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1. Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study

Author

Rosti, G, Brummendorf, T, Gjertsen, B, Giraldo-Castellano, P, Castagnetti, F, Gambacorti-Passerini, C, Ernst, T, Zhao, H, Kuttschreuter, L, Purcell, S, Giles, F, Hochhaus, A, Rosti G., Brummendorf T. H., Gjertsen B. T., Giraldo-Castellano P., Castagnetti F., Gambacorti-Passerini C., Ernst T., Zhao H., Kuttschreuter L., Purcell S., Giles F. J., Hochhaus A., Rosti, G, Brummendorf, T, Gjertsen, B, Giraldo-Castellano, P, Castagnetti, F, Gambacorti-Passerini, C, Ernst, T, Zhao, H, Kuttschreuter, L, Purcell, S, Giles, F, Hochhaus, A, Rosti G., Brummendorf T. H., Gjertsen B. T., Giraldo-Castellano P., Castagnetti F., Gambacorti-Passerini C., Ernst T., Zhao H., Kuttschreuter L., Purcell S., Giles F. J., and Hochhaus A.

Abstract

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome–positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65–74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65–74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.

Published
2024

4. Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS

Author

Ossenkoppele, G. J., Breems, D. A., Stuessi, G., van Norden, Y., Bargetzi, M., Biemond, B. J., A von dem Borne, P., Chalandon, Y., Cloos, J., Deeren, D., Fehr, M., Gjertsen, B., Graux, C., Huls, G., Janssen, J. J. J. W., Jaspers, A., Jongen-Lavrencic, M., de Jongh, E., Klein, S. K., van der Klift, M., van Marwijk Kooy, M., Maertens, J., Michaux, L., van der Poel, M. W. M., van Rhenen, A., Tick, L., Valk, P., Vekemans, M. C., van der Velden, W. J. F. M., de Weerdt, O., Pabst, T., Manz, M., and Löwenberg, B.

Published
2020
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6. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Author

Hochhaus, A, Gambacorti Passerini, C, Abboud, C, Gjertsen, B, Brummendorf, T, Smith, B, Ernst, T, Giraldo-Castellano, P, Olsson-Stromberg, U, Saussele, S, Bardy-Bouxin, N, Viqueira, A, Leip, E, Russell-Smith, T, Leone, J, Rosti, G, Watts, J, Giles, F, Abruzzese, E, Akard, L, Bosi, A, Cervantes, F, Charbonnier, A, Di Raimondo, F, Etienne, G, Garcia Gutierrez, V, Guerci-Bresler, A, Hjorth-Hansen, H, Karsenti, J, Kelly, K, Le Coutre, P, Martinez Chamorro, C, Oehler, V, Orti Pascual, G, Petzer, A, Pungolino, E, Rege-Cambrin, G, Rigal-Huguet, F, Roboz, G, Rousselot, P, Sanchez-Guijo, F, Sanz Santillana, G, Schafhausen, P, Scheid, C, Schmidt, S, Specchia, G, Steegmann, J, Stenke, L, Hochhaus A., Gambacorti Passerini C., Abboud C., Gjertsen B. T., Brummendorf T. H., Smith B. D., Ernst T., Giraldo-Castellano P., Olsson-Stromberg U., Saussele S., Bardy-Bouxin N., Viqueira A., Leip E., Russell-Smith T. A., Leone J., Rosti G., Watts J., Giles F. J., Abruzzese E., Akard L. P., Bosi A., Cervantes F., Charbonnier A., Di Raimondo F., Etienne G., Garcia Gutierrez V., Guerci-Bresler A. P., Hjorth-Hansen H., Karsenti J. M., Kelly K. R., Le Coutre P., Martinez Chamorro C., Oehler V. G., Orti Pascual G., Petzer A., Pungolino E., Rege-Cambrin G., Rigal-Huguet F., Roboz G. J., Rousselot P., Sanchez-Guijo F. M., Sanz Santillana G., Schafhausen P., Scheid C., Schmidt S., Specchia G., Steegmann J. L., Stenke L., Hochhaus, A, Gambacorti Passerini, C, Abboud, C, Gjertsen, B, Brummendorf, T, Smith, B, Ernst, T, Giraldo-Castellano, P, Olsson-Stromberg, U, Saussele, S, Bardy-Bouxin, N, Viqueira, A, Leip, E, Russell-Smith, T, Leone, J, Rosti, G, Watts, J, Giles, F, Abruzzese, E, Akard, L, Bosi, A, Cervantes, F, Charbonnier, A, Di Raimondo, F, Etienne, G, Garcia Gutierrez, V, Guerci-Bresler, A, Hjorth-Hansen, H, Karsenti, J, Kelly, K, Le Coutre, P, Martinez Chamorro, C, Oehler, V, Orti Pascual, G, Petzer, A, Pungolino, E, Rege-Cambrin, G, Rigal-Huguet, F, Roboz, G, Rousselot, P, Sanchez-Guijo, F, Sanz Santillana, G, Schafhausen, P, Scheid, C, Schmidt, S, Specchia, G, Steegmann, J, Stenke, L, Hochhaus A., Gambacorti Passerini C., Abboud C., Gjertsen B. T., Brummendorf T. H., Smith B. D., Ernst T., Giraldo-Castellano P., Olsson-Stromberg U., Saussele S., Bardy-Bouxin N., Viqueira A., Leip E., Russell-Smith T. A., Leone J., Rosti G., Watts J., Giles F. J., Abruzzese E., Akard L. P., Bosi A., Cervantes F., Charbonnier A., Di Raimondo F., Etienne G., Garcia Gutierrez V., Guerci-Bresler A. P., Hjorth-Hansen H., Karsenti J. M., Kelly K. R., Le Coutre P., Martinez Chamorro C., Oehler V. G., Orti Pascual G., Petzer A., Pungolino E., Rege-Cambrin G., Rigal-Huguet F., Roboz G. J., Rousselot P., Sanchez-Guijo F. M., Sanz Santillana G., Schafhausen P., Scheid C., Schmidt S., Specchia G., Steegmann J. L., and Stenke L.

Abstract

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

Published
2020

7. P548: BEMCENTINIB COMBINED WITH LOW-DOSE CYTARABINE IS EFFICACIOUS AND WELL TOLERATED IN RELAPSED AML PATIENTS UNFIT FOR INTENSIVE CHEMOTHERAPY. UPDATES FROM THE ONGOING PHASE II TRIAL (NCT02488408)

Author

Loges, S., primary, Heuser, M., additional, Chromik, J., additional, Sutamtewagul, G., additional, Kapp-Schwoerer, S., additional, Crugnola, M., additional, Di Renzo, N., additional, Lemoli, R., additional, Mattei, D., additional, Ben-Batalla, I., additional, Waizenegger, J., additional, Rieckmann, L.-M., additional, Janning, M., additional, Imbusch, C. D., additional, Beumer, N., additional, Micklem, D., additional, Gorcea-Carson, C., additional, Lawson, G., additional, Nautiyal, J., additional, Deharo, S., additional, Fiedler, W., additional, Alvarado-Valero, Y., additional, and Gjertsen, B., additional

Published
2022
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9. Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS

Author

Ossenkoppele, G.J., Breems, D.A., Stuessi, G., Norden, Y. van, Bargetzi, M., Biemond, B.J., Borne, P.A. von dem, Chalandon, Y., Cloos, J., Deeren, D., Fehr, M., Gjertsen, B., Graux, C., Huls, G., Janssen, J.J.J.W., Jaspers, A., Jongen-Lavrencic, M., Jongh, E. de, Klein, S.K., Klift, M. van der, Kooy, M.V., Maertens, J., Micheaux, L., Poel, M.W.M. van der, Rhenen, A. van, Tick, L., Valk, P., Vekemans, M.C., Velden, W.J.F.M. van der, Weerdt, O. de, Pabst, T., Manz, M., Lowenberg, B., Havelange, Moors, I., Obberg, F. van, Maertens, J.A., Hodossy, B., Vansteenweghen, S., Lammertijn, L., Sonet, A., Triffet, A., Gjertsen, B.T., Passweg, J., Heim, D., Giovanni, S., Betticher, D., Spertini, O., Gregor, M., Hess, U., Manz, M.G., Loosdrecht, A. van de, Janssen, J.J.W.M., Esser, J.W.J. van, Brouwer, R.E., Lammeren-Venema, D. van, Levin, M.D., Tick, L.W., Legdeur, M.C.J.C., Vellenga, E., Hoogendoorn, M., Veelken, J.H., Schouten, H.C., Cornelissen, J., Wouters, B., Raaijmakers, H.G.M., Kuball, J., Dutch-Belgian Hemato-Oncology, Swiss Grp Clinical Canc Res SAKK, Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Haematology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer Treatment and quality of life, Hematology laboratory, Hematology, Department of History, International Institute of Social Studies, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Service d'hématologie, and UCL - (SLuc) Service d'hématologie

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Phases of clinical research, HIGH-DOSE LENALIDOMIDE, ACUTE MYELOID-LEUKEMIA, THERAPY, 03 medical and health sciences, 0302 clinical medicine, Older patients, SDG 3 - Good Health and Well-being, Internal medicine, medicine, 610 Medicine & health, Adverse effect, Lenalidomide, Chemotherapy, business.industry, Intensive treatment, Myeloid leukemia, Hematology, ADULTS, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Cytarabine, business, medicine.drug
Abstract

Contains fulltext : 225470.pdf (Publisher’s version ) (Closed access) More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Published
2020
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14. Inferior outcome of addition of the aminopeptidase inhibitor tosedostat to standard intensive treatment for elderly patients with aml and high risk mds

Author

Janssen, J. (Jeroen), Löwenberg, B. (Bob), Manz, M. (Markus), Bargetzi, M. (Mario), Biemond, B.J. (Bart), Borne, P.A.K. (Peter) von dem, Breems, D.A. (Dimitri), Brouwer, R.E. (Rolf), Chalandon, Y. (Yves), Deeren, D. (Dries), Efthymiou, A. (Anna), Gjertsen, B.-T. (Bjørn-Tore), Graux, C. (Carlos), Gregor, M. (Michael), Heim, D. (Dominik), Hess, U. (Urs), Hoogendoorn, M. (Mels), Jaspers, A. (Aurelie), Jie, A. (Asiong), Jongen-Lavrencic, M. (Mojca), Klein, S. (Saskia), Klift, M. (Marjolein) van der, Kuball, J. (Jürgen), van Lammeren - Venema, D. (Danielle), Legdeur, M.C.J.C. (M. C J C), Loosdrecht, A.A. (Arjan) van de, Maertens, J. (Johan), Kooy, M.M. (Marinus van Marwijk), Moors, I. (Ine), Nijziel, M.R. (Marten), van Obbergh, F. (Florence), Oosterveld, M. (Margriet), Pabst, T. (Thomas), van der Poel, M. (Marjolein), Sinnige, H. (Harm), Spertini, O. (Olivier), Terpstra, W. (Wim), Tick, L.W. (Lidwine), Velden, W.J.F.M. (Walter) van der, Vekemans, M.-C. (Marie-Christiane), Vellenga, E. (Edo), Weerdt, O. (Okke) de, Westerweel, P. (Peter), Stussi, G. (Georg), Norden, Y. (Yvette) van, Ossenkoppele, G.J. (Gert), Janssen, J. (Jeroen), Löwenberg, B. (Bob), Manz, M. (Markus), Bargetzi, M. (Mario), Biemond, B.J. (Bart), Borne, P.A.K. (Peter) von dem, Breems, D.A. (Dimitri), Brouwer, R.E. (Rolf), Chalandon, Y. (Yves), Deeren, D. (Dries), Efthymiou, A. (Anna), Gjertsen, B.-T. (Bjørn-Tore), Graux, C. (Carlos), Gregor, M. (Michael), Heim, D. (Dominik), Hess, U. (Urs), Hoogendoorn, M. (Mels), Jaspers, A. (Aurelie), Jie, A. (Asiong), Jongen-Lavrencic, M. (Mojca), Klein, S. (Saskia), Klift, M. (Marjolein) van der, Kuball, J. (Jürgen), van Lammeren - Venema, D. (Danielle), Legdeur, M.C.J.C. (M. C J C), Loosdrecht, A.A. (Arjan) van de, Maertens, J. (Johan), Kooy, M.M. (Marinus van Marwijk), Moors, I. (Ine), Nijziel, M.R. (Marten), van Obbergh, F. (Florence), Oosterveld, M. (Margriet), Pabst, T. (Thomas), van der Poel, M. (Marjolein), Sinnige, H. (Harm), Spertini, O. (Olivier), Terpstra, W. (Wim), Tick, L.W. (Lidwine), Velden, W.J.F.M. (Walter) van der, Vekemans, M.-C. (Marie-Christiane), Vellenga, E. (Edo), Weerdt, O. (Okke) de, Westerweel, P. (Peter), Stussi, G. (Georg), Norden, Y. (Yvette) van, and Ossenkoppele, G.J. (Gert)

Abstract

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation wa

Published
2021
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17. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

Author

Mateos, Maria-Victoria, Blacklock, Hilary, Schjesvold, Fredrik, Oriol, Albert, Simpson, David, George, Anupkumar, Goldschmidt, Hartmut, Larocca, Alessandra, Chanan-Khan, Asher, Sherbenou, Daniel, Avivi, Irit, Benyamini, Noam, Iida, Shinsuke, Matsumoto, Morio, Suzuki, Kenshi, Ribrag, Vincent, Usmani, Saad Z, Jagannath, Sundar, Ocio, Enrique M, Rodriguez-Otero, Paula, San Miguel, Jesus, Kher, Uma, Farooqui, Mohammed, Liao, Jason, Marinello, Patricia, Lonial, Sagar, KEYNOTE-183 Investigators, Nicol A, Grigoriadis G, Catalano J, LeBlanc R, Elemary M, Bahlis N, Facon T, Karlin L, Ribrag V, Attal M, Goldschmidt H, Engelhardt M, Weisel K, Mackensen A, Nagler A, Ben Yehuda D, Avivi I, Benyamini N, Magen-Nativ H, Palumbo A, Cavo M, Tobinai K, Iida S, Chou T, Suzuki K, Kosugi H, Taniwaki M, Sunami K, Matsumoto M, Ando K, Ganly P, Blacklock H, Simpson D, George A, Schjesvold F, Gjertsen B, Lahuerta J, Blade J, Oriol Rocafiguera A, Mateos M, Rodriguez-Otero P, Larson S, Atanackovic D, Devarakonda S, Bitran J, Zonder J, Morganstein N, Hay M, Chanan-Khan A, Saylors G, Kio E, Oliff I, Kirkel D, Shtivelband M, Yuen C, Yee A, Shah J, Htut M, Raza S, Chhabra S, Stiff P, Hari P, Bank B, Malek E, Gasparetto C, Faroun Y, Sherbenou D, Kreisle W, Singhal S, Rosenblatt J, Usmani S, Lee W, Safah H, Lutzky J, Suh J, Pan D, Baron A, Manges R, Steis R, Oliveira M, Moreb J, Callander N, Anz B, Raptis A, Stampleman L, Melear J, Boyd T, Garbo L, Klein L, Shao S, Lyons R, McIntyre K, Tarantolo S, Yasenchak C, Yimer H., Mateos, Maria-Victoria, Blacklock, Hilary, Schjesvold, Fredrik, Oriol, Albert, Simpson, David, George, Anupkumar, Goldschmidt, Hartmut, Larocca, Alessandra, Chanan-Khan, Asher, Sherbenou, Daniel, Avivi, Irit, Benyamini, Noam, Iida, Shinsuke, Matsumoto, Morio, Suzuki, Kenshi, Ribrag, Vincent, Usmani, Saad Z, Jagannath, Sundar, Ocio, Enrique M, Rodriguez-Otero, Paula, San Miguel, Jesu, Kher, Uma, Farooqui, Mohammed, Liao, Jason, Marinello, Patricia, Lonial, Sagar, KEYNOTE-183 Investigator, and Nicol A, Grigoriadis G, Catalano J, LeBlanc R, Elemary M, Bahlis N, Facon T, Karlin L, Ribrag V, Attal M, Goldschmidt H, Engelhardt M, Weisel K, Mackensen A, Nagler A, Ben Yehuda D, Avivi I, Benyamini N, Magen-Nativ H, Palumbo A, Cavo M, Tobinai K, Iida S, Chou T, Suzuki K, Kosugi H, Taniwaki M, Sunami K, Matsumoto M, Ando K, Ganly P, Blacklock H, Simpson D, George A, Schjesvold F, Gjertsen B, Lahuerta J, Blade J, Oriol Rocafiguera A, Mateos M, Rodriguez-Otero P, Larson S, Atanackovic D, Devarakonda S, Bitran J, Zonder J, Morganstein N, Hay M, Chanan-Khan A, Saylors G, Kio E, Oliff I, Kirkel D, Shtivelband M, Yuen C, Yee A, Shah J, Htut M, Raza S, Chhabra S, Stiff P, Hari P, Bank B, Malek E, Gasparetto C, Faroun Y, Sherbenou D, Kreisle W, Singhal S, Rosenblatt J, Usmani S, Lee W, Safah H, Lutzky J, Suh J, Pan D, Baron A, Manges R, Steis R, Oliveira M, Moreb J, Callander N, Anz B, Raptis A, Stampleman L, Melear J, Boyd T, Garbo L, Klein L, Shao S, Lyons R, McIntyre K, Tarantolo S, Yasenchak C, Yimer H.

Subjects
Male, medicine.medical_specialty, Pembrolizumab, Antibodies, Monoclonal, Humanized, Dexamethasone, Drug Administration Schedule, 03 medical and health sciences, Pembrolizumab, pomalidomide, dexamethasone, KEYNOTE-183, 0302 clinical medicine, Recurrence, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progression-free survival, Survival rate, Multiple myeloma, Aged, Proportional Hazards Models, Lenalidomide, Aged, 80 and over, Performance status, business.industry, Hematology, medicine.disease, Pomalidomide, Interim analysis, Progression-Free Survival, Thalidomide, Survival Rate, Myocarditis, Editorial Commentary, Treatment Outcome, Stevens-Johnson Syndrome, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, business, 030215 immunology, medicine.drug
Abstract

Summary Background Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov , number NCT02576977 , and it is closed for accrual. Findings Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5–10·9). Median progression-free survival was 5·6 months (95% CI 3·7–7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9–not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37–58) versus 60% (49–69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05–2·22; p=0·98). Median overall survival was not reached (95% CI 12·9–not reached) versus 15·2 months (12·7–not reached; HR 1·61; 95% CI 0·91–2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74–88) versus 90% (82–95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. Interpretation The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

Published
2019

20. Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS

Author

UCL - (SLuc) Centre du cancer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Ossenkoppele, G. J., Breems, D. A., Stuessi, G., van Norden, Y., Bargetzi, M., Biemond, B. J., A von dem Borne, P., Chalandon, Y., Cloos, J., Deeren, D., Fehr, M., Gjertsen, B., Graux, Carlos, Huls, G., Janssen, J. J. J. W., Jaspers, A., Jongen-Lavrencic, M., de Jongh, E., Klein, S. K., van der Klift, M., van Marwijk Kooy, M., Maertens, J., Michaux, L., van der Poel, M. W. M., van Rhenen, A., Tick, L., Valk, P., Vekemans, Marie-Christiane, van der Velden, W. J. F. M., de Weerdt, O., Pabst, T., Manz, M., Löwenberg, B., Havelange, Violaine, Sonet, Anne, UCL - (SLuc) Centre du cancer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Ossenkoppele, G. J., Breems, D. A., Stuessi, G., van Norden, Y., Bargetzi, M., Biemond, B. J., A von dem Borne, P., Chalandon, Y., Cloos, J., Deeren, D., Fehr, M., Gjertsen, B., Graux, Carlos, Huls, G., Janssen, J. J. J. W., Jaspers, A., Jongen-Lavrencic, M., de Jongh, E., Klein, S. K., van der Klift, M., van Marwijk Kooy, M., Maertens, J., Michaux, L., van der Poel, M. W. M., van Rhenen, A., Tick, L., Valk, P., Vekemans, Marie-Christiane, van der Velden, W. J. F. M., de Weerdt, O., Pabst, T., Manz, M., Löwenberg, B., Havelange, Violaine, and Sonet, Anne

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

27. CLINICAL AND IMMUNOLOGICAL EFFECTS OF NILOTINIB IN COMBINATION WITH PEGYLATED INTERFERON-A2B IN PATIENTS WITH SUBOPTIMAL MOLECULAR RESPONSE ON IMATINIB (NORDDUTCHCML009)

Author

Geelen, I., Strömberg, Ulla Ohlsson, Mustjoki, S., Richter, J., Blijlevens, N., Smit, W., Gjertsen, B., Gedde-Dahl, T., Markevärn, B., Koppes, M., Westerweel, P., Janssen, J., Hjorth-Hansen, H., Geelen, I., Strömberg, Ulla Ohlsson, Mustjoki, S., Richter, J., Blijlevens, N., Smit, W., Gjertsen, B., Gedde-Dahl, T., Markevärn, B., Koppes, M., Westerweel, P., Janssen, J., and Hjorth-Hansen, H.

Published
2017

30. Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients

Author

Hjorth-Hansen, H., Stentoft, J., Richter, J., Koskenvesa, P., Höglund, Martin, Dreimane, A., Porkka, K., Gedde-Dahl, T., Gjertsen, B. T., Gruber, F. X., Stenke, L., Eriksson, K. M., Markevarn, B., Lubking, A., Vestergaard, H., Udby, L., Bjerrum, O. W., Persson, Inger, Mustjoki, S., Olsson-Strömberg, Ulla, Hjorth-Hansen, H., Stentoft, J., Richter, J., Koskenvesa, P., Höglund, Martin, Dreimane, A., Porkka, K., Gedde-Dahl, T., Gjertsen, B. T., Gruber, F. X., Stenke, L., Eriksson, K. M., Markevarn, B., Lubking, A., Vestergaard, H., Udby, L., Bjerrum, O. W., Persson, Inger, Mustjoki, S., and Olsson-Strömberg, Ulla

Abstract

Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.

Published
2016
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31. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia

Author

Kontro, M, primary, Kumar, A, additional, Majumder, M M, additional, Eldfors, S, additional, Parsons, A, additional, Pemovska, T, additional, Saarela, J, additional, Yadav, B, additional, Malani, D, additional, Fløisand, Y, additional, Höglund, M, additional, Remes, K, additional, Gjertsen, B T, additional, Kallioniemi, O, additional, Wennerberg, K, additional, Heckman, C A, additional, and Porkka, K, additional

Published
2016
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32. CD62L Expression on T Cells is Decreased in Patients with Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) and Predicts Response to Therapy with Frontline Nilotinib

Author

Sopper, S., Mustjoki, S., Loskog, Angelica, Gjertsen, B., Mark, U., Haenig, J., Jurjonas, N., Gastl, G., Giles, F., Hochhaus, A., Ossenkoppele, G., Porkka, K., Wolf, D., Sopper, S., Mustjoki, S., Loskog, Angelica, Gjertsen, B., Mark, U., Haenig, J., Jurjonas, N., Gastl, G., Giles, F., Hochhaus, A., Ossenkoppele, G., Porkka, K., and Wolf, D.

Published
2014

34. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients

Author

Mustjoki, S., Richter, J., Barbany, G., Ehrencrona, H., Fioretos, T., Gedde-Dahl, T., Gjertsen, B. T., Hovland, R., Hernesniemi, S., Josefsen, D., Koskenvesa, P., Dybedal, I., Markevarn, B., Olofsson, T., Olsson-Stromberg, U., Rapakko, K., Thunberg, Sarah, Stenke, L., Simonsson, B., Porkka, K., Hjorth-Hansen, H., Grp, Nordic CML Study, Mustjoki, S., Richter, J., Barbany, G., Ehrencrona, H., Fioretos, T., Gedde-Dahl, T., Gjertsen, B. T., Hovland, R., Hernesniemi, S., Josefsen, D., Koskenvesa, P., Dybedal, I., Markevarn, B., Olofsson, T., Olsson-Stromberg, U., Rapakko, K., Thunberg, Sarah, Stenke, L., Simonsson, B., Porkka, K., Hjorth-Hansen, H., and Grp, Nordic CML Study

Abstract

Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38=) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P = 0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P = 0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients., QC 20170419

Published
2013
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36. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis

Author

Gausdal, G, primary, Wergeland, A, additional, Skavland, J, additional, Nguyen, E, additional, Pendino, F, additional, Rouhee, N, additional, McCormack, E, additional, Herfindal, L, additional, Kleppe, R, additional, Havemann, U, additional, Schwede, F, additional, Bruserud, Ø, additional, Gjertsen, B T, additional, Lanotte, M, additional, Ségal-Bendirdjian, E, additional, and Døskeland, S O, additional

Published
2013
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37. Mdm2 controls CREB-dependent transactivation and initiation of adipocyte differentiation

Author

Hallenborg, P, primary, Feddersen, S, additional, Francoz, S, additional, Murano, I, additional, Sundekilde, U, additional, Petersen, R K, additional, Akimov, V, additional, Olson, M V, additional, Lozano, G, additional, Cinti, S, additional, Gjertsen, B T, additional, Madsen, L, additional, Marine, J-C, additional, Blagoev, B, additional, and Kristiansen, K, additional

Published
2012
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38. HOXgene expression predicts response to BCL-2 inhibition in acute myeloid leukemia

Author

Kontro, M, Kumar, A, Majumder, M M, Eldfors, S, Parsons, A, Pemovska, T, Saarela, J, Yadav, B, Malani, D, Fløisand, Y, Höglund, M, Remes, K, Gjertsen, B T, Kallioniemi, O, Wennerberg, K, Heckman, C A, and Porkka, K

Abstract

Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivosensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1and IDH1/IDH2. A striking selective overexpression of specific HOXAand HOXBgene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivoresponses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XLand BAXexpression. As new therapy options for AML are urgently needed, the specific HOXgene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.

Published
2017
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50. Fine mapping of 28S rRNA sites specifically cleaved in cells undergoing apoptosis.

Author

Houge, G, Robaye, Bernard, Eikhom, T S, Golstein Golaire, Jacqueline, Mellgren, G, Gjertsen, B T, Lanotte, Michele, Døskeland, Stein O, Houge, G, Robaye, Bernard, Eikhom, T S, Golstein Golaire, Jacqueline, Mellgren, G, Gjertsen, B T, Lanotte, Michele, and Døskeland, Stein O

Abstract

Bona fide apoptosis in rat and human leukemia cells, rat thymocytes, and bovine endothelial cells was accompanied by limited and specific cleavage of polysome-associated and monosome-associated 28S rRNA, with 18S rRNA being spared. Specific 28S rRNA cleavage was observed in all instances of apoptotic death accompanied by internucleosomal DNA fragmentation, with cleavage of 28S rRNA and of DNA being linked temporally. This indicates that 28S rRNA fragmentation may be as general a feature of apoptosis as internucleosomal DNA fragmentation and that concerted specific cleavage of intra- and extranuclear polynucleotides occurs in apoptosis. Apoptosis-associated cleavage sites were mapped to the 28S rRNA divergent domains D2, D6 (endothelial cells), and D8. The D2 cuts occurred in hairpin loop junctions considered to be buried in the intact ribosome, suggesting that this rRNA region becomes a target for RNase attack in apoptotic cells. D8 was cleaved in two exposed UU(U) sequences in bulge loops. Treatment with agents causing necrotic cell death or aging of cell lysates failed to produce any detectable limited D2 cleavage but did produce a more generalized cleavage in the D8 region. Of potential functional interest was the finding that the primary cuts in D2 exactly flanked a 0.3-kb hypervariable subdomain (D2c), allowing excision of the latter. The implication of hypervariable rRNA domains in apoptosis represents the first association of any functional process with these enigmatic parts of the ribosomes., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
1995

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