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3. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome

Author

Grob, Tim, Al Hinai, Adil S.A., Sanders, Mathijs A., Kavelaars, François G., Rijken, Melissa, Gradowska, Patrycja L., Biemond, Bart J., Breems, Dimitri A., Maertens, Johan, van Marwijk Kooy, Marinus, Pabst, Thomas, de Weerdt, Okke, Ossenkoppele, Gert J., van de Loosdrecht, Arjan A., Huls, Gerwin A., Cornelissen, Jan J., Beverloo, H. Berna, Löwenberg, Bob, Jongen-Lavrencic, Mojca, and Valk, Peter J.M.

Published
2022
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4. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial

Author

Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjen A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren-Venema, Daniëlle, Halkes, Constantijn J.M., Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L., Legdeur, Marie-Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A.M., Breems, Dimitri A., Jaspers, Aurélie, Legrand, Ollivier, Terpstra, Wim E., Boersma, Rinske S., Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W., Beel, Karolien, Maertens, Johan A., Beverloo, H. Berna, Bakkus, Marleen, Homburg, Christa H.E., de Haas, Valerie, van der Velden, Vincent H.J., and Cornelissen, Jan J.

Published
2022
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5. Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi‐state modeling

Author

Hermans, Sjoerd J. F., primary, van Norden, Yvette, additional, Versluis, Jurjen, additional, Rijneveld, Anita W., additional, van der Holt, Bronno, additional, de Weerdt, Okke, additional, Biemond, Bart J., additional, van de Loosdrecht, Arjan A., additional, van der Wagen, Lotte E., additional, Bellido, Mar, additional, van Gelder, Michel, additional, van der Velden, Walter J. F. M., additional, Selleslag, Dominik, additional, van Lammeren‐Venema, Daniëlle, additional, van der Velden, Vincent H. J., additional, de Wreede, Liesbeth C., additional, Postmus, Douwe, additional, Pignatti, Francesco, additional, and Cornelissen, Jan J., additional

Published
2024
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6. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

Author

Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J., Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W., Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J.F.M., Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W.J., Bargetzi, Mario, Klein, Saskia K., Gadisseur, Alain, Westerweel, Peter E., Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A., Hoogendoorn, Mels, Legdeur, Marie-Cecile J.C., Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T., Janssen, Jeroen J.W.M., Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J.M., van Elssen, Catharina H.M.J., Manz, Markus G., Floisand, Yngvar, and Ossenkoppele, Gert J.

Published
2021
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7. Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling

Author

Hermans, Sjoerd J.F., van Norden, Yvette, Versluis, Jurjen, Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjan A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren-Venema, Daniëlle, van der Velden, Vincent H.J., de Wreede, Liesbeth C., Postmus, Douwe, Pignatti, Francesco, Cornelissen, Jan J., Hermans, Sjoerd J.F., van Norden, Yvette, Versluis, Jurjen, Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjan A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren-Venema, Daniëlle, van der Velden, Vincent H.J., de Wreede, Liesbeth C., Postmus, Douwe, Pignatti, Francesco, and Cornelissen, Jan J.

Abstract

Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Published
2024

9. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial

Author

van de Donk, Niels WCJ, van der Holt, Bronno, Minnema, Monique C, Vellenga, Edo, Croockewit, Sandra, Kersten, Marie José, von dem Borne, Peter A, Ypma, Paula, Schaafsma, Ron, de Weerdt, Okke, Klein, Saskia K, Delforge, Michel, Levin, Mark-David, Bos, Gerard M, Jie, Kon-Siong G, Sinnige, Harm, Coenen, Jules LLM, de Waal, Esther G, Zweegman, Sonja, Sonneveld, Pieter, and Lokhorst, Henk M

Published
2018
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10. ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)–Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial

Author

Fermé, Christophe, Thomas, José, Brice, Pauline, Casasnovas, Olivier, Vranovsky, Andrej, Bologna, Serge, Lugtenburg, Pieternella J., Bouabdallah, Réda, Carde, Patrice, Sebban, Catherine, Eghbali, Houchingue, Salles, Gilles, van Imhoff, Gustaaf W., Thyss, Antoine, Noordijk, Evert M., Reman, Oumédaly, Lybeert, Marnix L.M., Janvier, Maud, Spina, Michele, Audhuy, Bruno, Raemaekers, John M.M., Delarue, Richard, Anglaret, Bruno, de Weerdt, Okke, Marjanovic, Zora, Tersteeg, Robbert J.H.A., de Jong, Daphne, Brière, Josette, and Henry-Amar, Michel

Published
2017
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11. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML

Author

Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, van Norden, Yvette, Biemond, Bart J., Schouten, Harry C., Spertini, Olivier, Vellenga, Edo, Graux, Carlos, Havelange, Violaine, de Greef, Georgine E., de Weerdt, Okke, Legdeur, Marie-Cecile J.C., Kuball, Juergen, Kooy, Marinus van Marwijk, Gjertsen, Bjorn T., Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A., van Lammeren-Venema, Daniëlle, Hodossy, Beata, Breems, Dimitri A., Chalandon, Yves, Passweg, Jakob, Valk, Peter J.M., Manz, Markus G., and Ossenkoppele, Gert J.

Published
2017
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13. The HOVON 100 Study in Adult Acute Lymphoblastic Leukemia Re-Analysed By Multi-State Modeling: Benefits and Risks of Clofarabine

Author

Hermans, Sjoerd J.F., primary, Norden, Yvette, additional, Versluis, Jurjen, additional, Rijneveld, Anita W., additional, De Weerdt, Okke, additional, Biemond, Bart J., additional, van de Loosdrecht, Arjan A., additional, Van der Wagen, Lotte E., additional, Bellido, Mar, additional, Van Gelder, Michel, additional, Van der Velden, Walter J.F.M., additional, Selleslag, Dominik, additional, van Lammeren, Danielle, additional, van der Velden, Vincent H.J., additional, de Wreede, Liesbeth C., additional, Postmus, Douwe, additional, Pignatti, Francesco, additional, and Cornelissen, Jan J., additional

Published
2022
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15. Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with AML and high risk MDS

Author

Janssen, Jeroen, primary, Löwenberg, Bob, additional, Manz, Markus, additional, Biemond, Bart, additional, Westerweel, Peter, additional, Klein, Saskia, additional, Fehr, Martin, additional, Sinnige, Harm, additional, Efthymiou, Anna, additional, Legdeur, M, additional, Pabst, Thomas, additional, Gregor, Michael, additional, Poel, Marjolein van der, additional, Deeren, Dries, additional, Tick, Lidwine, additional, Jongen-Lavrencic, Mojca, additional, Obbergh, Florence, additional, Boersma, Rinske, additional, de Weerdt, Okke, additional, Chalandon, Yves, additional, Heim, Dominik, additional, spertini, Olivier, additional, Sluis, Geerte van, additional, Graux, Carlos, additional, Stuessi, Georg., additional, Norden, Yvette van, additional, and Ossenkoppele, Gert, additional

Published
2022
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16. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial.

Author

UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - (SLuc) Service d'hématologie, Rijneveld, Anita W, van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J, van de Loosdrecht, Arjen A, van der Wagen, Lotte E, Bellido, Mar, van Gelder, Michel, van der Velden, Walter J F M, Selleslag, Dominik, van Lammeren-Venema, Daniëlle, Halkes, Constantijn J M, Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L, Legdeur, Marie-Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A M, Breems, Dimitri A, Jaspers, Aurélie, Legrand, Ollivier, Terpstra, Wim E, Boersma, Rinske S, Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W, Beel, Karolien, Maertens, Johan A, Beverloo, H Berna, Bakkus, Marleen, Homburg, Christa H E, de Haas, Valerie, van der Velden, Vincent H J, Cornelissen, Jan J, Dutch-Belgian HOVON Cooperative group, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - (SLuc) Service d'hématologie, Rijneveld, Anita W, van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J, van de Loosdrecht, Arjen A, van der Wagen, Lotte E, Bellido, Mar, van Gelder, Michel, van der Velden, Walter J F M, Selleslag, Dominik, van Lammeren-Venema, Daniëlle, Halkes, Constantijn J M, Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L, Legdeur, Marie-Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A M, Breems, Dimitri A, Jaspers, Aurélie, Legrand, Ollivier, Terpstra, Wim E, Boersma, Rinske S, Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W, Beel, Karolien, Maertens, Johan A, Beverloo, H Berna, Bakkus, Marleen, Homburg, Christa H E, de Haas, Valerie, van der Velden, Vincent H J, Cornelissen, Jan J, and Dutch-Belgian HOVON Cooperative group

Abstract

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.

Published
2022

17. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL:the HOVON-100 trial

Author

Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjen A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren-Venema, Danie€lle, Halkes, Constantijn J.M., Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L., Legdeur, Marie Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A.M., Breems, Dimitri A., Jaspers, Aurelie, Legrand, Ollivier, Terpstra, Wim E., Boersma, Rinske S., Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W., Beel, Karolien, Maertens, Johan A., Beverloo, H. Berna, Bakkus, Marleen, Homburg, Christa H.E., de Haas, Valerie, van der Velden, Vincent H.J., Cornelissen, Jan J., Rijneveld, Anita W., van der Holt, Bronno, de Weerdt, Okke, Biemond, Bart J., van de Loosdrecht, Arjen A., van der Wagen, Lotte E., Bellido, Mar, van Gelder, Michel, van der Velden, Walter J.F.M., Selleslag, Dominik, van Lammeren-Venema, Danie€lle, Halkes, Constantijn J.M., Fijnheer, Rob, Havelange, Violaine, van Sluis, Geerte L., Legdeur, Marie Cecile, Deeren, Dries, Gadisseur, Alain, Sinnige, Harm A.M., Breems, Dimitri A., Jaspers, Aurelie, Legrand, Ollivier, Terpstra, Wim E., Boersma, Rinske S., Mazure, Dominiek, Triffet, Agnes, Tick, Lidwine W., Beel, Karolien, Maertens, Johan A., Beverloo, H. Berna, Bakkus, Marleen, Homburg, Christa H.E., de Haas, Valerie, van der Velden, Vincent H.J., and Cornelissen, Jan J.

Abstract

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients #40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients .40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD2 after consolidation 1 in arm A vs 75/81 (93%) in arm B (P 5 .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity.

Published
2022

18. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

Author

Ossenkoppele, Gert J., Stussi, Georg, Maertens, Johan, van Montfort, Kees, Biemond, Bart J., Breems, Dimitri, Ferrant, August, Graux, Carlos, de Greef, Georgine E., Halkes, C. J.M., Hoogendoorn, Mels, Hollestein, Rene M., Jongen-Lavrencic, Mojca, Levin, Mark D., van de Loosdrecht, Arjan A., van Marwijk Kooij, Marinus, van Norden, Yvette, Pabst, Thomas, Schouten, Harry C., Vellenga, Edo, Verhoef, Gregor E.G., de Weerdt, Okke, Wijermans, Pierre, Passweg, Jakob R., and Löwenberg, Bob

Published
2012
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20. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma

Author

Lokhorst, Henk M., van der Holt, Bronno, Zweegman, Sonja, Vellenga, Edo, Croockewit, Sandra, van Oers, Marinus H., von dem Borne, Peter, Wijermans, Pierre, Schaafsma, Ron, de Weerdt, Okke, Wittebol, Shulamiet, Delforge, Michel, Berenschot, Henriëtte, Bos, Gerard M., Jie, Kon-Siong G., Sinnige, Harm, van Marwijk-Kooy, Marinus, Joosten, Peter, Minnema, Monique C., van Ammerlaan, Rianne, and Sonneveld, Pieter

Published
2010
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21. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J, Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W, Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J F M, Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W J, Bargetzi, Mario, Klein, Saskia K, Gadisseur, Alain, Westerweel, Peter E, Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A, Hoogendoorn, Mels, Legdeur, Marie-Cecile J C, Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T, Janssen, Jeroen J W M, Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J M, van Elssen, Catharina H M J, Manz, Markus G, Floisand, Yngvar, Ossenkoppele, Gert J, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J, Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W, Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J F M, Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W J, Bargetzi, Mario, Klein, Saskia K, Gadisseur, Alain, Westerweel, Peter E, Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A, Hoogendoorn, Mels, Legdeur, Marie-Cecile J C, Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T, Janssen, Jeroen J W M, Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J M, van Elssen, Catharina H M J, Manz, Markus G, Floisand, Yngvar, and Ossenkoppele, Gert J

Abstract

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.

Published
2021

22. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial

Author

CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J, Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W, Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J F M, Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W J, Bargetzi, Mario, Klein, Saskia K, Gadisseur, Alain, Westerweel, Peter E, Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A, Hoogendoorn, Mels, Legdeur, Marie-Cecile J C, Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T, Janssen, Jeroen J W M, Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J M, van Elssen, Catharina H M J, Manz, Markus G, Floisand, Yngvar, Ossenkoppele, Gert J, CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, Gradowska, Patrycja, Biemond, Bart J, Spertini, Olivier, Vellenga, Edo, Griskevicius, Laimonas, Tick, Lidwine W, Jongen-Lavrencic, Mojca, van Marwijk Kooy, Marinus, Vekemans, Marie-Christiane, van der Velden, Walter J F M, Beverloo, Berna, Michaux, Lucienne, Graux, Carlos, Deeren, Dries, de Weerdt, Okke, van Esser, Joost W J, Bargetzi, Mario, Klein, Saskia K, Gadisseur, Alain, Westerweel, Peter E, Veelken, Hendrik, Gregor, Michael, Silzle, Tobias, van Lammeren-Venema, Daniëlle, Moors, Ine, Breems, Dimitri A, Hoogendoorn, Mels, Legdeur, Marie-Cecile J C, Fischer, Thomas, Kuball, Juergen, Cornelissen, Jan, Porkka, Kimmo, Juliusson, Gunnar, Meyer, Peter, Höglund, Martin, Gjertsen, Bjorn T, Janssen, Jeroen J W M, Huls, Gerwin, Passweg, Jakob, Cloos, Jacqueline, Valk, Peter J M, van Elssen, Catharina H M J, Manz, Markus G, Floisand, Yngvar, and Ossenkoppele, Gert J

Published
2021

23. Carfilzomib Combined With Thalidomide and Low-dose Dexamethasone for Remission Induction and Consolidation in Newly Diagnosed Transplant Eligible Patients With Multiple Myeloma: 8 vs 4 Induction Cycles; the Carthadex Trial

Author

Afdeling Hematologie, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Wester, Ruth, Zweegman, Sonja, van der Holt, Bronno, Kersten, Marie José, Vellenga, Edo, van Marwijk-Kooy, Marinus, Asselbergs, Emelie, de Weerdt, Okke, Minnema, Monique C, Lonergan, Sarah, Palumbo, Antonio, Broijl, Annemiek, Sonneveld, Pieter, Afdeling Hematologie, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Wester, Ruth, Zweegman, Sonja, van der Holt, Bronno, Kersten, Marie José, Vellenga, Edo, van Marwijk-Kooy, Marinus, Asselbergs, Emelie, de Weerdt, Okke, Minnema, Monique C, Lonergan, Sarah, Palumbo, Antonio, Broijl, Annemiek, and Sonneveld, Pieter

Published
2020

24. Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial

Author

MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Doorduijn, Jeanette K, Zijlstra, Josee M, Lugtenburg, Pieternella J, Kersten, Marie Josee, Böhmer, Lara H, Minnema, Monique C, MacKenzie, Marius A, van Marwijk Kooij, Rien, de Jongh, Eva, Snijders, Tjeerd J F, de Weerdt, Okke, van Gelder, Michel, Hoogendoorn, Mels, Leys, Rineke B L, Kibbelaar, Robby E, de Jong, Daphne, Chitu, Dana A, Van't Veer, Mars B, Kluin-Nelemans, Hanneke C, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Doorduijn, Jeanette K, Zijlstra, Josee M, Lugtenburg, Pieternella J, Kersten, Marie Josee, Böhmer, Lara H, Minnema, Monique C, MacKenzie, Marius A, van Marwijk Kooij, Rien, de Jongh, Eva, Snijders, Tjeerd J F, de Weerdt, Okke, van Gelder, Michel, Hoogendoorn, Mels, Leys, Rineke B L, Kibbelaar, Robby E, de Jong, Daphne, Chitu, Dana A, Van't Veer, Mars B, and Kluin-Nelemans, Hanneke C

Published
2020

25. Carfilzomib Combined With Thalidomide and Low-dose Dexamethasone for Remission Induction and Consolidation in Newly Diagnosed Transplant Eligible Patients With Multiple Myeloma:8 vs 4 Induction Cycles; the Carthadex Trial

Author

Wester, Ruth, Zweegman, Sonja, van der Holt, Bronno, Kersten, Marie José, Vellenga, Edo, van Marwijk-Kooy, Marinus, Asselbergs, Emelie, de Weerdt, Okke, Minnema, Monique C., Lonergan, Sarah, Palumbo, Antonio, Broijl, Annemiek, Sonneveld, Pieter, Wester, Ruth, Zweegman, Sonja, van der Holt, Bronno, Kersten, Marie José, Vellenga, Edo, van Marwijk-Kooy, Marinus, Asselbergs, Emelie, de Weerdt, Okke, Minnema, Monique C., Lonergan, Sarah, Palumbo, Antonio, Broijl, Annemiek, and Sonneveld, Pieter

Published
2020

27. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme

Author

van der Helm, Lieke H., Alhan, Canan, Wijermans, Pierre W., van Marwijk Kooy, Marinus, Schaafsma, Ron, Biemond, Bart J., Beeker, Aart, Hoogendoorn, Mels, van Rees, Bastiaan P., de Weerdt, Okke, Wegman, Jurgen, Libourel, Ward J., Luykx-de Bakker, Sylvia A., Minnema, Monique C., Brouwer, Rolf E., Croon-de Boer, Fransien, Eefting, Matthijs, Jie, Kon-Siong G., van de Loosdrecht, Arjan A., Koedam, Jan, Veeger, Nic J. G. M, Vellenga, Edo, and Huls, Gerwin

Published
2011
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28. Carfilzomib Combined With Thalidomide and Low‐dose Dexamethasone for Remission Induction and Consolidation in Newly Diagnosed Transplant Eligible Patients With Multiple Myeloma: 8 vs 4 Induction Cycles; the Carthadex Trial

Author

Wester, Ruth, primary, Zweegman, Sonja, additional, van der Holt, Bronno, additional, Kersten, Marie José, additional, Vellenga, Edo, additional, van Marwijk‐Kooy, Marinus, additional, Asselbergs, Emelie, additional, de Weerdt, Okke, additional, Minnema, Monique C., additional, Lonergan, Sarah, additional, Palumbo, Antonio, additional, Broijl, Annemiek, additional, and Sonneveld, Pieter, additional

Published
2020
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29. Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Author

Verkleij, Christie P.M., primary, Minnema, Monique C., additional, de Weerdt, Okke, additional, Bosman, Patricia W.C., additional, Frerichs, Kristine A., additional, Croockewit, Alexandra J., additional, Klein, Saskia K., additional, Bos, Gerard, additional, Mutis, Tuna, additional, Plattel, Wouter J., additional, van der Spek, Ellen, additional, Broyl, Annemiek, additional, Sonneveld, Pieter, additional, Zweegman, Sonja, additional, Levin, Mark-David, additional, and Van De Donk, Niels W. C. J., additional

Published
2019
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30. Phase 2 study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma, the carthadex trial

Author

Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, van Marwijk Kooy, Marinus, de Weerdt, Okke, Minnema, Monique, Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk, Broijl, Annemiek, Sonneveld, Pieter, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Abstract

This is a phase 2 dose escalation trial of carfilzomib in combination with thalidomide and dexamethasone for induction and consolidation in transplant-eligible patients with newly diagnosed multiple myeloma. The results of 4 dose levels are reported. Induction therapy consisted of 4 cycles of carfilzomib 20/27 mg/m2 (n=50), 20/36 mg/m2 (n=20), 20/45 mg/m2 (n=21) and 20/56 mg/m2 (n=20) on days 1, 2, 8, 9, 15, 16 of a 28-day cycle; thalidomide 200 mg on day 1 through 28 and dexamethasone 40 mg weekly. Induction therapy was followed by high dose melphalan and autologous stem cell transplantation and consolidation therapy with 4 cycles of carfilzomib, thalidomide and dexamethasone in the same schedule except a lower dose of thalidomide (50 mg). Very good partial response rate or better and complete response rate or better after induction therapy were 65% and 18% respectively, increasing to 86% and 63% respectively after consolidation therapy. In all cohorts combined, after a median follow-up of 58.7 months, median progression-free survival was 58 months (95% CI 45-67 months). Median overall survival was 83 months (95% CI 83 months-not reached). Grade 3/4 adverse events consisted mainly of infections, respiratory disorders, skin and vascular disorders in 11%, 8%, 9%, and 9% respectively. Only in 1 patient grade 3 polyneuropathy was reported. Cardiac events were limited, grade 3/4 in 5% of patients. Carfilzomib, thalidomide and dexamethasone as induction and consolidation treatment after high dose melphalan and autologous stem cell transplantation is highly efficacious and safe in transplant-eligible patients with newly diagnosed multiple myeloma. This study was registered at http://www.trialregister.nl as #NTR2422.

Published
2019

31. Richtlijn Acute promyelocytenleukemie (APL): richtlijnen voor diagnostiek en behandeling

Author

Huls, Geert, Lowenberg, B., van de Loosdrecht, A.A., Janssen, J.J.W.M., Jongen-Lavrencic, M., Raaijmakers, M., Wouters, B., Von dem Borne, Peter A., Kuball, Jurgen, Biemond, Bart J., Van Gelder, Michel, van der Velden, W.J.F.M, de Weerdt, Okke, van Marwijk Kooy, Rien, Klein, Saskia, van der Poel, M., van Rhenen, A., Jong, J.J.M. de, Valk, P, van der Reijden, B., Cornelissen, J.J., Vellenga, Edo, Ossenkoppele, G., Stem Cell Aging Leukemia and Lymphoma, and Guided Treatment in Optimal Selected Cancer Patients

Abstract

Acute myeloïde leukemie (AML) is een heterogene ziekte die wordt gekenmerkt door (oligo)klonale maligne hematopoëse met een blokkade in de differentiatie en daardoor een excessieve toename van leukemische blasten. Acute promyelocytenleukemie (APL) is een zeldzame variant van AML die zich goed laat behandelen met ATRA-bevattende therapie. Vanwege complicaties van de ziekte (trombose, bloeding) is vroege herkenning en start van behandeling extreem belangrijk. Het is daarom belangrijk dat diagnostiek en behandeling van APL-patiënten in de dagelijkse praktijk zorgvuldig en gestructureerd plaatsvindt. Hieronder bespreken we de richtlijnen voor diagnostiek en behandeling zoals de HOVONLeukemiewerkgroep denkt dat die voor APL zou moeten plaatsvinden

Published
2018

32. Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

Author

Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, Kooy, Marinus van Marwijk, de Weerdt, Okke, Minnema, Monique, Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk, Broijl, Annemiek, Sonneveld, Pieter, Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, Kooy, Marinus van Marwijk, de Weerdt, Okke, Minnema, Monique, Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk, Broijl, Annemiek, and Sonneveld, Pieter

Published
2019

33. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients

Author

Huls, Gerwin, Chitu, Dana A, Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, Biemond, Bart J, Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J, Vellenga, Edo, Löwenberg, Bob, Huls, Gerwin, Chitu, Dana A, Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, Biemond, Bart J, Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J, Vellenga, Edo, and Löwenberg, Bob

Published
2019

34. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients

Author

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, UCL - (SLuc) Service d'hématologie, Huls, Gerwin, Chitu, Dana A., Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A., Biemond, Bart J., Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J., Vellenga, Edo, Löwenberg, Bob, 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, UCL - (SLuc) Service d'hématologie, Huls, Gerwin, Chitu, Dana A., Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A., Biemond, Bart J., Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J., Vellenga, Edo, and Löwenberg, Bob

Abstract

The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).

Published
2019

35. Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

Author

MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, Kooy, Marinus van Marwijk, de Weerdt, Okke, Minnema, Monique, Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk, Broijl, Annemiek, Sonneveld, Pieter, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, Kooy, Marinus van Marwijk, de Weerdt, Okke, Minnema, Monique, Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk, Broijl, Annemiek, and Sonneveld, Pieter

Published
2019

36. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients

Author

MS Hematologie, Cancer, Regenerative Medicine and Stem Cells, Infection & Immunity, CTI Kuball, Huls, Gerwin, Chitu, Dana A, Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, Biemond, Bart J, Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J, Vellenga, Edo, Löwenberg, Bob, MS Hematologie, Cancer, Regenerative Medicine and Stem Cells, Infection & Immunity, CTI Kuball, Huls, Gerwin, Chitu, Dana A, Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, Biemond, Bart J, Sinnige, Harm, Hodossy, Beata, Graux, Carlos, van Marwijk Kooy, Rien, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jürgen, Deeren, Dries, Terpstra, Wim, Vekemans, Marie-Christiane, Ossenkoppele, Gert J, Vellenga, Edo, and Löwenberg, Bob

Published
2019

37. Eight versus four induction cycles of Carfilzomib, Thalidomide and Low-dose Dexamethasone: the Carthadex trial

Author

Wester, Ruth, primary, Zweegman, Sonja, additional, Van der Holt, Bronno, additional, Jose, Kersten Marie, additional, Vellenga, Edo, additional, van Marwijk-Kooy, Marinus, additional, Asselbergs, Emelie, additional, de Weerdt, Okke, additional, Minnema, Monique, additional, Lonergan, Sarah, additional, Palumbo, Antonio, additional, Broijl, Annemiek, additional, and Sonneveld, Pieter, additional

Published
2019
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38. Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial

Author

Wester, Ruth, primary, van der Holt, Bronno, additional, Asselbergs, Emelie, additional, Zweegman, Sonja, additional, Kersten, Marie Jose, additional, Vellenga, Edo, additional, van Marwijk Kooy, Marinus, additional, de Weerdt, Okke, additional, Minnema, Monique, additional, Lonergan, Sarah, additional, Palumbo, Antonio, additional, Lokhorst, Henk, additional, Broijl, Annemiek, additional, and Sonneveld, Pieter, additional

Published
2019
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39. Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (>= 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III Randomized Multicentre Study (EudraCT 2008-001290-15)

Author

Huls, Geert, Chitu, Dana, Havelange, Violaine, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjen, Biemond, Bart J., Sinnege, Harm, Hodossy, Beata, Graux, Carlos, Kooij, Marinus van Marwijk, de Weerdt, Okke, Breems, Dimitri, Klein, Saskia, Kuball, Jurgen, Ossenkoppele, Gert J., Lowenberg, Bob, Vellenga, Edo, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Published
2017

40. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial

Author

MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, van de Donk, Niels WCJ, van der Holt, Bronno, Minnema, Monique C., Vellenga, Edo, Croockewit, Sandra, Kersten, Marie José, von dem Borne, Peter A., Ypma, Paula, Schaafsma, Ron, de Weerdt, Okke, Klein, Saskia K., Delforge, Michel, Levin, Mark David, Bos, Gerard M., Jie, Kon Siong G., Sinnige, Harm, Coenen, Jules LLM, de Waal, Esther G., Zweegman, Sonja, Sonneveld, Pieter, Lokhorst, Henk M., MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, van de Donk, Niels WCJ, van der Holt, Bronno, Minnema, Monique C., Vellenga, Edo, Croockewit, Sandra, Kersten, Marie José, von dem Borne, Peter A., Ypma, Paula, Schaafsma, Ron, de Weerdt, Okke, Klein, Saskia K., Delforge, Michel, Levin, Mark David, Bos, Gerard M., Jie, Kon Siong G., Sinnige, Harm, Coenen, Jules LLM, de Waal, Esther G., Zweegman, Sonja, Sonneveld, Pieter, and Lokhorst, Henk M.

Published
2018

42. Carfilzomib Combined with Thalidomide and Low-Dose Dexamethasone for Remission Induction and Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma: The Carthadex Trial

Author

Wester, Ruth, van der Holt, Bronno, Asselbergs, Emelie, Zweegman, Sonja, Kersten, Marie Jose, Vellenga, Edo, Kooij, Marinus van Marwijk, de Weerdt, Okke, Minnema, Monique C., Lonergan, Sarah, Palumbo, Antonio, Lokhorst, Henk M., Broyl, Annemiek, Iskander, Karim Saad, Sonneveld, Pieter, Hematology, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Treatment and quality of life, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Abstract

Introduction This phase 2 dose escalation trial of the European Myeloma Network investigated the combination of Carfilzomib with Thalidomide and dexamethasone (KTd) in newly diagnosed, transplant-eligible patients with multiple myeloma (MM) as induction and consolidation treatment (abstract ASH 2016 # 1141). We investigated the effect of intensified induction with 8 cycles of KTd (56 mg/m2 ) as compared with standard 4 cycles (27 - 56 mg/m2) on depth of response before and after high-dose Melphalan (HDM). Methods In this multicenter, open-label phase 2 trial, patients aged between 18 and 65 years with transplant eligible, newly diagnosed symptomatic MM were included. Four dose levels of Carfilzomib combined with Thalidomide and dexamethasone (KTd) for 4 cycles of induction therapy were used. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27, 36, 45 or 56 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. After induction, stem cell harvest was performed after Cyclophosphamide priming (2 to 4 g/m2 ) and G-CSF. Following HDM (200 mg/m2 ) and autologous stem cell transplantation, consolidation treatment consisted of 4 cycles of KTd in the same schedule except for a lower dose of Thalidomide (50mg) (abstract ASH 2016 # 1141). Next we investigated the potential benefit of prolonged induction therapy on response depth prior to and following HDM by using 8 cycles of KTd at the highest dose of Carfilzomib (56mg/m2 ) in the same schedule. The primary endpoint was response after induction therapy, specifically complete response (CR) and very good partial response (VGPR). Other endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results A total of 137 eligible patients were included. We report the response of 26 patients treated with 8 cycles of KTd induction therapy versus 111 patients treated with 4 cycles of KTd induction therapy with different dose levels of Carfilzomib. Median follow-up was 48 months [range 8-81 months]. Median age was 57 years. ISS stages I/II/III were 43%/35%/21% respectively. With 8 KTd, response after induction was CR/sCR in 27%, ≥ VGPR in 92% and ≥ PR in 96%. In contrast, with 4 KTd at 56 mg/m2 (20 patients) response after induction was CR/sCR in 20%, ≥ VGPR in 80% and ≥ PR in 90%. CR/sCR rate with 8 KTd increased to 42% after HDM and to 62% after consolidation treatment. In comparison, with 4 KTd at 56 mg/m2 CR/sCR rate increased to 30% after HDM and 65% after consolidation treatment. All dose levels combined given for 4 induction cycles showed response after induction of CR/sCR in 18%, ≥ VGPR in 65% and ≥ PR in 93%. CR/sCR rate increased to 31% after HDM and to 64% after consolidation treatment. See Table 1. Response based on risk status by ISS/FISH with 8 KTd showed a difference in CR/sCR rate after consolidation between standard risk (10/13, 77%) and high risk (3/8, 38%). High risk was defined as t(4;14) and/or del17p and/or add1q and/or ISS3. With 4 KTd at 56 mg/m2 CR/sCR rate in standard and high risk patients was 100% (7/7) and 50% (5/10) respectively. In all dose levels combined given for 4 induction cycles CR/sCR rate was 70% (32/46) and 58% (25/43) in standard and high risk patients respectively. Cardiac events grade 3 and 4 in patients treated with 8 KTd occurred in 2 patients (8%, heart failure). In comparison with 4 KTd at 56 mg/m2 heart failure grade 3 was reported in one patient (5%). In all dose levels combined given for 4 induction cycles cardiac events grade 3 and 4 included three patients with heart failure and 1 patient with chest pain (4%). In patients treated with 8 KTd PFS and OS at 12 months was 100%. With 4 KTd at 56 mg/m2 PFS and OS were 95% and 100% respectively and in all dose levels combined given for 4 induction cycles PFS and OS were 90% and 95% respectively at 12 months. Before ASH we will update results of PFS and OS. Conclusions Treatment with 8 induction cycles of KTd resulted in a deeper response before HDM and autologous stem cell transplantation. However, depth of response was comparable after consolidation treatment between patients treated with 4 and 8 induction cycles. Effect on survival will be analyzed when longer follow-up is available. (Table Presented).

Published
2017

43. Improved Survival with Thalidomide Before and after Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma: Long-Term Results from the HOVON-50 Study

Author

van de Donk, Niels, primary, van der Holt, Bronno, additional, Minnema, Monique C., additional, Vellenga, Edo, additional, Croockewit, Sandra, additional, Kersten, Marie José, additional, von dem Borne, Peter A., additional, Ypma, Paula, additional, Schaafsma, Ron, additional, de Weerdt, Okke, additional, Klein, Saskia K., additional, Delforge, Michel, additional, Levin, Mark-David, additional, Bos, Gerard M., additional, Jie, Kon-Siong G., additional, Sinnige, Harm, additional, Coenen, Jules L.L.M., additional, de Waal, Esther G., additional, Zweegman, Sonja, additional, Sonneveld, Pieter, additional, and Lokhorst, Henk M., additional

Published
2018
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44. Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission

Author

Versluis, Jurjen, primary, Kalin, Burak, additional, Zeijlemaker, Wendelien, additional, Passweg, Jakob, additional, Graux, Carlos, additional, Manz, Markus G., additional, Vekemans, Marie-Christiane, additional, Biemond, Bart J., additional, Legdeur, Marie-Cecile J.C., additional, Kooy, Marinus van Marwijk, additional, de Weerdt, Okke, additional, Wijermans, Pierre W., additional, Hoogendoorn, Mels, additional, Bargetzi, Mario J., additional, Kuball, Juergen, additional, Schouten, Harry C., additional, van der Velden, Vincent H.J., additional, Janssen, Jeroen J.W.M., additional, Pabst, Thomas, additional, Lowenberg, Bob, additional, Jongen-Lavrencic, Mojca, additional, Schuurhuis, Gerrit Jan, additional, Ossenkoppele, Gert, additional, and Cornelissen, Jan J., additional

Published
2017
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45. Therapeutic value of clofarabine in younger and middle aged (18 - 65 yrs) adults with newly diagnosed AML.

Author

UCL - SSS/IREC/MONT-Pôle Mont Godinne, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, van Norden, Yvette, Biemond, Bart J, Schouten, Harry C, Spertini, Olivier, Vellenga, Edo, Graux, Carlos, Havelange, Violaine, de Greef, Georgine E, de Weerdt, Okke, Legdeur, Marie-Cecile J C, Kuball, Juergen, van Marwijk Kooy, Marinus, Gjertsen, Bjorn T, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, van Lammeren-Venema, Daniëlle, Hodossy, Beata, Breems, Dimitri A, Chalandon, Yves, Passweg, Jakob, Valk, Peter J M, Manz, Markus G, Ossenkoppele, Gert J, Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), Swiss Group for Clinical Cancer Research (SAKK), UCL - SSS/IREC/MONT-Pôle Mont Godinne, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, van Norden, Yvette, Biemond, Bart J, Schouten, Harry C, Spertini, Olivier, Vellenga, Edo, Graux, Carlos, Havelange, Violaine, de Greef, Georgine E, de Weerdt, Okke, Legdeur, Marie-Cecile J C, Kuball, Juergen, van Marwijk Kooy, Marinus, Gjertsen, Bjorn T, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, van Lammeren-Venema, Daniëlle, Hodossy, Beata, Breems, Dimitri A, Chalandon, Yves, Passweg, Jakob, Valk, Peter J M, Manz, Markus G, Ossenkoppele, Gert J, Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), and Swiss Group for Clinical Cancer Research (SAKK)

Abstract

Clofarabine has demonstrated antileukemic activity in acute myeloid leukemia (AML) but has yet to be critically evaluated in younger adults in the frontline with standard chemotherapy. We compared two induction regimens in newly diagnosed patients aged 18-65 with AML/high risk MDS, i.e., idarubicine-cytarabine (cycle I) and amsacrine-cytarabine (cycle II) without or with clofarabine (10 mg/m(2) on days 1-5 of each of both cycles). Consolidation involved chemotherapy with or without hematopoietic stem cell transplantation. Event free survival (EFS, primary endpoint) and other clinical endpoints and toxicities were assessed. 402 and 393 evaluable patients were randomized to the control or clofarabine induction treatment arms. Complete remission rates (89%) did not differ but were attained faster with clofarabine (66% versus 75% after cycle I). Clofarabine added grade III-IV toxicities, and delayed hematological recovery. At a median follow up of 36 months, the study reveals no differences in overall survival and EFS between the control (EFS 35% ±3 (SE) at 4 years) and clofarabine treatments (38% ±3) but a markedly reduced relapse rate (44% ± 3 versus 35% ± 3) in favor of clofarabine and an increased death probability in remission (15% ±2 versus 22% ±3). In the subgroup analyses, clofarabine improved OS and EFS for European-Leukemia-Net ELN 2010 Intermediate-I prognostic risk AML (EFS 26 % ±4 versus 40% ±5 at 4 years, Cox-P=0.002) and for the intermediate risk genotype NPM1wild type/FLT3 without internal-tandem-duplications (EFS 18% ±5 versus 40% ±7, Cox- P<0.001). Clofarabine improves survival in subsets of intermediate-risk AML only.

Published
2017

46. Graft-Versus-Leukemia Effect of Allogeneic Stem-Cell Transplantation and Minimal Residual Disease in Patients With Acute Myeloid Leukemia in First Complete Remission.

Author

UCL - (SLuc) Centre du cancer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, Versluis, Jurjen, Kalin, Burak, Zeijlemaker, Wendelien, Passweg, Jakob, Graux, Carlos, Manz, Markus G, Vekemans, Marie-Christiane, Biemond, Bart J, Legdeur, Marie-Cecile J C, Kooy, Marinus van Marwijk, de Weerdt, Okke, Wijermans, Pierre W, Hoogendoorn, Mels, Bargetzi, Mario J, Kuball, Juergen, Schouten, Harry C, van der Velden, Vincent H J, Janssen, Jeroen J W M, Pabst, Thomas, Lowenberg, Bob, Jongen-Lavrencic, Mojca, Schuurhuis, Gerrit Jan, Ossenkoppele, Gert, Cornelissen, Jan J, UCL - (SLuc) Centre du cancer, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'hématologie, Versluis, Jurjen, Kalin, Burak, Zeijlemaker, Wendelien, Passweg, Jakob, Graux, Carlos, Manz, Markus G, Vekemans, Marie-Christiane, Biemond, Bart J, Legdeur, Marie-Cecile J C, Kooy, Marinus van Marwijk, de Weerdt, Okke, Wijermans, Pierre W, Hoogendoorn, Mels, Bargetzi, Mario J, Kuball, Juergen, Schouten, Harry C, van der Velden, Vincent H J, Janssen, Jeroen J W M, Pabst, Thomas, Lowenberg, Bob, Jongen-Lavrencic, Mojca, Schuurhuis, Gerrit Jan, Ossenkoppele, Gert, and Cornelissen, Jan J

Abstract

The detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) may improve future risk-adapted treatment strategies. We assessed whether MRD-positive and MRD-negative patients with AML benefit differently from the graft-versus-leukemia effect of allogeneic hematopoietic stem-cell transplantation (alloHSCT). A total of 1,511 patients were treated in subsequent Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research AML trials, of whom 547 obtained a first complete remission, received postremission treatment (PRT), and had available flow cytometric MRD before PRT. MRD positivity was defined as more than 0.1% cells with a leukemia-associated immunophenotype within the WBC compartment. PRT consisted of alloHSCT (n = 282), conventional PRT by a third cycle of chemotherapy (n = 160), or autologous hematopoietic stem-cell transplantation (n = 105). MRD was positive in 129 patients (24%) after induction chemotherapy before proceeding to PRT. Overall survival and relapse-free survival were significantly better in patients without MRD before PRT compared with MRD-positive patients (65% ± 2% 50% ± 5% at 4 years; = .002; and 58% ± 3% 38% ± 4%; < .001, respectively), which was mainly because of a lower cumulative incidence of relapse (32% ± 2% compared with 54% ± 4%; < .001, respectively). Multivariable analysis with adjustment for covariables showed that the incidence of relapse was significantly reduced after alloHSCT compared with chemotherapy or autologous hematopoietic stem cell transplantation (hazard ratio [HR], 0.36; < .001), which was similarly exerted in both MRD-negative and MRD-positive patients (HR, 0.38; < .001; and HR, 0.35; < .001, respectively). The graft-versus-leukemia effect of alloHSCT is equally present in MRD-positive and MRD-negative patients, which advocates a personalized application of alloHSCT, taking into account the risk of relapse determined by AML risk group and MRD status, as

Published
2017

47. ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)–Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial

Author

Externen Hematologie, Other research (not in main researchprogram), UMC Utrecht, MS Radiotherapie, Cancer, Fermé, Christophe, Thomas, José, Brice, Pauline, Casasnovas, Olivier, Vranovsky, Andrej, Bologna, Serge, Lugtenburg, Pieternella J, Bouabdallah, Réda, Carde, Patrice, Sebban, Catherine, Eghbali, Houchingue, Salles, Gilles, Van Imhoff, Gustaaf W., Thyss, Antoine, Noordijk, Evert M., Reman, Oumédaly, Lybeert, Marnix L.M., Janvier, Maud, Spina, Michele, Audhuy, Bruno, Raemaekers, John M M, Delarue, Richard, Anglaret, Bruno, de Weerdt, Okke, Marjanovic, Zora, Tersteeg, Robbert J.H.A., de Jong, Daphne, Brière, Josette, Henry-Amar, Michel, for the European Organisation for Research and Treatment of Cancer Lymphoma Group, and, the Groupe d'Étude des Lymphomes de l'Adulte, Externen Hematologie, Other research (not in main researchprogram), UMC Utrecht, MS Radiotherapie, Cancer, Fermé, Christophe, Thomas, José, Brice, Pauline, Casasnovas, Olivier, Vranovsky, Andrej, Bologna, Serge, Lugtenburg, Pieternella J, Bouabdallah, Réda, Carde, Patrice, Sebban, Catherine, Eghbali, Houchingue, Salles, Gilles, Van Imhoff, Gustaaf W., Thyss, Antoine, Noordijk, Evert M., Reman, Oumédaly, Lybeert, Marnix L.M., Janvier, Maud, Spina, Michele, Audhuy, Bruno, Raemaekers, John M M, Delarue, Richard, Anglaret, Bruno, de Weerdt, Okke, Marjanovic, Zora, Tersteeg, Robbert J.H.A., de Jong, Daphne, Brière, Josette, Henry-Amar, Michel, for the European Organisation for Research and Treatment of Cancer Lymphoma Group, and, and the Groupe d'Étude des Lymphomes de l'Adulte

Published
2017

48. Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML

Author

Stamceltransplantatieteam, CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, van Norden, Yvette, Biemond, Bart J., Schouten, Harry C., Spertini, Olivier, Vellenga, Edo, Graux, Carlos, Havelange, Violaine, de Greef, Georgine E, De Weerdt, Okke, Legdeur, Marie-Cecile J C, Kuball, Juergen, van Marwijk Kooy, Marinus, Gjertsen, Bjorn T, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, van Lammeren-Venema, Daniëlle, Hodossy, Beata, Breems, Dimitri A, Chalandon, Yves, Passweg, Jakob, Valk, Peter J M, Manz, Markus G, Ossenkoppele, Gert J, Stamceltransplantatieteam, CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Löwenberg, Bob, Pabst, Thomas, Maertens, Johan, van Norden, Yvette, Biemond, Bart J., Schouten, Harry C., Spertini, Olivier, Vellenga, Edo, Graux, Carlos, Havelange, Violaine, de Greef, Georgine E, De Weerdt, Okke, Legdeur, Marie-Cecile J C, Kuball, Juergen, van Marwijk Kooy, Marinus, Gjertsen, Bjorn T, Jongen-Lavrencic, Mojca, van de Loosdrecht, Arjan A, van Lammeren-Venema, Daniëlle, Hodossy, Beata, Breems, Dimitri A, Chalandon, Yves, Passweg, Jakob, Valk, Peter J M, Manz, Markus G, and Ossenkoppele, Gert J

Published
2017

49. ABVD or BEACOPP baseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)–Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial

Author

Fermé, Christophe, primary, Thomas, José, additional, Brice, Pauline, additional, Casasnovas, Olivier, additional, Vranovsky, Andrej, additional, Bologna, Serge, additional, Lugtenburg, Pieternella J., additional, Bouabdallah, Réda, additional, Carde, Patrice, additional, Sebban, Catherine, additional, Eghbali, Houchingue, additional, Salles, Gilles, additional, van Imhoff, Gustaaf W., additional, Thyss, Antoine, additional, Noordijk, Evert M., additional, Reman, Oumédaly, additional, Lybeert, Marnix L.M., additional, Janvier, Maud, additional, Spina, Michele, additional, Audhuy, Bruno, additional, Raemaekers, John M.M., additional, Delarue, Richard, additional, Anglaret, Bruno, additional, de Weerdt, Okke, additional, Marjanovic, Zora, additional, Tersteeg, Robbert J.H.A., additional, de Jong, Daphne, additional, Brière, Josette, additional, and Henry-Amar, Michel, additional

Published
2017
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50. Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Author

Wester, Ruth, primary, van der Holt, Bronno, additional, Asselbergs, Emelie, additional, van Duin, Mark, additional, Zweegman, Sonja, additional, Kersten, Marie Jose, additional, Vellenga, Edo, additional, van Marwijk Kooy, Marinus, additional, de Weerdt, Okke, additional, Minnema, Monique, additional, Lonergan, Sarah, additional, Palumbo, Antonio, additional, Lokhorst, Henk M., additional, Broijl, Annemiek, additional, and Sonneveld, Pieter, additional

Published
2016
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