.1%), nausea (34.3%), anaemia and constipation (31.4% each) and stomatitis (20.0%; 17.1% JNJ-74856665 related) with JNJ+AZA; and diarrhoea (27.6%), neutropenia (27.6%) and stomatitis (13.8%) with JNJ+VEN. TEAEs in ≥10% of patients are in Table 2. In the mono-R/R, JNJ+AZA and JNJ+VEN arms, 82.1%, 94.3% and 86.2% of patients, respectively, experienced Grade ≥3 TEAEs (JNJ-74856665 related in 34.5%, 31.4% and 27.6% of patients) (Table S6). Furthermore, 72.6%, 71.4% and 75.9% of patients, respectively, experienced SAEs (JNJ-74856665 related in 19.0%, 17.1% and 13.8%) (Table S7).

DLTs (Table S8) due to mucositis occurred in 14.3% of patients in the mono-R/R arm (stomatitis, 13.1%; anal inflammation, 1.2%; and vulvovaginal inflammation, 1.2%). With JNJ+AZA, 11.4% of patients experienced DLTs, most commonly maculopapular rash (5.7%). With JNJ+VEN, 13.8% of patients experienced DLTs, including stomatitis (10.3%). No DLTs occurred in the mono-LR arm. Mucositis and diarrhoea of any grade were considered AEs of special interest. Overall, 33.3% of patients experienced ≥1 JNJ-74856665-related TEAE of mucositis (DLTs, 9.2%), which included anal inflammation, glossitis, mucosal inflammation, pharyngeal inflammation, stomatitis and vulvovaginal inflammation (Table S9). Median (range) mucositis onset across treatment arms was 23 (1–358) days, and most events were Grade 2 (45.1%) or 3 (33.3%). Grade ≥2 mucositis was observed in 60.0%, 30.4% and 13.6% of patients treated with >5, 2.6–5 and <2.6 mg JNJ-74856665, respectively (Table S10). Overall, 17.6% of patients experienced JNJ-74856665-related diarrhoea (no DLTs). Median (range) diarrhoea onset across treatment arms was 35.5 (1–132) days, and most events were Grade ≤2 (88.9%).

ORR for the mono-R/R arm was 4.8% (4/84; Figure S7). For AML, ORR was 1.5% (1/66; best overall response [bOR] of complete response with incomplete haematological recovery [CRi])—2 (3%) additional patients achieved a bOR of morphologic leukaemia-free state (MLFS) and 3 (4.5%) achieved a bOR of stable disease (SD). For MDS, ORR was 16.7% (3/18; all bOR of marrow CR [mCR])—3 (16.7%) additional patients had a bOR of SD. In the mono-LR arm, ORR was 20% (1/5; bOR of mCR)—an additional patient (20%) had a bOR of SD. With JNJ+AZA, ORR was 8.6% (3/35) (AML, 10% [2/20 (both bOR of CRi) plus 2 MLFS and 4 SD]; MDS, 7.1% [1/14 (bOR of mCR) plus 1 SD]; CMML-2, 0% [0/1]). With JNJ+VEN, ORR was 3.4% (1/29) (AML, 4.2% [1/24 (bOR of CR without minimal residual disease or minimal residual disease-negative)] plus 1 SD; MDS, 0% [0/5]).

Increased plasma DHO concentrations were observed following JNJ-74856665 treatment across treatment arms and disease states (Figure S8). Trends towards lower fold change in DHO concentrations were observed with JNJ-74856665 combination therapy versus monotherapy, and towards higher concentrations of DHO in patients with versus without stomatitis (any grade).

Clinical development of JNJ-74856665 was driven by single-agent, preclinical activity showing significant dose-dependent increase in survival and tumour growth inhibition in xenograft models at doses of 0.062–0.25 mg/kg, and significant increased life span occurred with JNJ-74856665, JNJ+AZA and JNJ+VEN, and with JNJ+AZA versus AZA or VEN alone. Biological activity of JNJ-74856665 starting at the lowest administered dose (0.3 mg daily) was confirmed in the phase 1 study. Most frequent toxicity with JNJ-74856665 was mucositis at all dose levels in a dose-dependent manner. Planned drug holidays helped reduce incidence and mitigate severity of stomatitis but also may have affected efficacy. Limited clinical activity was observed, and dose escalation was extensively constrained by dose-dependent toxicity, particularly mucositis, leading to early enrolment stop. In a responder analysis (Supporting Information), responses were seen across treatment arms; however, a common predictor of response was not identified among the limited number of responders, and no additive or synergistic effects of combination therapy were observed clinically. DHO plasma concentrations increased after treatment, providing evidence of target engagement. Whether full, uninterrupted inhibition of DHODH led to improved outcomes in patients with AML and MDS is unknown. While efficacy was limited, observed target engagement and transient limited responses support the potential for clinical activity with DHODHi, as monotherapy or in combination with other agents. Approaches to minimise dose interruptions, mitigate mucositis and identify predictor-of-response biomarkers could aid further development of DHODHi in these populations.

All authors participated in the research. Kathryn Bradford (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) conceived and designed the research study. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter, Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Ulrike Philippar (preclinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Ana Alfonso Piérola supervised the research. Emma Searle, Thomas Cluzeau, Jordi Esteve, Emmanuel Gyan, Austin Kulasekararaj, Daniel Morillo, Jenny O'Nions, Arnaud Pigneux, Emmanuel Raffoux, Christian Recher, David Valcárcel, Harriet S. Walter and Emmanuel Gyan acquired the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), Stan Gaj (preclinical study; clinical study biomarker data), E. Christine Pietsch (preclinical study), Xiaochun Zhang (preclinical study), Tammy Bush (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical) analysed and interpreted the data. Kathryn Bradford (clinical study), Adetokunbo Oluwasanjo (clinical study), Martin Curtis (clinical study), E. Christine Pietsch (preclinical study), Christina D. Guttke (clinical study biomarkers, preclinical), Rachel Pearson (statistician, clinical study) wrote the manuscript, and all authors critically reviewed and/or revised the manuscript.

Emma Searle reports consulting fees from Sanofi, BMS, Johnson & Johnson, Syndax, Cellcentric, Sumitomo, Beigene & Pfizer; meeting and/or travel support from Johnson & Johnson, Abbvie, Beigene, and Menarini Stemline; payment or honoraria from Astellas, Jazz Pharma, Johnson & Johnson, Abbvie & Pfizer; participation on a data safety monitoring board or advisory board for Dark Blue Therapeutics, Sanofi, BMS, Johnson &Johnson, Syndax, Pfizer and Sumitomo; and leadership or fiduciary role (unpaid) with British Society of Haematology Research and Grants (Committee Chair) and ECMC Haematology Network Group (Deputy Chair). Thomas Cluzeau reports consulting fees from Abbvie, Jazz Pharma, Novartis, Agios, Servier, BluePrint and BMS; payment or honoraria from Novartis, Astellas, BMS, Jazz Pharma, Servier, and Incyte; meeting and/or travel support from Pfizer, BMS, Novartis, Abbvie, Servier, Gilead; and participation on a data safety monitoring board or advisory board for BMS, Novartis and KEROS. Jenny O'Nions reports payment or honoraria from Jazz and Astellas; meeting and/or travel support from Janssen, Abbvie, Servier and Jazz; and participation on a data safety monitoring board or advisory board for Abbvie. Christian Recher reports grants or contracts from Abbvie, Astellas, BMS, Jazz Pharma and Iqvia; payment or honoraria from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; meeting and/or travel support from Abbvie, Astellas, BMS, Jazz Pharma, Novartis and Servier; and participation on a data safety monitoring board or advisory board for Abbvie, Astellas, BMS, Jazz Pharma, Novartis, Servier and Takeda. Emmanuel Gyan reports grants or contracts from Novartis; consulting fees from Janssen, Sanofi, Abbvie and Incyte; payment or honoraria from Gilead and Roche; meeting and/or travel support from Roche; and receipt of equipment, materials, drugs, medical writing, gifts or other services from BMS and Sandoz. Daniel Morillo reports payment or honoraria from Abbvie and GSK; and meeting and/or travel support from Roche, Janssen and Kite. Jordi Esteve reports grants or contracts (to CETLAM cooperative group) from Jazz and Pfizer; payment or honoraria from Abbvie and Jazz; and meeting and/or travel support from Abbvie. Austin Kulasekararaj reports consulting fees from Novartis, SOBI, Alexion/AstraZeneca, Novartis and Roche; payment or honoraria from Celgene/BMS, Novartis, SOBI, Alexion/AstraZeneca, Roche, Samsung, and Amgen; meeting and/or travel support from SOBI and Alexion/AstraZeneca; and participation on a data safety monitoring board or advisory board for Agious, Roche and Biocryst. Emmanuel Raffoux reports consulting fees from Servier and BMS; and payment or honoraria from Servier, BMS and Astellas. Harriet Walter reports research funding paid by Janssen to institutions; medical education grant from Pfizer and research funding from Isogenica and Gilead; payment or honoraria from Abbvie; and participation on a data safety monitoring board or advisory board for Beigene, Eli Lilly and Genmab. Arnaud Pigneux has nothing to report. David Valcárcel reports consulting fees from Amgen, BMS/Celgene, Kite/Gilead, Novartis, SOBI, Astellas, Jazz, MSD and Sanofi; payment or honoraria from Amgen, BMS/Celgene, Grifols, Jazz, MSD, Pfizer, SOBI, Astellas, GEBRO, Janssen, Kite/Gilead, Novartis, Sanofi and Agios; meeting and/or travel support from BMS/Celgene, Jazz, SOBI, Novartis and Sanofi; and participation on a data safety monitoring board or advisory board for Novartis, SOBI, BMS/Celgene, Jazz, Servier, Amgen and Grifols. Nikki Daskalakis, Jacqueline Bussolari, E. Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo (at time of study conduct), Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy and Wim van Dijck are employees of Janssen and may hold company stock in the company. E. Christine Pietsch and Christina Guttke also report patents planned, issued or pending, and Ulrike Philippar also reports a leadership or fiduciary role with J&J Belgium (Board of Directors). Ana Alfonso Piérola reports grants or contracts from AstraZeneca; consulting fees from Jazz Pharmaceuticals and Astellas; payment or honoraria from Novartis, BMS, Jazz Pharmaceuticals, Astellas and Abbvie; and meeting and/or travel support from Kite, BMS and Novartis.

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来源期刊
CiteScore
8.60
自引率
4.60%
发文量
565
审稿时长
1 months
期刊介绍: The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.
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