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2. Multiscale statistical testing for connectome-wide association studies in fMRI

Author

Bellec, P., Benhajali, Y., Carbonell, F., Dansereau, C., Albouy, G., Pelland, M., Craddock, C., Collignon, O., Doyon, J., Stip, E., and Orban, P.

Subjects
Quantitative Biology - Quantitative Methods, Computer Science - Computer Vision and Pattern Recognition, Statistics - Applications
Abstract

Alterations in brain connectivity have been associated with a variety of clinical disorders using functional magnetic resonance imaging (fMRI). We investigated empirically how the number of brain parcels (or scale) impacted the results of a mass univariate general linear model (GLM) on connectomes. The brain parcels used as nodes in the connectome analysis were functionnally defined by a group cluster analysis. We first validated that a classic Benjamini-Hochberg procedure with parametric GLM tests did control appropriately the false-discovery rate (FDR) at a given scale. We then observed on realistic simulations that there was no substantial inflation of the FDR across scales, as long as the FDR was controlled independently within each scale, and the presence of true associations could be established using an omnibus permutation test combining all scales. Second, we observed both on simulations and on three real resting-state fMRI datasets (schizophrenia, congenital blindness, motor practice) that the rate of discovery varied markedly as a function of scales, and was relatively higher for low scales, below 25. Despite the differences in discovery rate, the statistical maps derived at different scales were generally very consistent in the three real datasets. Some seeds still showed effects better observed around 50, illustrating the potential benefits of multiscale analysis. On real data, the statistical maps agreed well with the existing literature. Overall, our results support that the multiscale GLM connectome analysis with FDR is statistically valid and can capture biologically meaningful effects in a variety of experimental conditions., Comment: 54 pages, 12 main figures, 1 main table, 10 supplementary figures, 1 supplementary table

Published
2014

3. Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3

Author

Levis, M, Hamadani, M, Logan, B, Jones, R, Singh, A, Litzow, M, Wingard, J, Papadopoulos, E, Perl, A, Soiffer, R, Ustun, C, Ueda Oshima, M, Uy, G, Waller, E, Vasu, S, Solh, M, Mishra, A, Muffly, L, Kim, H, Mikesch, J, Najima, Y, Onozawa, M, Thomson, K, Nagler, A, Wei, A, Marcucci, G, Geller, N, Hasabou, N, Delgado, D, Rosales, M, Hill, J, Gill, S, Nuthethi, R, King, D, Wittsack, H, Mendizabal, A, Devine, S, Horowitz, M, Chen, Y, Agura, E, Altman, J, Anagnostopoulos, A, Anand, S, Artz, A, Aulitzky, W, Balderman, S, Ballen, K, Becker, M, Beguin, Y, Berkahn, L, Berneman, Z, Bhatt, V, Bilmon, I, Bonifazi, F, Briggs, A, Bruno, B, Brunstein, C, Byrne, M, Byrne, J, Cabrero, M, Cairoli, R, Carrum, G, Cerny, J, Cheong, J, Ciceri, F, Colorado, M, Cook, R, Couriel, D, Craddock, C, Damon, L, Deol, A, Desbrosses, Y, Di Grazia, C, Di Stasi, A, Dias, A, Dorritie, K, Essell, J, Eto, T, Farag, S, Forcade, E, Frankfurt, O, Fujiwara, S, Fukuda, T, Fukushima, K, Furst, S, Goto, T, Hall, A, Hatta, S, Hicheri, Y, Horwitz, M, Hou, H, How, J, Howard, D, Hsu, W, Huynh, A, Irvine, D, Ishikawa, T, Jamieson, K, Jedrzejczak, W, Jethava, Y, Jimenez, A, Jung, C, Kanda, J, Karakasis, D, Kato, J, Kekre, N, Khera, N, Klein, A, Kobbe, G, Kornblit, B, Kota, V, Lachance, S, Leber, B, Lee, C, Lee, J, Lin, T, Liu, T, Martelli, M, Martinez, C, Matsuoka, K, Mccarty, J, Mendez, L, Michelis, F, Mineishi, S, Mohty, M, Moors, I, Motyckova, G, Mueller, L, Nakamae, H, Nakano, N, Nathan, S, Nicholson, E, Norkin, M, Ogawa, Y, Olesen, G, Oluwole, O, Pantin, J, Paulson, K, Pemberton, L, Perera, T, Piatkowska-Jakubas, B, Poire, X, Protheroe, R, Rambaldi, A, Ritchie, D, Ross, K, Rubio, M, Santarone, S, Sanz Caballer, J, Sawa, M, Schaar, D, Scheid, C, Schriber, J, Seropian, S, Shah, N, Shore, T, Gil, J, Sobecks, R, Socie, G, Sprague, K, Spyridonidis, A, Stelljes, M, Stiff, P, Stuart, R, Tanaka, M, Tandra, A, Tholouli, E, Thomas, X, Tiribelli, M, Tomlinson, B, Tsirigotis, P, Tzachanis, D, Uchida, N, Ueda, M, Valcarcel Ferreiras, D, Wagner, E, Watson, A, Weisdorf, D, Wolschke, C, Wrobel, T, Yakoub-Agha, I, Yamauchi, T, Yared, J, Yeh, S, Yoon, S, Yoshihara, S, Null, N, Levis, Mark J., Hamadani, Mehdi, Logan, Brent, Jones, Richard J., Singh, Anurag K., Litzow, Mark, Wingard, John R., Papadopoulos, Esperanza B., Perl, Alexander E., Soiffer, Robert J., Ustun, Celalettin, Ueda Oshima, Masumi, Uy, Geoffrey L., Waller, Edmund K., Vasu, Sumithra, Solh, Melhem, Mishra, Asmita, Muffly, Lori, Kim, Hee-Je, Mikesch, Jan-Henrik, Najima, Yuho, Onozawa, Masahiro, Thomson, Kirsty, Nagler, Arnon, Wei, Andrew H., Marcucci, Guido, Geller, Nancy L., Hasabou, Nahla, Delgado, David, Rosales, Matt, Hill, Jason, Gill, Stanley C., Nuthethi, Rishita, King, Denise, Wittsack, Heather, Mendizabal, Adam, Devine, Steven M., Horowitz, Mary M., Chen, Yi-Bin, Agura, Ed, Altman, Jessica, Anagnostopoulos, Achiles, Anand, Sarah, Artz, Andrew, Aulitzky, Walter, Balderman, Sophia, Ballen, Karen, Becker, Michael, Beguin, Yves, Berkahn, Leanne, Berneman, Zwi, Bhatt, Vijaya, Bilmon, Ian, Bonifazi, Francesca, Briggs, Adrienne, Bruno, Benedetto, Brunstein, Claudio, Byrne, Michael, Byrne, Jenny, Cabrero, Monica, Cairoli, Roberto, Carrum, George, Cerny, Jan, Cheong, June-Won, Ciceri, Fabio, Colorado, Mercedes, Cook, Rachel, Couriel, Daniel, Craddock, Charles, Damon, Lloyd, Deol, Abhinav, Desbrosses, Yohan, Devine, Steve, Di Grazia, Carmela, Di Stasi, Antonio, Dias, Ajoy, Dorritie, Kathy, Essell, James, Eto, Tetsuya, Farag, Sherif, Forcade, Edouard, Frankfurt, Olga, Fujiwara, Shinichiro, Fukuda, Takahiro, Fukushima, Kentaro, Furst, Sabine, Goto, Tatsunori, Hall, Aric, Hatta, Shunsuke, Hicheri, Yosr, Horwitz, Mitchell, Hou, Hsin-An, How, Jonathan, Howard, Dianna, Hsu, Wei-Hsun (Blake), Huynh, Anne, Irvine, David, Ishikawa, Takayuki, Jamieson, Katarzyna, Jedrzejczak, Wieslaw, Jethava, Yogesh, Jimenez, Antonio, Jung, Chul Won, Kanda, Junya, Karakasis, Dimitrios, Kato, Jun, Kekre, Natasha, Khera, Nandita, Klein, Andreas, Kobbe, Guido, Kornblit, Brian, Kota, Vamsi, Lachance, Silvy, Leber, Brian, Lee, Catherine, Lee, Je Hwan, Lin, Tung-Liang, Liu, Ta-Chih, Martelli, Maurizio, Martinez, Carmen, Matsuoka, Kenichi, McCarty, John, Mendez, Lourdes, Michelis, Fotios, Mineishi, Shin, Mohty, Mohamad, Moors, Ine, Motyckova, Gabriela, Mueller, Lutz, Nakamae, Hirohisa, Nakano, Nobuaki, Nathan, Sunita, Nicholson, Emma, Norkin, Maxim, Ogawa, Yoshiaki, Olesen, Gitte, Oluwole, Olalekan, Pantin, Jeremy, Paulson, Kristjan, Pemberton, Lucy, Perera, Travis, Piatkowska-Jakubas, Beata, Poire, Xavier, Protheroe, Rachel, Rambaldi, Alessandro, Ritchie, David, Ross, Kelly, Rubio, Marie-Therese, Santarone, Stella, Sanz Caballer, Jaime, Sawa, Masashi, Schaar, Dale, Scheid, Christoph, Schriber, Jeffrey, Seropian, Stuart, Shah, Nilay, Shah, Nirav, Shore, Tsiporah, Gil, Jorge Sierra, Singh, Anurag, Sobecks, Ronald, Socie, Gerard, Soiffer, Robert, Sprague, Kellie, Spyridonidis, Alexandros, Stelljes, Matthias, Stiff, Patrick, Stuart, Robert, Tanaka, Masatsugu, Tandra, Anand, Tholouli, Eleni, Thomas, Xavier, Tiribelli, Mario, Tomlinson, Benjamin, Tsirigotis, Panagiotis, Tzachanis, Dimitrios, Uchida, Naoyuki, Ueda, Masumi, Valcarcel Ferreiras, David, Wagner, Eva, Watson, Anne-Marie, Weisdorf, Daniel, Wolschke, Christine, Wrobel, Tomasz, Yakoub-Agha, Ibrahim, Yamauchi, Takuji, Yared, Jean, Yeh, Su-Peng, Yoon, Sung-Soo, Yoshihara, Satoshi, null, null, Levis, M, Hamadani, M, Logan, B, Jones, R, Singh, A, Litzow, M, Wingard, J, Papadopoulos, E, Perl, A, Soiffer, R, Ustun, C, Ueda Oshima, M, Uy, G, Waller, E, Vasu, S, Solh, M, Mishra, A, Muffly, L, Kim, H, Mikesch, J, Najima, Y, Onozawa, M, Thomson, K, Nagler, A, Wei, A, Marcucci, G, Geller, N, Hasabou, N, Delgado, D, Rosales, M, Hill, J, Gill, S, Nuthethi, R, King, D, Wittsack, H, Mendizabal, A, Devine, S, Horowitz, M, Chen, Y, Agura, E, Altman, J, Anagnostopoulos, A, Anand, S, Artz, A, Aulitzky, W, Balderman, S, Ballen, K, Becker, M, Beguin, Y, Berkahn, L, Berneman, Z, Bhatt, V, Bilmon, I, Bonifazi, F, Briggs, A, Bruno, B, Brunstein, C, Byrne, M, Byrne, J, Cabrero, M, Cairoli, R, Carrum, G, Cerny, J, Cheong, J, Ciceri, F, Colorado, M, Cook, R, Couriel, D, Craddock, C, Damon, L, Deol, A, Desbrosses, Y, Di Grazia, C, Di Stasi, A, Dias, A, Dorritie, K, Essell, J, Eto, T, Farag, S, Forcade, E, Frankfurt, O, Fujiwara, S, Fukuda, T, Fukushima, K, Furst, S, Goto, T, Hall, A, Hatta, S, Hicheri, Y, Horwitz, M, Hou, H, How, J, Howard, D, Hsu, W, Huynh, A, Irvine, D, Ishikawa, T, Jamieson, K, Jedrzejczak, W, Jethava, Y, Jimenez, A, Jung, C, Kanda, J, Karakasis, D, Kato, J, Kekre, N, Khera, N, Klein, A, Kobbe, G, Kornblit, B, Kota, V, Lachance, S, Leber, B, Lee, C, Lee, J, Lin, T, Liu, T, Martelli, M, Martinez, C, Matsuoka, K, Mccarty, J, Mendez, L, Michelis, F, Mineishi, S, Mohty, M, Moors, I, Motyckova, G, Mueller, L, Nakamae, H, Nakano, N, Nathan, S, Nicholson, E, Norkin, M, Ogawa, Y, Olesen, G, Oluwole, O, Pantin, J, Paulson, K, Pemberton, L, Perera, T, Piatkowska-Jakubas, B, Poire, X, Protheroe, R, Rambaldi, A, Ritchie, D, Ross, K, Rubio, M, Santarone, S, Sanz Caballer, J, Sawa, M, Schaar, D, Scheid, C, Schriber, J, Seropian, S, Shah, N, Shore, T, Gil, J, Sobecks, R, Socie, G, Sprague, K, Spyridonidis, A, Stelljes, M, Stiff, P, Stuart, R, Tanaka, M, Tandra, A, Tholouli, E, Thomas, X, Tiribelli, M, Tomlinson, B, Tsirigotis, P, Tzachanis, D, Uchida, N, Ueda, M, Valcarcel Ferreiras, D, Wagner, E, Watson, A, Weisdorf, D, Wolschke, C, Wrobel, T, Yakoub-Agha, I, Yamauchi, T, Yared, J, Yeh, S, Yoon, S, Yoshihara, S, Null, N, Levis, Mark J., Hamadani, Mehdi, Logan, Brent, Jones, Richard J., Singh, Anurag K., Litzow, Mark, Wingard, John R., Papadopoulos, Esperanza B., Perl, Alexander E., Soiffer, Robert J., Ustun, Celalettin, Ueda Oshima, Masumi, Uy, Geoffrey L., Waller, Edmund K., Vasu, Sumithra, Solh, Melhem, Mishra, Asmita, Muffly, Lori, Kim, Hee-Je, Mikesch, Jan-Henrik, Najima, Yuho, Onozawa, Masahiro, Thomson, Kirsty, Nagler, Arnon, Wei, Andrew H., Marcucci, Guido, Geller, Nancy L., Hasabou, Nahla, Delgado, David, Rosales, Matt, Hill, Jason, Gill, Stanley C., Nuthethi, Rishita, King, Denise, Wittsack, Heather, Mendizabal, Adam, Devine, Steven M., Horowitz, Mary M., Chen, Yi-Bin, Agura, Ed, Altman, Jessica, Anagnostopoulos, Achiles, Anand, Sarah, Artz, Andrew, Aulitzky, Walter, Balderman, Sophia, Ballen, Karen, Becker, Michael, Beguin, Yves, Berkahn, Leanne, Berneman, Zwi, Bhatt, Vijaya, Bilmon, Ian, Bonifazi, Francesca, Briggs, Adrienne, Bruno, Benedetto, Brunstein, Claudio, Byrne, Michael, Byrne, Jenny, Cabrero, Monica, Cairoli, Roberto, Carrum, George, Cerny, Jan, Cheong, June-Won, Ciceri, Fabio, Colorado, Mercedes, Cook, Rachel, Couriel, Daniel, Craddock, Charles, Damon, Lloyd, Deol, Abhinav, Desbrosses, Yohan, Devine, Steve, Di Grazia, Carmela, Di Stasi, Antonio, Dias, Ajoy, Dorritie, Kathy, Essell, James, Eto, Tetsuya, Farag, Sherif, Forcade, Edouard, Frankfurt, Olga, Fujiwara, Shinichiro, Fukuda, Takahiro, Fukushima, Kentaro, Furst, Sabine, Goto, Tatsunori, Hall, Aric, Hatta, Shunsuke, Hicheri, Yosr, Horwitz, Mitchell, Hou, Hsin-An, How, Jonathan, Howard, Dianna, Hsu, Wei-Hsun (Blake), Huynh, Anne, Irvine, David, Ishikawa, Takayuki, Jamieson, Katarzyna, Jedrzejczak, Wieslaw, Jethava, Yogesh, Jimenez, Antonio, Jung, Chul Won, Kanda, Junya, Karakasis, Dimitrios, Kato, Jun, Kekre, Natasha, Khera, Nandita, Klein, Andreas, Kobbe, Guido, Kornblit, Brian, Kota, Vamsi, Lachance, Silvy, Leber, Brian, Lee, Catherine, Lee, Je Hwan, Lin, Tung-Liang, Liu, Ta-Chih, Martelli, Maurizio, Martinez, Carmen, Matsuoka, Kenichi, McCarty, John, Mendez, Lourdes, Michelis, Fotios, Mineishi, Shin, Mohty, Mohamad, Moors, Ine, Motyckova, Gabriela, Mueller, Lutz, Nakamae, Hirohisa, Nakano, Nobuaki, Nathan, Sunita, Nicholson, Emma, Norkin, Maxim, Ogawa, Yoshiaki, Olesen, Gitte, Oluwole, Olalekan, Pantin, Jeremy, Paulson, Kristjan, Pemberton, Lucy, Perera, Travis, Piatkowska-Jakubas, Beata, Poire, Xavier, Protheroe, Rachel, Rambaldi, Alessandro, Ritchie, David, Ross, Kelly, Rubio, Marie-Therese, Santarone, Stella, Sanz Caballer, Jaime, Sawa, Masashi, Schaar, Dale, Scheid, Christoph, Schriber, Jeffrey, Seropian, Stuart, Shah, Nilay, Shah, Nirav, Shore, Tsiporah, Gil, Jorge Sierra, Singh, Anurag, Sobecks, Ronald, Socie, Gerard, Soiffer, Robert, Sprague, Kellie, Spyridonidis, Alexandros, Stelljes, Matthias, Stiff, Patrick, Stuart, Robert, Tanaka, Masatsugu, Tandra, Anand, Tholouli, Eleni, Thomas, Xavier, Tiribelli, Mario, Tomlinson, Benjamin, Tsirigotis, Panagiotis, Tzachanis, Dimitrios, Uchida, Naoyuki, Ueda, Masumi, Valcarcel Ferreiras, David, Wagner, Eva, Watson, Anne-Marie, Weisdorf, Daniel, Wolschke, Christine, Wrobel, Tomasz, Yakoub-Agha, Ibrahim, Yamauchi, Takuji, Yared, Jean, Yeh, Su-Peng, Yoon, Sung-Soo, Yoshihara, Satoshi, and null, null

Abstract

PURPOSEAllogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit.METHODSAdults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS.RESULTSThree hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P =.0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P =.0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P =.575).CONCLUSIONAlthough the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Published
2024

4. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Ruggeri, A, de Wreede, L, Muller, C, Crivello, P, Bonneville, E, Petersdorf, E, Socie, G, Dubois, V, Niittyvuopio, R, Perasaari, J, Yakoub-Agha, I, Cornelissen, J, Wieten, L, Gedde-Dahl, T, Forcade, E, Crawley, C, Marsh, S, Gandemer, V, Tholouli, E, Bulabois, C, Huynh, A, Choi, G, Deconinck, E, Itala-Remes, M, Lenhoff, S, Bengtsson, M, Johansson, J, van Gorkom, G, Hoogenboom, J, Vago, L, Rocha, V, Bonini, C, Chabannon, C, Fleischhauer, K, Clausen, J, Holter, W, Kalhs, P, Beguin, Y, Bron, D, Deeren, D, Lung, W, Kerre, T, Poire, X, Selleslag, D, Schroyens, W, Jindra, P, Mayer, J, Vydra, J, Zak, P, Nielsen, B, Sengeloev, H, Kaare, A, Partanen, A, Bay, J, Bertrand, Y, Blaise, D, Bourhis, J, Chevallier, P, Cluzeau, T, Damaj, G, Fegueux, N, Guyotat, D, Hunault-Berger, M, Labussiere-Wallet, H, Leleu, X, Lioure, B, Maury, S, Michel, G, Mohty, M, Rubio, M, Tilly, H, Turlure, P, Bethge, W, Casper, J, Einsele, H, Ganser, A, Kroger, N, Martin, S, Platzbecker, U, Reinhardt, C, Schafer-Eckart, K, Thurner, L, Valerius, T, Wulf, G, Karakasis, D, Spyridonidis, A, Hauser, P, Remenyi, P, Reykdal, S, Mousavi, A, Angelucci, E, Arcese, W, Benedetti, F, Bernasconi, P, Biondi, A, Bonifazi, F, Carella, A, Carluccio, P, Casini, M, Cavanna, L, Ciceri, F, Cimino, G, Corradini, P, Fanin, R, Galieni, P, Grillo, G, Iori, A, La Nasa, G, Locatelli, F, Marotta, G, Martino, M, Mazza, P, Mordini, N, Musso, M, Olivieri, A, Pavone, V, Pane, F, Petrini, M, Pioltelli, P, Rambaldi, A, Ruggeri, M, Saccardi, R, Santarone, S, Scime, R, Sica, S, Tarella, C, Velardi, A, Visani, G, Zecca, M, Tanase, A, Kulagin, A, Savchenko, V, Lopez, C, Amor, A, Lopez, J, Caballero, D, Duarte, R, Cascon, M, Porras, R, Perez-Simon, J, Rovira, M, Sanz, J, Carrete, J, Cammenga, J, Isaksson, C, Mielke, S, Chalandon, Y, Passweg, J, Schanz, U, Meijer, E, Kuball, J, Veelken, J, Apperley, J, Bloor, A, Byrne, J, Carpenter, B, Clark, A, Collin, M, Craddock, C, Gibson, B, Khan, A, Martin, M, Medd, P, Nicholson, E, Orchard, K, Patel, A, Peniket, A, Potter, V, Snowden, J, Wilson, K, Ruggeri A., de Wreede L. C., Muller C. R., Crivello P., Bonneville E. F., Petersdorf E. W., Socie G., Dubois V., Niittyvuopio R., Perasaari J., Yakoub-Agha I., Cornelissen J. J., Wieten L., Gedde-Dahl T., Forcade E., Crawley C. R., Marsh S. G. E., Gandemer V., Tholouli E., Bulabois C. -E., Huynh A., Choi G., Deconinck E., Itala-Remes M., Lenhoff S., Bengtsson M., Johansson J. -E., van Gorkom G., Hoogenboom J. D., Vago L., Rocha V., Bonini C., Chabannon C., Fleischhauer K., Clausen J., Holter W., Kalhs P., Beguin Y., Bron D., Deeren D., Lung W. K., Kerre T., Poire X., Selleslag D., Schroyens W., Jindra P., Mayer J., Vydra J., Zak P., Nielsen B., Sengeloev H., Kaare A., Partanen A., Bay J., Bertrand Y., Blaise D., Bourhis J. H., Chevallier P., Cluzeau T., Damaj G., Fegueux N., Guyotat D., Hunault-Berger M., Labussiere-Wallet H., Leleu X., Lioure B., Maury S., Michel G., Mohty M., Rubio M. T., Tilly H., Turlure P., Bethge W., Casper J., Einsele H., Ganser A., Kroger N., Martin S., Platzbecker U., Reinhardt C., Schafer-Eckart K., Thurner L., Valerius T., Wulf G. G., Karakasis D., Spyridonidis A., Hauser P., Remenyi P., Reykdal S., Mousavi A., Angelucci E., Arcese W., Benedetti F., Bernasconi P., Biondi A., Bonifazi F., Carella A. M., Carluccio P., Casini M., Cavanna L., Ciceri F., Cimino G., Corradini P., Fanin R., Galieni P., Grillo G., Iori A. P., La Nasa G., Locatelli F., Marotta G., Martino M., Mazza P., Mordini N., Musso M., Olivieri A., Pavone V., Pane F., Petrini M., Pioltelli P., Rambaldi A., Ruggeri M., Saccardi R., Santarone S., Scime R., Sica S., Tarella C., Velardi A., Visani G., Zecca M., Tanase A., Kulagin A., Savchenko V., Lopez C. A., Amor A. A., Lopez J. L. B., Caballero D., Duarte R., Cascon M. J. P., Porras R. P., Perez-Simon J. A., Rovira M., Sanz J., Carrete J. P. T., Cammenga J., Isaksson C., Mielke S., Chalandon Y., Passweg J., Schanz U., Meijer E., Kuball J., Veelken J. H., Apperley J., Bloor A., Byrne J., Carpenter B., Clark A., Collin M., Craddock C., Gibson B. E., Khan A., Martin M., Medd P., Nicholson E., Orchard K., Patel A., Peniket A., Potter V., Snowden J., Wilson K. M. O., Ruggeri, A, de Wreede, L, Muller, C, Crivello, P, Bonneville, E, Petersdorf, E, Socie, G, Dubois, V, Niittyvuopio, R, Perasaari, J, Yakoub-Agha, I, Cornelissen, J, Wieten, L, Gedde-Dahl, T, Forcade, E, Crawley, C, Marsh, S, Gandemer, V, Tholouli, E, Bulabois, C, Huynh, A, Choi, G, Deconinck, E, Itala-Remes, M, Lenhoff, S, Bengtsson, M, Johansson, J, van Gorkom, G, Hoogenboom, J, Vago, L, Rocha, V, Bonini, C, Chabannon, C, Fleischhauer, K, Clausen, J, Holter, W, Kalhs, P, Beguin, Y, Bron, D, Deeren, D, Lung, W, Kerre, T, Poire, X, Selleslag, D, Schroyens, W, Jindra, P, Mayer, J, Vydra, J, Zak, P, Nielsen, B, Sengeloev, H, Kaare, A, Partanen, A, Bay, J, Bertrand, Y, Blaise, D, Bourhis, J, Chevallier, P, Cluzeau, T, Damaj, G, Fegueux, N, Guyotat, D, Hunault-Berger, M, Labussiere-Wallet, H, Leleu, X, Lioure, B, Maury, S, Michel, G, Mohty, M, Rubio, M, Tilly, H, Turlure, P, Bethge, W, Casper, J, Einsele, H, Ganser, A, Kroger, N, Martin, S, Platzbecker, U, Reinhardt, C, Schafer-Eckart, K, Thurner, L, Valerius, T, Wulf, G, Karakasis, D, Spyridonidis, A, Hauser, P, Remenyi, P, Reykdal, S, Mousavi, A, Angelucci, E, Arcese, W, Benedetti, F, Bernasconi, P, Biondi, A, Bonifazi, F, Carella, A, Carluccio, P, Casini, M, Cavanna, L, Ciceri, F, Cimino, G, Corradini, P, Fanin, R, Galieni, P, Grillo, G, Iori, A, La Nasa, G, Locatelli, F, Marotta, G, Martino, M, Mazza, P, Mordini, N, Musso, M, Olivieri, A, Pavone, V, Pane, F, Petrini, M, Pioltelli, P, Rambaldi, A, Ruggeri, M, Saccardi, R, Santarone, S, Scime, R, Sica, S, Tarella, C, Velardi, A, Visani, G, Zecca, M, Tanase, A, Kulagin, A, Savchenko, V, Lopez, C, Amor, A, Lopez, J, Caballero, D, Duarte, R, Cascon, M, Porras, R, Perez-Simon, J, Rovira, M, Sanz, J, Carrete, J, Cammenga, J, Isaksson, C, Mielke, S, Chalandon, Y, Passweg, J, Schanz, U, Meijer, E, Kuball, J, Veelken, J, Apperley, J, Bloor, A, Byrne, J, Carpenter, B, Clark, A, Collin, M, Craddock, C, Gibson, B, Khan, A, Martin, M, Medd, P, Nicholson, E, Orchard, K, Patel, A, Peniket, A, Potter, V, Snowden, J, Wilson, K, Ruggeri A., de Wreede L. C., Muller C. R., Crivello P., Bonneville E. F., Petersdorf E. W., Socie G., Dubois V., Niittyvuopio R., Perasaari J., Yakoub-Agha I., Cornelissen J. J., Wieten L., Gedde-Dahl T., Forcade E., Crawley C. R., Marsh S. G. E., Gandemer V., Tholouli E., Bulabois C. -E., Huynh A., Choi G., Deconinck E., Itala-Remes M., Lenhoff S., Bengtsson M., Johansson J. -E., van Gorkom G., Hoogenboom J. D., Vago L., Rocha V., Bonini C., Chabannon C., Fleischhauer K., Clausen J., Holter W., Kalhs P., Beguin Y., Bron D., Deeren D., Lung W. K., Kerre T., Poire X., Selleslag D., Schroyens W., Jindra P., Mayer J., Vydra J., Zak P., Nielsen B., Sengeloev H., Kaare A., Partanen A., Bay J., Bertrand Y., Blaise D., Bourhis J. H., Chevallier P., Cluzeau T., Damaj G., Fegueux N., Guyotat D., Hunault-Berger M., Labussiere-Wallet H., Leleu X., Lioure B., Maury S., Michel G., Mohty M., Rubio M. T., Tilly H., Turlure P., Bethge W., Casper J., Einsele H., Ganser A., Kroger N., Martin S., Platzbecker U., Reinhardt C., Schafer-Eckart K., Thurner L., Valerius T., Wulf G. G., Karakasis D., Spyridonidis A., Hauser P., Remenyi P., Reykdal S., Mousavi A., Angelucci E., Arcese W., Benedetti F., Bernasconi P., Biondi A., Bonifazi F., Carella A. M., Carluccio P., Casini M., Cavanna L., Ciceri F., Cimino G., Corradini P., Fanin R., Galieni P., Grillo G., Iori A. P., La Nasa G., Locatelli F., Marotta G., Martino M., Mazza P., Mordini N., Musso M., Olivieri A., Pavone V., Pane F., Petrini M., Pioltelli P., Rambaldi A., Ruggeri M., Saccardi R., Santarone S., Scime R., Sica S., Tarella C., Velardi A., Visani G., Zecca M., Tanase A., Kulagin A., Savchenko V., Lopez C. A., Amor A. A., Lopez J. L. B., Caballero D., Duarte R., Cascon M. J. P., Porras R. P., Perez-Simon J. A., Rovira M., Sanz J., Carrete J. P. T., Cammenga J., Isaksson C., Mielke S., Chalandon Y., Passweg J., Schanz U., Meijer E., Kuball J., Veelken J. H., Apperley J., Bloor A., Byrne J., Carpenter B., Clark A., Collin M., Craddock C., Gibson B. E., Khan A., Martin M., Medd P., Nicholson E., Orchard K., Patel A., Peniket A., Potter V., Snowden J., and Wilson K. M. O.

Published
2023

5. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Ruggeri, A., de Wreede, L. C., Muller, C. R., Crivello, P., Bonneville, E. F., Petersdorf, E. W., Socie, G., Dubois, V., Niittyvuopio, R., Perasaari, J., Yakoub-Agha, I., Cornelissen, J. J., Wieten, L., Gedde-Dahl, T., Forcade, E., Crawley, C. R., Marsh, S. G. E., Gandemer, V., Tholouli, E., Bulabois, C. -E., Huynh, A., Choi, G., Deconinck, E., Itala-Remes, M., Lenhoff, S., Bengtsson, M., Johansson, J. -E., van Gorkom, G., Hoogenboom, J. D., Vago, L., Rocha, V., Bonini, C., Chabannon, C., Fleischhauer, K., Clausen, J., Holter, W., Kalhs, P., Beguin, Y., Bron, D., Deeren, D., Lung, W. K., Kerre, T., Poire, X., Selleslag, D., Schroyens, W., Jindra, P., Mayer, J., Vydra, J., Zak, P., Nielsen, B., Sengeloev, H., Kaare, A., Partanen, A., Bay, J., Bertrand, Y., Blaise, D., Bourhis, J. H., Chevallier, P., Cluzeau, T., Damaj, G., Fegueux, N., Guyotat, D., Hunault-Berger, M., Labussiere-Wallet, H., Leleu, X., Lioure, B., Maury, S., Michel, G., Mohty, M., Rubio, M. T., Tilly, H., Turlure, P., Bethge, W., Casper, J., Einsele, H., Ganser, A., Kroger, N., Martin, S., Platzbecker, U., Reinhardt, C., Schafer-Eckart, K., Thurner, L., Valerius, T., Wulf, G. G., Karakasis, D., Spyridonidis, A., Hauser, P., Remenyi, P., Reykdal, S., Mousavi, A., Angelucci, E., Arcese, W., Benedetti, F., Bernasconi, P., Biondi, A., Bonifazi, F., Carella, A. M., Carluccio, P., Casini, M., Cavanna, L., Ciceri, F., Cimino, G., Corradini, P., Fanin, R., Galieni, P., Grillo, G., Iori, A. P., La Nasa, G., Locatelli, Franco, Marotta, G., Martino, M., Mazza, P., Mordini, N., Musso, M., Olivieri, A., Pavone, V., Pane, F., Petrini, M., Pioltelli, P., Rambaldi, A., Ruggeri, M., Saccardi, R., Santarone, S., Scime, R., Sica, S., Tarella, C., Velardi, A., Visani, G., Zecca, M., Tanase, A., Kulagin, A., Savchenko, V., Lopez, C. A., Amor, A. A., Lopez, J. L. B., Caballero, D., Duarte, R., Cascon, M. J. P., Porras, R. P., Perez-Simon, J. A., Rovira, M., Sanz, J., Carrete, J. P. T., Cammenga, J., Isaksson, C., Mielke, S., Chalandon, Y., Passweg, J., Schanz, U., Meijer, E., Kuball, J., Veelken, J. H., Apperley, J., Bloor, A., Byrne, J., Carpenter, B., Clark, A., Collin, M., Craddock, C., Gibson, B. E., Khan, A., Martin, M., Medd, P., Nicholson, E., Orchard, K., Patel, A., Peniket, A., Potter, V., Snowden, J., Wilson, K. M. O., Locatelli F. (ORCID:0000-0002-7976-3654), Ruggeri, A., de Wreede, L. C., Muller, C. R., Crivello, P., Bonneville, E. F., Petersdorf, E. W., Socie, G., Dubois, V., Niittyvuopio, R., Perasaari, J., Yakoub-Agha, I., Cornelissen, J. J., Wieten, L., Gedde-Dahl, T., Forcade, E., Crawley, C. R., Marsh, S. G. E., Gandemer, V., Tholouli, E., Bulabois, C. -E., Huynh, A., Choi, G., Deconinck, E., Itala-Remes, M., Lenhoff, S., Bengtsson, M., Johansson, J. -E., van Gorkom, G., Hoogenboom, J. D., Vago, L., Rocha, V., Bonini, C., Chabannon, C., Fleischhauer, K., Clausen, J., Holter, W., Kalhs, P., Beguin, Y., Bron, D., Deeren, D., Lung, W. K., Kerre, T., Poire, X., Selleslag, D., Schroyens, W., Jindra, P., Mayer, J., Vydra, J., Zak, P., Nielsen, B., Sengeloev, H., Kaare, A., Partanen, A., Bay, J., Bertrand, Y., Blaise, D., Bourhis, J. H., Chevallier, P., Cluzeau, T., Damaj, G., Fegueux, N., Guyotat, D., Hunault-Berger, M., Labussiere-Wallet, H., Leleu, X., Lioure, B., Maury, S., Michel, G., Mohty, M., Rubio, M. T., Tilly, H., Turlure, P., Bethge, W., Casper, J., Einsele, H., Ganser, A., Kroger, N., Martin, S., Platzbecker, U., Reinhardt, C., Schafer-Eckart, K., Thurner, L., Valerius, T., Wulf, G. G., Karakasis, D., Spyridonidis, A., Hauser, P., Remenyi, P., Reykdal, S., Mousavi, A., Angelucci, E., Arcese, W., Benedetti, F., Bernasconi, P., Biondi, A., Bonifazi, F., Carella, A. M., Carluccio, P., Casini, M., Cavanna, L., Ciceri, F., Cimino, G., Corradini, P., Fanin, R., Galieni, P., Grillo, G., Iori, A. P., La Nasa, G., Locatelli, Franco, Marotta, G., Martino, M., Mazza, P., Mordini, N., Musso, M., Olivieri, A., Pavone, V., Pane, F., Petrini, M., Pioltelli, P., Rambaldi, A., Ruggeri, M., Saccardi, R., Santarone, S., Scime, R., Sica, S., Tarella, C., Velardi, A., Visani, G., Zecca, M., Tanase, A., Kulagin, A., Savchenko, V., Lopez, C. A., Amor, A. A., Lopez, J. L. B., Caballero, D., Duarte, R., Cascon, M. J. P., Porras, R. P., Perez-Simon, J. A., Rovira, M., Sanz, J., Carrete, J. P. T., Cammenga, J., Isaksson, C., Mielke, S., Chalandon, Y., Passweg, J., Schanz, U., Meijer, E., Kuball, J., Veelken, J. H., Apperley, J., Bloor, A., Byrne, J., Carpenter, B., Clark, A., Collin, M., Craddock, C., Gibson, B. E., Khan, A., Martin, M., Medd, P., Nicholson, E., Orchard, K., Patel, A., Peniket, A., Potter, V., Snowden, J., Wilson, K. M. O., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2023

6. Optimizing real time fMRI neurofeedback for therapeutic discovery and development

Author

Stoeckel, L.E., Garrison, K.A., Ghosh, S.S., Wighton, P., Hanlon, C.A., Gilman, J.M., Greer, S., Turk-Browne, N.B., deBettencourt, M.T., Scheinost, D., Craddock, C., Thompson, T., Calderon, V., Bauer, C.C., George, M., Breiter, H.C., Whitfield-Gabrieli, S., Gabrieli, J.D., LaConte, S.M., Hirshberg, L., Brewer, J.A., Hampson, M., Van Der Kouwe, A., Mackey, S., and Evins, A.E.

Published
2014
Full Text
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7. TP53-mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions

Author

Daver, NG, Maiti, A, Kadia, TM, Vyas, P, Majeti, R, Wei, AH, Garcia-Manero, G, Craddock, C, Sallman, DA, and Kantarjian, HM

Subjects
Oncology, Article
Abstract

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent–based regimens, or venetoclax-based therapies compared with non–TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity. Significance: Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent–based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.

Published
2022

15. S238: MATCHED RELATED VERSUS UNRELATED VERSUS HAPLOIDENTICAL DONORS FOR ALLOGENEIC TRANSPLANTATION IN AML PATIENTS ACHIEVING FIRST COMPLETE REMISSION AFTER TWO INDUCTION COURSES: A STUDY FROM THE ALWP/EBMT

Author

Nagler, A., primary, Labopin, M., additional, Mielke, S., additional, Passweg, J., additional, Blaise, D., additional, Gedde-Dahl, T., additional, Cornelissen, J. J., additional, Salmenniemi, U., additional, Yakoub-Agha, I., additional, Reményi, P., additional, Socié, G., additional, Van Gorkom, G., additional, Labussière-Wallet, H., additional, Huang, X.-J., additional, Thérèse Rubio, M., additional, Byrne, J. L, additional, Craddock, C., additional, Griskevicius, L., additional, Ciceri, F., additional, and Mohty, M., additional

Published
2022
Full Text
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16. P561: VIALE-T: A RANDOMIZED, OPEN-LABEL, PHASE 3 STUDY OF VENETOCLAX IN COMBINATION WITH AZACITIDINE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Author

Craddock, C., primary, Platzbecker, U., additional, Heuser, M., additional, Pullarkat, V., additional, Chaudhury, S., additional, Wu, D., additional, Addo, S., additional, Chyla, B., additional, Jiang, Q., additional, Lee, P., additional, and Wolff, J. E., additional

Published
2022
Full Text
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17. Additional cytogenetic features determine outcome in patients allografted for TP53 mutant acute myeloid leukemia

Author

Loke, J., Labopin, M., Craddock, C., Cornelissen, J.J.L.M, Labussière-Wallet, H., Wagner-Drouet, E.M., Gorkom, G. van, Schaap, N.P.M., Kröger, N.M., Veelken, J.H., Rovira, M., Menard, A.L., Bug, G., Bazarbachi, A., Giebel, S., Brissot, E., Nagler, A., Esteve, J., Mohty, M., Loke, J., Labopin, M., Craddock, C., Cornelissen, J.J.L.M, Labussière-Wallet, H., Wagner-Drouet, E.M., Gorkom, G. van, Schaap, N.P.M., Kröger, N.M., Veelken, J.H., Rovira, M., Menard, A.L., Bug, G., Bazarbachi, A., Giebel, S., Brissot, E., Nagler, A., Esteve, J., and Mohty, M.

Abstract

Contains fulltext : 282630.pdf (Publisher’s version ) (Open Access), BACKGROUND: The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo-SCT) for this patient group, although this has not been studied in a large cohort. METHODS: A total of 780 patients with AML in first complete remission, with either intermediate- or adverse-risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation. RESULTS: Two-year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7-43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1-68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p-) and/or complex karyotype (CK) (n = 53, 29.6%), 2-year OS was 65.2% (95% CI, 48.4-77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p- and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2-34; P = .001). CONCLUSIONS: In summary, the adverse prognostic effect of TP53 mutations in AML following an allo-SCT is not evident in patients with neither co-occurring 17p- and/or CK, and these data inform decisions regarding allo-SCT in patients with TP53 mutant AML.

Published
2022

18. Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

Author

Hoeks, Marlijn, Bagguley, Tim, van Marrewijk, Corine, Smith, Alex, Bowen, David, Culligan, Dominic, Kolade, Seye, Symeonidis, Argiris, Garelius, Hege, Spanoudakis, Michail, Langemeijer, Saskia, Roelofs, Rian, Wiegerinck, Erwin, Tatic, Aurelia, Killick, Sally, Panagiotidis, Panagiotis, Stanca, Oana, Hellström-Lindberg, Eva, Cermak, Jaroslav, van der Klauw, Melanie, Wouters, Hanneke, van Kraaij, Marian, Blijlevens, Nicole, Swinkels, Dorine W., de Witte, Theo, Stauder, R., Walder, A., Pfeilstöcker, M., Schoenmetzler-Makrai, A., Burgstaller, S., Thaler, J., Mandac Rogulj, I., Krejci, M., Voglova, J., Rohon, P., Jonasova, A., Cermak, J., Mikulenkova, D., Hochova, I., Jensen, P. D., Holm, M. S., Kjeldsen, L., Dufva, I. H., Vestergaard, H., Re, D., Slama, B., Fenaux, P., Choufi, B., Cheze, S., Klepping, D., Salles, B., de Renzis, B., Willems, L., De Prost, D., Gutnecht, J., Courby, S., Siguret, V., Tertian, G., Pascal, L., Chaury, M., Wattel, E., Guerci, A., Legros, L., Itzykson, R., Ades, L., Isnard, F., Sanhes, L., Benramdane, R., Stamatoullas, A., Amé, S., Beyne-Rauzy, O., Gyan, E., Platzbecker, U., Badrakan, C., Germing, U., Lübbert, M., Schlenk, R., Kotsianidis, I., Tsatalas, C., Pappa, V., Galanopoulos, A., Michali, E., Panagiotidis, P., Viniou, N., Katsigiannis, A., Roussou, P., Terpos, E., Kostourou, A., Kartasis, Z., Pouli, A., Palla, K., Briasoulis, V., Hatzimichael, E., Vassilopoulos, G., Symeonidis, A., Kourakli, A., Zikos, P., Anagnostopoulos, A., Kotsopoulou, M., Megalakaki, K., Protopapa, M., Vlachaki, E., Konstantinidou, P., Stemer, G., Nemetz, A., Gotwin, U., Cohen, O., Koren, M., Levy, E., Greenbaum, U., Gino-Moor, S., Price, M., Ofran, Y., Winder, A., Goldshmidt, N., Elias, S., Sabag, R., Hellman, I., Ellis, M., Braester, A., Rosenbaum, H., Berdichevsky, S., Itzhaki, G., Wolaj, O., Yeganeh, S., Katz, O., Filanovsky, K., Dali, N., Mittelman, M., Malcovati, L., Fianchi, L., vd Loosdrecht, A., Matthijssen, V., Herbers, A., Pruijt, H., Aboosy, N., de Vries, F., Velders, G., Jacobs, E., Langemeijer, S., MacKenzie, M., Lensen, C., Kuijper, P., Madry, K., Camara, M., Almeida, A., Vulkan, G., Stanca Ciocan, O., Tatic, A., Savic, A., Pedro, C., Xicoy, B., Leiva, P., Munoz, J., Betes, V., Benavente, C., Lozano, M., Martinez, M., Iniesta, P., Bernal, T., Diez Campelo, M., Tormo, D., Andreu Lapiedra, R., Sanz, G., Hesse Sundin, E., Garelius, H., Karlsson, C., Antunovic, P., Jönsson, A., Brandefors, L., Nilsson, L., Kozlowski, P., Hellstrom-Lindberg, E., Grövdal, M., Larsson, K., Wallvik, J., Lorenz, F., Ejerblad, E., Culligan, D., Craddock, C., Kolade, S., Cahalin, P., Killick, S., Ackroyd, S., Wong, C., Warren, A., Drummond, M., Hall, C., Rothwell, K., Green, S., Ali, S., Bowen, D., Karakantza, M., Dennis, M., Jones, G., Parker, J., Bowen, A., Radia, R., Das-Gupta, E., Vyas, P., Nga, E., Creagh, D., Ashcroft, J., Mills, J., Bond, L., Life Course Epidemiology (LCE), and VU University medical center

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Iron Overload, Iron, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ferroportin, Lower risk, Gastroenterology, Article, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 03 medical and health sciences, 0302 clinical medicine, Hepcidin, Internal medicine, Humans, Medicine, Blood Transfusion, Prospective Studies, Aged, Soluble transferrin receptor, biology, business.industry, Transferrin saturation, Hematology, Middle Aged, Erythroferrone, Prognosis, 3. Good health, Survival Rate, Ferritin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, biology.protein, Erythropoiesis, Female, business, Myelodysplastic syndrome, Follow-Up Studies, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

Published
2021
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24. Correction: Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients (Bone Marrow Transplantation, (2020), 55, 6, (1114-1125), 10.1038/s41409-020-0803-y)

Author

Spyridonidis A., Labopin M., Savani B. N., Niittyvuopio R., Blaise D., Craddock C., Socie G., Platzbecker U., Beelen D., Milpied N., Cornelissen J. J., Ganser A., Huynh A., Griskevicius L., Giebel S., Aljurf M., Brissot E., Malard F., Esteve J., Peric Z., Baron F., Ruggeri A., Schmid C., Gilleece M., Gorin N. -C., Lanza F., Shouval R., Versluis J., Bug G., Floisand Y., Ciceri F., Sanz J., Bazarbachi A., Nagler A., Mohty M., Spyridonidis, A., Labopin, M., Savani, B. N., Niittyvuopio, R., Blaise, D., Craddock, C., Socie, G., Platzbecker, U., Beelen, D., Milpied, N., Cornelissen, J. J., Ganser, A., Huynh, A., Griskevicius, L., Giebel, S., Aljurf, M., Brissot, E., Malard, F., Esteve, J., Peric, Z., Baron, F., Ruggeri, A., Schmid, C., Gilleece, M., Gorin, N. -C., Lanza, F., Shouval, R., Versluis, J., Bug, G., Floisand, Y., Ciceri, F., Sanz, J., Bazarbachi, A., Nagler, A., and Mohty, M.

Abstract

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

Published
2020

25. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Author

Hoeks, M. Bagguley, T. van Marrewijk, C. Smith, A. Bowen, D. Culligan, D. Kolade, S. Symeonidis, A. Garelius, H. Spanoudakis, M. Langemeijer, S. Roelofs, R. Wiegerinck, E. Tatic, A. Killick, S. Panagiotidis, P. Stanca, O. Hellström-Lindberg, E. Cermak, J. van der Klauw, M. Wouters, H. van Kraaij, M. Blijlevens, N. Swinkels, D.W. de Witte, T. Stauder, R. Walder, A. Pfeilstöcker, M. Schoenmetzler-Makrai, A. Burgstaller, S. Thaler, J. Mandac Rogulj, I. Krejci, M. Voglova, J. Rohon, P. Jonasova, A. Cermak, J. Mikulenkova, D. Hochova, I. Jensen, P.D. Holm, M.S. Kjeldsen, L. Dufva, I.H. Vestergaard, H. Re, D. Slama, B. Fenaux, P. Choufi, B. Cheze, S. Klepping, D. Salles, B. de Renzis, B. Willems, L. De Prost, D. Gutnecht, J. Courby, S. Siguret, V. Tertian, G. Pascal, L. Chaury, M. Wattel, E. Guerci, A. Legros, L. Itzykson, R. Ades, L. Isnard, F. Sanhes, L. Benramdane, R. Stamatoullas, A. Amé, S. Beyne-Rauzy, O. Gyan, E. Platzbecker, U. Badrakan, C. Germing, U. Lübbert, M. Schlenk, R. Kotsianidis, I. Tsatalas, C. Pappa, V. Galanopoulos, A. Michali, E. Panagiotidis, P. Viniou, N. Katsigiannis, A. Roussou, P. Terpos, E. Kostourou, A. Kartasis, Z. Pouli, A. Palla, K. Briasoulis, V. Hatzimichael, E. Vassilopoulos, G. Symeonidis, A. Kourakli, A. Zikos, P. Anagnostopoulos, A. Kotsopoulou, M. Megalakaki, K. Protopapa, M. Vlachaki, E. Konstantinidou, P. Stemer, G. Nemetz, A. Gotwin, U. Cohen, O. Koren, M. Levy, E. Greenbaum, U. Gino-Moor, S. Price, M. Ofran, Y. Winder, A. Goldshmidt, N. Elias, S. Sabag, R. Hellman, I. Ellis, M. Braester, A. Rosenbaum, H. Berdichevsky, S. Itzhaki, G. Wolaj, O. Yeganeh, S. Katz, O. Filanovsky, K. Dali, N. Mittelman, M. Malcovati, L. Fianchi, L. vd Loosdrecht, A. Matthijssen, V. Herbers, A. Pruijt, H. Aboosy, N. de Vries, F. Velders, G. Jacobs, E. Langemeijer, S. MacKenzie, M. Lensen, C. Kuijper, P. Madry, K. Camara, M. Almeida, A. Vulkan, G. Stanca Ciocan, O. Tatic, A. Savic, A. Pedro, C. Xicoy, B. Leiva, P. Munoz, J. Betes, V. Benavente, C. Lozano, M. Martinez, M. Iniesta, P. Bernal, T. Diez Campelo, M. Tormo, D. Andreu Lapiedra, R. Sanz, G. Hesse Sundin, E. Garelius, H. Karlsson, C. Antunovic, P. Jönsson, A. Brandefors, L. Nilsson, L. Kozlowski, P. Hellstrom-Lindberg, E. Grövdal, M. Larsson, K. Wallvik, J. Lorenz, F. Ejerblad, E. Culligan, D. Craddock, C. Kolade, S. Cahalin, P. Killick, S. Ackroyd, S. Wong, C. Warren, A. Drummond, M. Hall, C. Rothwell, K. Green, S. Ali, S. Karakantza, M. Dennis, M. Jones, G. Parker, J. Bowen, A. Radia, R. Das-Gupta, E. Vyas, P. Nga, E. Creagh, D. Ashcroft, J. Mills, J. Bond, L. the EUMDS Registry Participants

Published
2021

26. Total body irradiation plus fludarabine compared to busulfan plus fludarabine as 'reduced-toxicity conditioning' for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT

Author

Giebel, S, Labopin, M, Sobczyk-Kruszelnicka, M, Stelljes, M, Byrne, JL, Fegueux, N, Beelen, DW, Rovira, M, Spyridonidis, A, Blaise, D, Bornhauser, M, Karadogan, I, Savani, BN, Nagler, A, Mohty, M, Martin, S, Chevallier, P, Neubauer, A, Damaj, G, Koc, Y, Ganser, A, Collin, M, Yakoub-Agha, I, Ozdogu, H, Araujo, MC, Itala-Remes, M, Orchard, K, Isaksson, C, Bethge, W, Martin, H, Aljurf, M, Faber, E, Caballero, D, Zak, P, Leleu, X, Bay, JO, Rohrlich, PS, Kroger, N, Huynh, A, Schafer-Eckart, K, Milpied, N, Lenhoff, S, Ho, A, Lopez, JLB, Mordini, N, Lioure, B, Halaburda, K, Olivieri, A, Gedde-Dahl, T, Protheroe, R, Tischer, J, Klammer, M, Clausen, J, Potter, V, Ladetto, M, Tilly, H, Deconinck, E, Brecht, A, Muller, LP, Heinicke, T, Carrete, JPT, Bazarbachi, A, Remenyi, P, Rubio, MT, Fanin, R, Perez-Simon, JA, Niels, M, Diez-Martin, JL, Arat, M, Hermine, O, Socie, G, Cornelissen, JJ, Santarone, S, Guyotat, D, Bulabois, CE, Bernasconi, P, Johansson, JE, Vrhovac, R, Greinix, H, Lorenzo, JLL, Apte, S, Craddock, C, Kobbe, G, Zahrani, MA, Dreger, P, Lange, A, Tbakhi, A, Meijer, E, Llamas, CV, Santasusana, JMR, Corradini, P, Benedetti, F, Rambaldi, A, Gandemer, V, Malfuson, JV, Kaare, A, Risitano, A, Petrini, M, Selleri, C, and Wu, DP

Abstract

The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) and total body irradiation at a dose of 8 Gy + fludarabine (TBI8Gy/Flu). In the entire study cohort (n = 518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p = 0.051), 59.5% vs. 65% (p = 0.15), 30% vs. 20% (p = 0.01), and 10% vs. 14% (p = 0.18), respectively. In multivariate model for patients

Published
2021

28. Impact of patient:donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT

Author

Loke, J., Labopin, M., Craddock, C., Niederwieser, D., Cornelissen, J., Afansayev, B., Jindra, P., Maertens, J., Blaise, D., Boriskina, K., Gramatzki, M., Ganser, A., Savani, B., Mohty, M., Nagler, A., Loke, J., Labopin, M., Craddock, C., Niederwieser, D., Cornelissen, J., Afansayev, B., Jindra, P., Maertens, J., Blaise, D., Boriskina, K., Gramatzki, M., Ganser, A., Savani, B., Mohty, M., and Nagler, A.

Abstract

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

Published
2021

34. Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Author

Halaburda, K, Labopin, M, Mailhol, A, Socie, G, Craddock, C, Aljurf, M, Beelen, D, Cornelissen, Jan, Bourhis, J H, Labussiere-Wallet, H, Blaise, D, Gedde-Dahl, T, Gilleece, M, Yakoub-Agha, I, Mufti, G, Esteve, J, Mohty, M, Nagler, A, Halaburda, K, Labopin, M, Mailhol, A, Socie, G, Craddock, C, Aljurf, M, Beelen, D, Cornelissen, Jan, Bourhis, J H, Labussiere-Wallet, H, Blaise, D, Gedde-Dahl, T, Gilleece, M, Yakoub-Agha, I, Mufti, G, Esteve, J, Mohty, M, and Nagler, A

Published
2020

35. Sp1 functions in a chromatin-dependent manner to augment human alpha-globin promoter activity

Author

Pondel, M.D., Murphy, S., Pearson, L., Craddock, C., and Proudfoot, N.J.

Subjects
Promoters (Genetics) -- Research, Binding sites (Biochemistry) -- Analysis, Globin genes -- Expression, Science and technology
Abstract

The 5' flanking region of the human [alpha]-globin gene is highly G+C rich and contains multiple copies of the consensus sequence for the Sp1 binding site. We investigated the role of this G+C-rich region in augmenting [alpha]-globin promoter activity in the presence of the far-upstream [alpha]-globin enhancer, HS-40. We show that in transiently transfected erythroid cells, deletion of the [alpha]-globin G+C-rich 5' flanking region has no effect on [alpha]-globin promoter activity. However, upon stable integration into chromatin, deletion of this region causes a nearly 90% decrease in promoter activity compared with expression from an [alpha]-globin promoter retaining this region. These results suggest that the [alpha]-globin G+C-rich 5' flanking region augments [alpha]-globin promoter activity in a chromatin-dependent manner. We further show that this G+C-rich region is required for the activation of [alpha]-globin gene expression during erythroid differentiation. Finally, we show by both footprint analysis and functional assays that the ability of the G+C-rich region to increase [alpha]-globin promoter activity from a stably integrated [alpha]-globin gene is mediated by its multiple binding sites for the transcription factor Sp1.

Published
1995

37. Long-term survival of patients with CLL after allogeneic transplantation: A report from the European Society for Blood and Marrow Transplantation

Author

Van Gelder, M, De Wreede, L, Bornhauser, M, Niederwieser, D, Karas, M, Anderson, N, Gramatzki, M, Dreger, P, Michallet, M, Petersen, E, Bunjes, D, Potter, M, Beelen, D, Cornelissen, J, Yakoub-Agha, I, Russell, N, Finke, J, Schoemans, H, Vitek, A, Urbano-Ispizua, A, Blaise, D, Volin, L, Chevallier, P, Caballero, D, Putter, H, Van Biezen, A, Henseler, A, Schonland, S, Kroger, N, Schetelig, J, Ehninger, G, Jindra, P, Sengeloev, H, Ispizua, A, Arnold, R, Veelken, J, Mufti, G, Milpied, N, Benedetto, B, Schaap, M, Leblond, V, Nikolousis, M, Hallek, M, Passweg, J, Ljungman, P, Masszi, T, Stelljes, M, Browne, P, Glass, B, Espiga, C, Bourhis, J, Roussy, G, Gribben, J, Foa, R, Sierra, J, Mayer, J, Thomson, K, Meijer, E, Blau, W, Holler, E, Bacigalupo, A, Guilhot, F, Carlson, K, Zachee, P, Ifrah, N, Marin, J, Socie, G, Mcquaker, G, Cortelezzi, A, Lenhoff, S, Tischer, J, Irrera, G, Fanin, R, Beguin, Y, Nagler, A, Mackinnon, S, Itala-Remes, M, Deconinck, E, Wulf, G, Corradini, P, Gilleece, M, Wing, B, Peniket, A, Ganser, A, Stuhler, G, Faber, E, Komarnicki, M, Kanz, L, Brune, M, Lamy, T, Sanz, M, Kyrcz-Krzemien, S, Orchard, K, Hunter, A, Sandstedt, A, Fegueux, N, Bandini, G, Robinson, S, Craddock, C, Crawley, C, Griskevicius, L, Bloor, A, Reman, O, Hilgendorf, I, Cannell, P, Ciceri, F, Kalhs, P, Sica, S, Greinix, H, Scime, R, Selleslag, D, Kruger, W, Huynh, A, Einsele, H, Bittenbring, J, Olivieri, A, Hermine, O, Gedde-Dahl, T, Zsiros, J, Guyotat, D, Cordonnier, C, Campos, A, Casini, M, Martinelli, G, Muller, L, Van Imhoff, G, Neubauer, A, Lioure, B, Hamladji, R, Noens, L, Theobald, M, Salvi, F, Ram, R, Poire, X, Or, R, Chalandon, Y, Solano, C, Wilson, K, Santasusana, J, Karakasis, D, Schafer-Eckart, K, Wahlin, A, Mohty, M, Velardi, A, Bron, D, Alegre, A, Cairoli, R, Marotta, G, Lange, A, Narni, F, Fauser, A, Rambaldi, A, Guillerm, G, Heras, I, Snowden, J, Wiktor-Jedrzejczak, W, Schanz, U, Cahn, J, Abecasis, M, Kobbe, G, Salim, R, Junghanss, C, Segel, E, Clement, L, Zak, P, Metzner, B, Espigado, I, Tilly, H, Schroyens, W, Favre, C, Russo, D, Gastl, G, Bay, J, Alessandrino, E, Majolino, I, Bosi, A, Zuckerman, T, Aljurf, M, Thomson, J, Pioltelli, P, Anagnostopoulos, A, Schouten, H, Tholouli, E, Gurman, G, Vural, F, Zver, S, Muniz, S, Afanasyev, B, Pohlreich, D, Hellmann, A, Rosler, W, Martin, S, Apperley, J, Finnegan, D, Renaud, M, Nemet, D, Culligan, D, Castagna, L, Cascavilla, N, Koh, M, Chacon, M, Ozdogu, H, Spencer, A, Llamas, C, Grasso, M, Lopez, S, Benedetti, F, Deeren, D, De Revel, T, Musso, M, Halaburda, K, Sureda, A, Angelucci, E, Diez-Martin, J, Hunter, H, Koc, Y, Bordessoule, D, Fouillard, L, Di Bartolomeo, P, Mazza, P, Novitzky, N, Peschel, C, Lopez, J, Cascon, M, Romeril, K, Schots, R, Brussel, H, Koistinen, P, Arcese, W, Aktan, M, Rodeghiero, F, Butler, A, Pizzuti, M, Melpignano, A, Carella, A, Valcarcel, D, De Toledo Codina, J, Galieni, P, Bader, P, Hahn, Cavanna, L, Sucak, G, Broom, A, Garcia, P, Nicolas-Virelizier, E, Rizzoli, V, Witz, F, Collin, M, Ringhoffer, M, Kansu, E, Martin, H, Moraleda, J, Pranger, D, Greil, R, Bazarbachi, A, Ozturk, M, Fagioli, F, Jantunen, E, Yeshurun, M, Altuntas, F, Bassan, R, Rohrlich, P, Jimenez, S, Glaisner, S, Vinante, O, Clausen, J, Lopez-Jimenez, J, Theunissen, K, Specchia, G, Pavone, V, Krauter, J, Edwards, D, Rifon, J, Everaus, H, Da Prada, G, Wattad, M, Milone, G, Walewski, J, Thieblemont, C, Nasa, G, Duchosal, M, Ferrara, F, Devidas, A, Delmer, A, Degos, L, Van Gelder M., De Wreede L. C., Bornhauser M., Niederwieser D., Karas M., Anderson N. S., Gramatzki M., Dreger P., Michallet M., Petersen E., Bunjes D., Potter M., Beelen D., Cornelissen J. J., Yakoub-Agha I., Russell N. H., Finke J., Schoemans H., Vitek A., Urbano-Ispizua A., Blaise D., Volin L., Chevallier P., Caballero D., Putter H., Van Biezen A., Henseler A., Schonland S., Kroger N., Schetelig J., Ehninger G., Jindra P., Sengeloev H., Russell N., Ispizua A. U., Arnold R., Veelken J. H., Mufti G., Milpied N., Benedetto B., Schaap M., Leblond V., Nikolousis M., Hallek M., Passweg J., Ljungman P., Masszi T., Stelljes M., Browne P., Glass B., Espiga C. R., Bourhis J. H., Roussy G., Gribben J., Foa R., Sierra J., Mayer J., Thomson K., Meijer E., Blau W., Holler E., Bacigalupo A., Guilhot F., Carlson K., Zachee P., Ifrah N., Marin J. R. C., Socie G., McQuaker G., Cortelezzi A., Lenhoff S., Tischer J., Irrera G., Fanin R., Beguin Y., Nagler A., Mackinnon S., Itala-Remes M., Deconinck E., Wulf G., Corradini P., Gilleece M., Wing B., Peniket A., Ganser A., Stuhler G., Faber E., Komarnicki M., Kanz L., Brune M., Lamy T., Sanz M., Kyrcz-Krzemien S., Orchard K., Hunter A., Sandstedt A., Fegueux N., Bandini G., Robinson S., Craddock C., Crawley C., Griskevicius L., Bloor A., Reman O., Hilgendorf I., Cannell P., Ciceri F., Kalhs P., Sica S., Greinix H., Scime R., Selleslag D., Kruger W., Huynh A., Einsele H., Bittenbring J., Olivieri A., Hermine O., Gedde-Dahl T., Zsiros J., Guyotat D., Cordonnier C., Campos A., Casini M., Martinelli G., Muller L. P., Van Imhoff G., Neubauer A., Lioure B., Hamladji R. -M., Noens L., Theobald M., Salvi F., Ram R., Poire X., Or R., Chalandon Y., Solano C., Wilson K., Santasusana J. M. R., Karakasis D., Schafer-Eckart K., Wahlin A., Mohty M., Velardi A., Bron D., Alegre A., Cairoli R., Marotta G., Lange A., Narni F., Fauser A., Rambaldi A., Guillerm G., Heras I., Snowden J., Wiktor-Jedrzejczak W., Schanz U., Cahn J. Y., Abecasis M., Kobbe G., Salim R., Junghanss C., Segel E. K., Clement L., Zak P., Metzner B., Espigado I., Tilly H., Schroyens W., Favre C., Russo D., Gastl G., Bay J. -O., Alessandrino E. P., Majolino I., Bosi A., Zuckerman T., Aljurf M., Thomson J., Pioltelli P., Anagnostopoulos A., Schouten H., Tholouli E., Gurman G., Vural F., Zver S., Muniz S. G., Afanasyev B., Pohlreich D., Hellmann A., Rosler W., Martin S., Apperley J., Finnegan D., Renaud M., Nemet D., Culligan D., Castagna L., Cascavilla N., Koh M., Chacon M. J., Ozdogu H., Spencer A., Llamas C. V., Grasso M., Lopez S. G., Benedetti F., Deeren D., De Revel T., Musso M., Halaburda K., Sureda A., Angelucci E., Diez-Martin J. L., Hunter H., Koc Y., Bordessoule D., Fouillard L., Di Bartolomeo P., Mazza P., Novitzky N., Peschel C., Lopez J. L. B., Cascon M. J. P., Romeril K. R., Schots R., Brussel H., Koistinen P., Arcese W., Aktan M., Rodeghiero F., Butler A., Pizzuti M., Melpignano A., Carella A. M., Valcarcel D., De Toledo Codina J. S., Galieni P., Bader P., Cavanna L., Sucak G., Broom A. J. M., Garcia P. G., Nicolas-Virelizier E., Rizzoli V., Witz F., Collin M., Ringhoffer M., Kansu E., Martin H., Moraleda J., Pranger D., Greil R., Bazarbachi A., Ozturk M., Fagioli F., Jantunen E., Yeshurun M., Altuntas F., Bassan R., Rohrlich P. -S., Jimenez S., Glaisner S., Vinante O., Clausen J., Lopez-Jimenez J., Theunissen K., Specchia G., Pavone V., Krauter J., Edwards D., Rifon J., Everaus H., Da Prada G. A., Wattad M., Milone G., Walewski J., Thieblemont C., Nasa G. L., Duchosal M., Ferrara F., Devidas A., Delmer A., Degos L., Van Gelder, M, De Wreede, L, Bornhauser, M, Niederwieser, D, Karas, M, Anderson, N, Gramatzki, M, Dreger, P, Michallet, M, Petersen, E, Bunjes, D, Potter, M, Beelen, D, Cornelissen, J, Yakoub-Agha, I, Russell, N, Finke, J, Schoemans, H, Vitek, A, Urbano-Ispizua, A, Blaise, D, Volin, L, Chevallier, P, Caballero, D, Putter, H, Van Biezen, A, Henseler, A, Schonland, S, Kroger, N, Schetelig, J, Ehninger, G, Jindra, P, Sengeloev, H, Ispizua, A, Arnold, R, Veelken, J, Mufti, G, Milpied, N, Benedetto, B, Schaap, M, Leblond, V, Nikolousis, M, Hallek, M, Passweg, J, Ljungman, P, Masszi, T, Stelljes, M, Browne, P, Glass, B, Espiga, C, Bourhis, J, Roussy, G, Gribben, J, Foa, R, Sierra, J, Mayer, J, Thomson, K, Meijer, E, Blau, W, Holler, E, Bacigalupo, A, Guilhot, F, Carlson, K, Zachee, P, Ifrah, N, Marin, J, Socie, G, Mcquaker, G, Cortelezzi, A, Lenhoff, S, Tischer, J, Irrera, G, Fanin, R, Beguin, Y, Nagler, A, Mackinnon, S, Itala-Remes, M, Deconinck, E, Wulf, G, Corradini, P, Gilleece, M, Wing, B, Peniket, A, Ganser, A, Stuhler, G, Faber, E, Komarnicki, M, Kanz, L, Brune, M, Lamy, T, Sanz, M, Kyrcz-Krzemien, S, Orchard, K, Hunter, A, Sandstedt, A, Fegueux, N, Bandini, G, Robinson, S, Craddock, C, Crawley, C, Griskevicius, L, Bloor, A, Reman, O, Hilgendorf, I, Cannell, P, Ciceri, F, Kalhs, P, Sica, S, Greinix, H, Scime, R, Selleslag, D, Kruger, W, Huynh, A, Einsele, H, Bittenbring, J, Olivieri, A, Hermine, O, Gedde-Dahl, T, Zsiros, J, Guyotat, D, Cordonnier, C, Campos, A, Casini, M, Martinelli, G, Muller, L, Van Imhoff, G, Neubauer, A, Lioure, B, Hamladji, R, Noens, L, Theobald, M, Salvi, F, Ram, R, Poire, X, Or, R, Chalandon, Y, Solano, C, Wilson, K, Santasusana, J, Karakasis, D, Schafer-Eckart, K, Wahlin, A, Mohty, M, Velardi, A, Bron, D, Alegre, A, Cairoli, R, Marotta, G, Lange, A, Narni, F, Fauser, A, Rambaldi, A, Guillerm, G, Heras, I, Snowden, J, Wiktor-Jedrzejczak, W, Schanz, U, Cahn, J, Abecasis, M, Kobbe, G, Salim, R, Junghanss, C, Segel, E, Clement, L, Zak, P, Metzner, B, Espigado, I, Tilly, H, Schroyens, W, Favre, C, Russo, D, Gastl, G, Bay, J, Alessandrino, E, Majolino, I, Bosi, A, Zuckerman, T, Aljurf, M, Thomson, J, Pioltelli, P, Anagnostopoulos, A, Schouten, H, Tholouli, E, Gurman, G, Vural, F, Zver, S, Muniz, S, Afanasyev, B, Pohlreich, D, Hellmann, A, Rosler, W, Martin, S, Apperley, J, Finnegan, D, Renaud, M, Nemet, D, Culligan, D, Castagna, L, Cascavilla, N, Koh, M, Chacon, M, Ozdogu, H, Spencer, A, Llamas, C, Grasso, M, Lopez, S, Benedetti, F, Deeren, D, De Revel, T, Musso, M, Halaburda, K, Sureda, A, Angelucci, E, Diez-Martin, J, Hunter, H, Koc, Y, Bordessoule, D, Fouillard, L, Di Bartolomeo, P, Mazza, P, Novitzky, N, Peschel, C, Lopez, J, Cascon, M, Romeril, K, Schots, R, Brussel, H, Koistinen, P, Arcese, W, Aktan, M, Rodeghiero, F, Butler, A, Pizzuti, M, Melpignano, A, Carella, A, Valcarcel, D, De Toledo Codina, J, Galieni, P, Bader, P, Hahn, Cavanna, L, Sucak, G, Broom, A, Garcia, P, Nicolas-Virelizier, E, Rizzoli, V, Witz, F, Collin, M, Ringhoffer, M, Kansu, E, Martin, H, Moraleda, J, Pranger, D, Greil, R, Bazarbachi, A, Ozturk, M, Fagioli, F, Jantunen, E, Yeshurun, M, Altuntas, F, Bassan, R, Rohrlich, P, Jimenez, S, Glaisner, S, Vinante, O, Clausen, J, Lopez-Jimenez, J, Theunissen, K, Specchia, G, Pavone, V, Krauter, J, Edwards, D, Rifon, J, Everaus, H, Da Prada, G, Wattad, M, Milone, G, Walewski, J, Thieblemont, C, Nasa, G, Duchosal, M, Ferrara, F, Devidas, A, Delmer, A, Degos, L, Van Gelder M., De Wreede L. C., Bornhauser M., Niederwieser D., Karas M., Anderson N. S., Gramatzki M., Dreger P., Michallet M., Petersen E., Bunjes D., Potter M., Beelen D., Cornelissen J. J., Yakoub-Agha I., Russell N. H., Finke J., Schoemans H., Vitek A., Urbano-Ispizua A., Blaise D., Volin L., Chevallier P., Caballero D., Putter H., Van Biezen A., Henseler A., Schonland S., Kroger N., Schetelig J., Ehninger G., Jindra P., Sengeloev H., Russell N., Ispizua A. U., Arnold R., Veelken J. H., Mufti G., Milpied N., Benedetto B., Schaap M., Leblond V., Nikolousis M., Hallek M., Passweg J., Ljungman P., Masszi T., Stelljes M., Browne P., Glass B., Espiga C. R., Bourhis J. H., Roussy G., Gribben J., Foa R., Sierra J., Mayer J., Thomson K., Meijer E., Blau W., Holler E., Bacigalupo A., Guilhot F., Carlson K., Zachee P., Ifrah N., Marin J. R. C., Socie G., McQuaker G., Cortelezzi A., Lenhoff S., Tischer J., Irrera G., Fanin R., Beguin Y., Nagler A., Mackinnon S., Itala-Remes M., Deconinck E., Wulf G., Corradini P., Gilleece M., Wing B., Peniket A., Ganser A., Stuhler G., Faber E., Komarnicki M., Kanz L., Brune M., Lamy T., Sanz M., Kyrcz-Krzemien S., Orchard K., Hunter A., Sandstedt A., Fegueux N., Bandini G., Robinson S., Craddock C., Crawley C., Griskevicius L., Bloor A., Reman O., Hilgendorf I., Cannell P., Ciceri F., Kalhs P., Sica S., Greinix H., Scime R., Selleslag D., Kruger W., Huynh A., Einsele H., Bittenbring J., Olivieri A., Hermine O., Gedde-Dahl T., Zsiros J., Guyotat D., Cordonnier C., Campos A., Casini M., Martinelli G., Muller L. P., Van Imhoff G., Neubauer A., Lioure B., Hamladji R. -M., Noens L., Theobald M., Salvi F., Ram R., Poire X., Or R., Chalandon Y., Solano C., Wilson K., Santasusana J. M. R., Karakasis D., Schafer-Eckart K., Wahlin A., Mohty M., Velardi A., Bron D., Alegre A., Cairoli R., Marotta G., Lange A., Narni F., Fauser A., Rambaldi A., Guillerm G., Heras I., Snowden J., Wiktor-Jedrzejczak W., Schanz U., Cahn J. Y., Abecasis M., Kobbe G., Salim R., Junghanss C., Segel E. K., Clement L., Zak P., Metzner B., Espigado I., Tilly H., Schroyens W., Favre C., Russo D., Gastl G., Bay J. -O., Alessandrino E. P., Majolino I., Bosi A., Zuckerman T., Aljurf M., Thomson J., Pioltelli P., Anagnostopoulos A., Schouten H., Tholouli E., Gurman G., Vural F., Zver S., Muniz S. G., Afanasyev B., Pohlreich D., Hellmann A., Rosler W., Martin S., Apperley J., Finnegan D., Renaud M., Nemet D., Culligan D., Castagna L., Cascavilla N., Koh M., Chacon M. J., Ozdogu H., Spencer A., Llamas C. V., Grasso M., Lopez S. G., Benedetti F., Deeren D., De Revel T., Musso M., Halaburda K., Sureda A., Angelucci E., Diez-Martin J. L., Hunter H., Koc Y., Bordessoule D., Fouillard L., Di Bartolomeo P., Mazza P., Novitzky N., Peschel C., Lopez J. L. B., Cascon M. J. P., Romeril K. R., Schots R., Brussel H., Koistinen P., Arcese W., Aktan M., Rodeghiero F., Butler A., Pizzuti M., Melpignano A., Carella A. M., Valcarcel D., De Toledo Codina J. S., Galieni P., Bader P., Cavanna L., Sucak G., Broom A. J. M., Garcia P. G., Nicolas-Virelizier E., Rizzoli V., Witz F., Collin M., Ringhoffer M., Kansu E., Martin H., Moraleda J., Pranger D., Greil R., Bazarbachi A., Ozturk M., Fagioli F., Jantunen E., Yeshurun M., Altuntas F., Bassan R., Rohrlich P. -S., Jimenez S., Glaisner S., Vinante O., Clausen J., Lopez-Jimenez J., Theunissen K., Specchia G., Pavone V., Krauter J., Edwards D., Rifon J., Everaus H., Da Prada G. A., Wattad M., Milone G., Walewski J., Thieblemont C., Nasa G. L., Duchosal M., Ferrara F., Devidas A., Delmer A., and Degos L.

Abstract

Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.

Published
2017

38. A Comparison of Inpatient and Outpatient-Based Chemotherapy Regimens for the Treatment of Acute Myeloid Leukaemia In The Elderly

Author

Daly, A B, Cuthbert, R, Finnegan, D, Arnold, C, Craddock, C, and McMullin, M F

Abstract

Introduction: Acute myeloid leukaemia (AML) is an aggressive haematological malignancy which is more common in the elderly and has a poor 5-year survival. There are no established beneficial interventions to treat AML in elderly patients. It is unclear whether outpatient delivery of palliative chemotherapies could reduce the burden of disease and hospitalisation for this group.Aims: To compare overall survival, response to treatment and supportive care needs between inpatient and outpatient-based treatments for AML in elderly patients.Materials & Methods: We undertook a retrospective cohort study in the Haematology Department at Belfast City Hospital comparing overall survival (OS), treatment responses and supportive care needs between inpatient and outpatient treatments for AML in elderly patients. Consecutive entrants to outpatient and inpatient based clinical trials between February 2013 and January 2017 were included. Case notes, chemotherapy charts, clinic letters, blood bank and electronic care records were analysed.Results: OS and rates of CR (complete remission), CRi (CR with incomplete count recovery) and PR (partial response) was not significantly different between inpatient and outpatient regimens with a median OS of 201 vs. 124 days, respectively. No response was observed in 35% of patients in the inpatient group compared with 65% of the outpatient group, however this did not reach significance. Of patients who achieved CR/CRi in the outpatient group, 75% relapsed at a median of 271 days, compared with 60% of the inpatient group at a median of 209 days. At least one grade 3-4 toxicity was experienced by 90% and 83.3% of inpatient and outpatient groups, respectively. There was no difference in six common grade 3-4 toxicities. Patients on the outpatient regimen spent fewer days in hospital but had a median packed red cell use of more than twice that of the inpatient group. No difference was noted in infections, days on antibiotics or platelet use.Discussion: Our data suggests that outpatient chemotherapy is safe and can reduce hospitalisation for elderly patients with AML, without a decline in OS or response rates. These results provide an important rationale to test the comparative efficacy of outpatient chemotherapy. Chemotherapy related toxicities remain a significant source of morbidity in this population and highlight the need to develop novel, targeted therapies for this age group.

Published
2019

39. Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation

Author

Gagelmann, N., Eikema, D.J., Stelljes, M., Beelen, D., de Wreede, L., Mufti, G., Knelange, N.S., Niederwieser, D., Friis, L.S., Ehninger, G., Nagler, A., Yakoub-Agha, I., Meijer, E., Ljungman, P., Maertens, J., Kanz, L., Lopez-Corral, L., Brecht, A., Craddock, C., Finke, J., Cornelissen, J.J., Bernasconi, P., Chevallier, P., Sierra, Jorge, Robin, M., Kröger, N., Universitat Autònoma de Barcelona, Hematology, CCA - Imaging and biomarkers, and CCA - Cancer Treatment and quality of life

Subjects
Male, BLOOD, IMPACT, medicine.medical_treatment, CYTOMEGALOVIRUS, Medizin, Hematopoietic stem cell transplantation, PROPHYLAXIS, Cohort Studies, 0302 clinical medicine, Risk Factors, Medicine, OUTCOMES, Framingham Risk Score, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Prognosis, Survival Rate, Female, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Adolescent, ACUTE MYELOID-LEUKEMIA, Risk Assessment, Article, 03 medical and health sciences, Young Adult, Internal medicine, Humans, Transplantation, Homologous, Survival rate, Aged, Science & Technology, Models, Statistical, business.industry, Proportional hazards model, MUTATIONS, Myelodysplastic syndromes, Nomogram, medicine.disease, Transplantation, MONOSOMAL KARYOTYPE, Nomograms, Myelodysplastic Syndromes, business, SYSTEM, 030215 immunology, Follow-Up Studies
Abstract

The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status 1%, and platelet count ≤50 × 109/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (P

Published
2019
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43. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT

Author

Burns, D M, Rana, S, Martin, E, Nagra, S, Ward, J, Osman, H, Bell, A I, Moss, P, Russell, N H, Craddock, C F, Fox, C P, and Chaganti, S

Subjects
Adult, Male, Herpesvirus 4, Human, Adolescent, Hematopoietic Stem Cell Transplantation, Middle Aged, Risk Assessment, Lymphoproliferative Disorders, Young Adult, surgical procedures, operative, hemic and lymphatic diseases, Humans, Original Article, Female, Virus Activation, Rituximab, Alemtuzumab, Aged, Retrospective Studies
Abstract

EBV-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed the incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (confidence interval (CI) 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis age⩾50 years was associated with significantly increased risk of EBV reactivation (hazard ratio (HR) 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with alemtuzumab. Furthermore, we report the clinically important observation that rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD.

Published
2016

44. The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT

Author

Schmidt-Hieber, M., Tridello, G., Ljungman, P., Mikulska, M., Knelange, N., Blaise, D., Socie, G., Volin, L., Blijlevens, N.M., Fegueux, N., Yakoub-Agha, I., Forcade, E., Maertens, J., Chevallier, P., Passweg, J., Cornelissen, J, Russell, N., Craddock, C., Bourhis, J.H., Marchand, T., Remenyi, P., Cahn, J.Y., Michallet, M., Montoto, S., Kroger, N., Glass, B., Styczynski, J., Schmidt-Hieber, M., Tridello, G., Ljungman, P., Mikulska, M., Knelange, N., Blaise, D., Socie, G., Volin, L., Blijlevens, N.M., Fegueux, N., Yakoub-Agha, I., Forcade, E., Maertens, J., Chevallier, P., Passweg, J., Cornelissen, J, Russell, N., Craddock, C., Bourhis, J.H., Marchand, T., Remenyi, P., Cahn, J.Y., Michallet, M., Montoto, S., Kroger, N., Glass, B., and Styczynski, J.

Abstract

Item does not contain fulltext, It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.

Published
2019

45. Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis

Author

Robin, M, Chevret, S, Koster, L, Wolschke, C, Yakoub-Agha, I, Bourhis, J H, Chevallier, P, Cornelissen, Jan, Remenyi, P, Maertens, J, Poire, X, Craddock, C, Socie, G, Itala-Remes, M, Schouten, HC, Marchand, T, Passweg, J, Blaise, D, Damaj, G, Ozkurt, ZN, Zuckerman, T, Cluzeau, T, Labussiere-Wallet, H, Cammenga, J, McLornan, D, Chalandon, Y, Kroger, N, Robin, M, Chevret, S, Koster, L, Wolschke, C, Yakoub-Agha, I, Bourhis, J H, Chevallier, P, Cornelissen, Jan, Remenyi, P, Maertens, J, Poire, X, Craddock, C, Socie, G, Itala-Remes, M, Schouten, HC, Marchand, T, Passweg, J, Blaise, D, Damaj, G, Ozkurt, ZN, Zuckerman, T, Cluzeau, T, Labussiere-Wallet, H, Cammenga, J, McLornan, D, Chalandon, Y, and Kroger, N

Published
2019

46. Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia

Author

Craddock, C, Versluis, J, Labopin, M, Socie, G, Huynh, A, Deconinck, E, Volin, L, Milpied, N, Bourhis, JH, Rambaldi, A, Chevallier, P, Blaise, D, Manz, M, Vellenga, E, Vekemans, MC, Maertens, J, Passweg, J, Vyas, P, Schmid, C, Löwenberg, B, Ossenkoppele, G, Mohty, M, Cornelissen, JJ, Nagler, A, HOVON‐SAKK, Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Department of Medicine, Clinicum, Department of Oncology, HUS Comprehensive Cancer Center, UCL - (SLuc) Service d'hématologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, and Hematology

Subjects
Oncology, Male, Disease, 0302 clinical medicine, Maintenance therapy, AML, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Cause of death, 1ST COMPLETE REMISSION, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Cohort, TRIAL, Female, Nucleophosmin, medicine.drug, Adult, medicine.medical_specialty, NPM1, Adolescent, Azacitidine, 3122 Cancers, maintenance therapy, stem cell transplantation, Acute myeloid leukaemia, 03 medical and health sciences, Young Adult, EUROPEAN LEUKEMIANET, Internal medicine, Internal Medicine, medicine, MYELODYSPLASTIC SYNDROMES, Humans, Transplantation, Homologous, AZACITIDINE, Aged, Retrospective Studies, OLDER, Peripheral Blood Stem Cell Transplantation, business.industry, intensive chemotherapy, Myelodysplastic syndromes, STEM-CELL TRANSPLANTATION, medicine.disease, Transplantation, MAINTENANCE, kinetics, 3121 General medicine, internal medicine and other clinical medicine, business, 030215 immunology, EBMT
Abstract

Background. Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT).Aims. The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized.Materials and Methods. We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone.Results. In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P Discussion and Conclusion. Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Published
2017

47. Embracing model-based designs for dose-finding trials

Author

Love, S, Brown, S, Weir, C, Harbron, C, Yap, C, Gaschler-Markefski, B, Matcham, J, Caffery, L, McKevitt, C, Clive, S, Craddock, C, Spicer, J, and Cornelius, V

Subjects
KEY STAKEHOLDERS, Time Factors, Maximum Tolerated Dose, PHASE, model-based design, CONTINUAL REASSESSMENT METHOD, Professional Competence, Surveys and Questionnaires, 3+3, ESCALATION, Humans, Oncology & Carcinogenesis, Science & Technology, Models, Statistical, Clinical Trials, Phase I as Topic, Dose-Response Relationship, Drug, phase I, I CLINICAL-TRIALS, ONCOLOGY, CANCER, Research Personnel, dose-finding trials, CRM, Attitude, CONFIRMATORY TRIALS, ADAPTIVE DESIGNS, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, Software, TOXICITIES
Abstract

Background Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose-finding, such as the continual reassessment method (CRM). Methods We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation. Results We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators’ preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome. ConclusionThere is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for does-finding trials in academia.

Published
2017
Full Text
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48. Quackery Chilli-too hot to handle?

Author

Craddock, C, Cathcart, P, and Stebbing, J

Subjects
Science & Technology, Oncology, Oncology & Carcinogenesis, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis
Published
2017

49. Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia

Author

Loke, J., Khan, J. N., Wilson, J. S., Craddock, C., and Wheatley, K.

Subjects
Mylotarg, Humanised monoclonal antibodies, Sialic Acid Binding Ig-like Lectin 3, CD33 antigen, Antineoplastic Agents, Hematology, Randomised clinical trials, Antibodies, Monoclonal, Humanized, Gemtuzumab, Acute myeloid leukaemia, RC0254, Meta-analysis, Leukemia, Myeloid, Acute, Aminoglycosides, Systematic review, Humans, Original Article, Randomized Controlled Trials as Topic
Abstract

Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO’s licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto’s odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84–0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90–1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed. Electronic supplementary material The online version of this article (doi:10.1007/s00277-014-2218-6) contains supplementary material, which is available to authorized users.

Published
2014

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