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1. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author

Palles, Claire, West, Hannah D., Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Palles, Claire, West, Hannah D., Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, and Lopez-Bigas, Nuria

Abstract

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Published
2022

2. Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens : a CIBMTR report

Author

Zhou, Zheng, Nath, Rajneesh, Cerny, Jan, Wang, Hai-Lin, Zhang, Mei-Jie, Abdel-Azim, Hisham, Agrawal, Vaibhav, Ahmed, Gulrayz, Al-Homsi, A. Samer, Aljurf, Mahmoud, Alkhateeb, Hassan B., Assal, Amer, Bacher, Ulrike, Bajel, Ashish, Bashir, Qaiser, Battiwalla, Minocher, Bhatt, Vijaya Raj, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Choe, Hannah, Copelan, Edward, Cutler, Corey, Damlaj, Moussab B., DeFilipp, Zachariah, De Lima, Marcos, Diaz, Miguel Angel, Farhadfar, Nosha, Foran, James, Freytes, Cesar O., Gerds, Aaron T., Gergis, Usama, Grunwald, Michael R., Gul, Zartash, Hamadani, Mehdi, Hashmi, Shahrukh, Hertzberg, Mark, Hildebrandt, Gerhard C., Hossain, Nasheed, Inamoto, Yoshihiro, Isola, Luis, Jain, Tania, Kamble, Rammurti T., Khan, Muhammad Waqas, Kharfan-Dabaja, Mohamed A., Kebriaei, Partow, Kekre, Natasha, Khera, Nandita, Lazarus, Hillard M., Liesveld, Jane L., Litzow, Mark, Liu, Hongtao, Marks, David, I, Martino, Rodrigo, Mathews, Vikram, Mishra, Asmita, Murthy, Hemant S., Nagler, Arnon, Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Olin, Rebecca, Olsson, Richard F., Palmisiano, Neil, Patel, Sagar S., Patnaik, Mrinal M., Pawarode, Attaphol, Perales, Miguel-Angel, Politikos, Ioannis, Popat, Uday, Rizzieri, David, Sandmaier, Brenda M., Savani, Bipin N., Seo, Sachiko, Shah, Nirav N., Uy, Geoffrey L., Valcarcel, David, Verdonck, Leo F., Waller, Edmund K., Wang, Youjin, Weisdorf, Daniel, Wirk, Baldeep, Wong, Eric, Yared, Jean A., Saber, Wael, Zhou, Zheng, Nath, Rajneesh, Cerny, Jan, Wang, Hai-Lin, Zhang, Mei-Jie, Abdel-Azim, Hisham, Agrawal, Vaibhav, Ahmed, Gulrayz, Al-Homsi, A. Samer, Aljurf, Mahmoud, Alkhateeb, Hassan B., Assal, Amer, Bacher, Ulrike, Bajel, Ashish, Bashir, Qaiser, Battiwalla, Minocher, Bhatt, Vijaya Raj, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Choe, Hannah, Copelan, Edward, Cutler, Corey, Damlaj, Moussab B., DeFilipp, Zachariah, De Lima, Marcos, Diaz, Miguel Angel, Farhadfar, Nosha, Foran, James, Freytes, Cesar O., Gerds, Aaron T., Gergis, Usama, Grunwald, Michael R., Gul, Zartash, Hamadani, Mehdi, Hashmi, Shahrukh, Hertzberg, Mark, Hildebrandt, Gerhard C., Hossain, Nasheed, Inamoto, Yoshihiro, Isola, Luis, Jain, Tania, Kamble, Rammurti T., Khan, Muhammad Waqas, Kharfan-Dabaja, Mohamed A., Kebriaei, Partow, Kekre, Natasha, Khera, Nandita, Lazarus, Hillard M., Liesveld, Jane L., Litzow, Mark, Liu, Hongtao, Marks, David, I, Martino, Rodrigo, Mathews, Vikram, Mishra, Asmita, Murthy, Hemant S., Nagler, Arnon, Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Olin, Rebecca, Olsson, Richard F., Palmisiano, Neil, Patel, Sagar S., Patnaik, Mrinal M., Pawarode, Attaphol, Perales, Miguel-Angel, Politikos, Ioannis, Popat, Uday, Rizzieri, David, Sandmaier, Brenda M., Savani, Bipin N., Seo, Sachiko, Shah, Nirav N., Uy, Geoffrey L., Valcarcel, David, Verdonck, Leo F., Waller, Edmund K., Wang, Youjin, Weisdorf, Daniel, Wirk, Baldeep, Wong, Eric, Yared, Jean A., and Saber, Wael

Abstract

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Published
2020
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3. Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia : A Center for International Blood and Marrow Transplant Research Study

Author

DeFilipp, Zachariah, Ancheta, Richard, Liu, Ying, Hu, Zhen-Huan, Gale, Robert Peter, Snyder, David, Schouten, Harry C, Kalaycio, Matt, Hildebrandt, Gerhard C, Ustun, Celalettin, Daly, Andrew, Ganguly, Siddhartha, Inamoto, Yoshihiro, Litzow, Mark, Szer, Jeffrey, Savoie, Mary Lynn, Hossain, Nasheed, Kharfan-Dabaja, Mohamed A, Hamadani, Mehdi, Reshef, Ran, Bajel, Ashish, Schultz, Kirk R, Gadalla, Shahinaz, Gerds, Aaron, Liesveld, Jane, Juckett, Mark B, Kamble, Rammurti, Hashmi, Shahrukh, Abdel-Azim, Hisham, Solh, Melhem, Bacher, Ulrike, Lazarus, Hillard, Olsson, Richard, Cahn, Jean-Yves, Grunwald, Michael R, Savani, Bipin N, Yared, Jean, Rowe, Jacob M, Cerny, Jan, Chaudhri, Naeem A, Aljurf, Mahmoud, Beitinjaneh, Amer, Seo, Sachiko, Nishihori, Taiga, Hsu, Jack W, Ramanathan, Muthalagu, Alyea, Edwin, Popat, Uday, Sobecks, Ronald, Saber, Wael, DeFilipp, Zachariah, Ancheta, Richard, Liu, Ying, Hu, Zhen-Huan, Gale, Robert Peter, Snyder, David, Schouten, Harry C, Kalaycio, Matt, Hildebrandt, Gerhard C, Ustun, Celalettin, Daly, Andrew, Ganguly, Siddhartha, Inamoto, Yoshihiro, Litzow, Mark, Szer, Jeffrey, Savoie, Mary Lynn, Hossain, Nasheed, Kharfan-Dabaja, Mohamed A, Hamadani, Mehdi, Reshef, Ran, Bajel, Ashish, Schultz, Kirk R, Gadalla, Shahinaz, Gerds, Aaron, Liesveld, Jane, Juckett, Mark B, Kamble, Rammurti, Hashmi, Shahrukh, Abdel-Azim, Hisham, Solh, Melhem, Bacher, Ulrike, Lazarus, Hillard, Olsson, Richard, Cahn, Jean-Yves, Grunwald, Michael R, Savani, Bipin N, Yared, Jean, Rowe, Jacob M, Cerny, Jan, Chaudhri, Naeem A, Aljurf, Mahmoud, Beitinjaneh, Amer, Seo, Sachiko, Nishihori, Taiga, Hsu, Jack W, Ramanathan, Muthalagu, Alyea, Edwin, Popat, Uday, Sobecks, Ronald, and Saber, Wael

Abstract

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.

Published
2020
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4. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission

Author

Rashidi, Armin, Hamadani, Mehdi, Zhang, Mei-Jie, Wang, Hai-Lin, Abdel-Azim, Hisham, Aljurf, Mahmoud, Assal, Amer, Bajel, Ashish, Bashey, Asad, Battiwalla, Minoo, Beitinjaneh, Amer M., Bejanyan, Nelli, Bhatt, Vijaya Raj, Bolanos-Meade, Javier, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Ciurea, Stefan, Copelan, Edward, Cutler, Corey, Daly, Andrew, Diaz, Miguel-Angel, Farhadfar, Nosha, Gale, Robert P., Ganguly, Siddhartha, Grunwald, Michael R., Hahn, Theresa, Hashmi, Shahrukh, Hildebrandt, Gerhard C., Holland, H. Kent, Hossain, Nasheed, Kanakry, Christopher G., Kharfan-Dabaja, Mohamed A., Khera, Nandita, Koc, Yener, Lazarus, Hillard M., Lee, Jong-Wook, Maertens, Johan, Martino, Rodrigo, McGuirk, Joseph, Munker, Reinhold, Murthy, Hemant S., Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Palmisiano, Neil, Patel, Sagar, Pidala, Joseph, Olin, Rebecca, Olsson, Richard F., Oran, Betul, Ringden, Olov, Rizzieri, David, Rowe, Jacob, Savoie, Mary Lynn, Schultz, Kirk R., Seo, Sachiko, Shaffer, Brian C., Singh, Anurag, Solh, Melhem, Stockerl-Goldstein, Keith, Verdonck, Leo F., Wagner, John, Waller, Edmund K., De Lima, Marcos, Sandmaier, Brenda M., Litzow, Mark, Weisdorf, Dan, Romee, Rizwan, Saber, Wael, Rashidi, Armin, Hamadani, Mehdi, Zhang, Mei-Jie, Wang, Hai-Lin, Abdel-Azim, Hisham, Aljurf, Mahmoud, Assal, Amer, Bajel, Ashish, Bashey, Asad, Battiwalla, Minoo, Beitinjaneh, Amer M., Bejanyan, Nelli, Bhatt, Vijaya Raj, Bolanos-Meade, Javier, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Ciurea, Stefan, Copelan, Edward, Cutler, Corey, Daly, Andrew, Diaz, Miguel-Angel, Farhadfar, Nosha, Gale, Robert P., Ganguly, Siddhartha, Grunwald, Michael R., Hahn, Theresa, Hashmi, Shahrukh, Hildebrandt, Gerhard C., Holland, H. Kent, Hossain, Nasheed, Kanakry, Christopher G., Kharfan-Dabaja, Mohamed A., Khera, Nandita, Koc, Yener, Lazarus, Hillard M., Lee, Jong-Wook, Maertens, Johan, Martino, Rodrigo, McGuirk, Joseph, Munker, Reinhold, Murthy, Hemant S., Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Palmisiano, Neil, Patel, Sagar, Pidala, Joseph, Olin, Rebecca, Olsson, Richard F., Oran, Betul, Ringden, Olov, Rizzieri, David, Rowe, Jacob, Savoie, Mary Lynn, Schultz, Kirk R., Seo, Sachiko, Shaffer, Brian C., Singh, Anurag, Solh, Melhem, Stockerl-Goldstein, Keith, Verdonck, Leo F., Wagner, John, Waller, Edmund K., De Lima, Marcos, Sandmaier, Brenda M., Litzow, Mark, Weisdorf, Dan, Romee, Rizwan, and Saber, Wael

Abstract

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

Published
2019
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5. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.

Author

Rashidi, Armin, Hamadani, Mehdi, Zhang, Mei-Jie, Wang, Hai-Lin, Abdel-Azim, Hisham, Aljurf, Mahmoud, Assal, Amer, Bajel, Ashish, Bashey, Asad, Battiwalla, Minoo, Beitinjaneh, Amer M., Bejanyan, Nelli, Bhatt, Vijaya Raj, Bolaños-Meade, Javier, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Ciurea, Stefan, Copelan, Edward, Cutler, Corey, Daly, Andrew, Diaz, Miguel-Angel, Farhadfar, Nosha, Gale, Robert P., Ganguly, Siddhartha, Grunwald, Michael R., Hahn, Theresa, Hashmi, Shahrukh, Hildebrandt, Gerhard C., Holland, H. Kent, Hossain, Nasheed, Kanakry, Christopher G, Kharfan-Dabaja, Mohamed A., Khera, Nandita, Koc, Yener, Lazarus, Hillard M., Lee, Jong-Wook, Maertens, Johan, Martino, Rodrigo, McGuirk, Joseph, Munker, Reinhold, Murthy, Hemant S., Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Palmisiano, Neil D., Patel, Sagar, Pidala, Joseph, Olin, Rebecca, Olsson, Richard F., Oran, Betul, Ringden, Olov, Rizzieri, David, Rowe, Jacob, Savoie, Mary Lynn, Schultz, Kirk R., Seo, Sachiko, Shaffer, Brian C., Singh, Anurag, Solh, Melhem, Stockerl-Goldstein, Keith, Verdonck, Leo F., Wagner, John, Waller, Edmund K., De Lima, Marcos, Sandmaier, Brenda M., Litzow, Mark, Weisdorf, Dan, Romee, Rizwan, Saber, Wael, Rashidi, Armin, Hamadani, Mehdi, Zhang, Mei-Jie, Wang, Hai-Lin, Abdel-Azim, Hisham, Aljurf, Mahmoud, Assal, Amer, Bajel, Ashish, Bashey, Asad, Battiwalla, Minoo, Beitinjaneh, Amer M., Bejanyan, Nelli, Bhatt, Vijaya Raj, Bolaños-Meade, Javier, Byrne, Michael, Cahn, Jean-Yves, Cairo, Mitchell, Ciurea, Stefan, Copelan, Edward, Cutler, Corey, Daly, Andrew, Diaz, Miguel-Angel, Farhadfar, Nosha, Gale, Robert P., Ganguly, Siddhartha, Grunwald, Michael R., Hahn, Theresa, Hashmi, Shahrukh, Hildebrandt, Gerhard C., Holland, H. Kent, Hossain, Nasheed, Kanakry, Christopher G, Kharfan-Dabaja, Mohamed A., Khera, Nandita, Koc, Yener, Lazarus, Hillard M., Lee, Jong-Wook, Maertens, Johan, Martino, Rodrigo, McGuirk, Joseph, Munker, Reinhold, Murthy, Hemant S., Nakamura, Ryotaro, Nathan, Sunita, Nishihori, Taiga, Palmisiano, Neil D., Patel, Sagar, Pidala, Joseph, Olin, Rebecca, Olsson, Richard F., Oran, Betul, Ringden, Olov, Rizzieri, David, Rowe, Jacob, Savoie, Mary Lynn, Schultz, Kirk R., Seo, Sachiko, Shaffer, Brian C., Singh, Anurag, Solh, Melhem, Stockerl-Goldstein, Keith, Verdonck, Leo F., Wagner, John, Waller, Edmund K., De Lima, Marcos, Sandmaier, Brenda M., Litzow, Mark, Weisdorf, Dan, Romee, Rizwan, and Saber, Wael

Abstract

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P 5 .15), leukemia-free survival (P 5 .50), nonrelapse mortality (P 5 .16), relapse (P 5 .90), or grade II-IV acute GVHD (P 5 .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P, .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients. © 2019 American Society of Hematology. All rights reserved.

Published
2019

6. Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma

Author

Radivoyevitch, Tomas, Dean, Robert M., Shaw, Bronwen E., Brazauskas, Ruta, Tecca, Heather R., Molenaar, Remco J., Battiwalla, Minoo, Savani, Bipin N., Flowers, Mary E. D., Cooke, Kenneth R., Hamilton, Betty K., Kalaycio, Matt, Maciejewski, Jaroslaw P., Ahmed, Ibrahim, Akpek, Gorgun, Bajel, Ashish, Buchbinder, David, Cahn, Jean-Yves, D'Souza, Anita, Daly, Andrew, DeFilipp, Zachariah, Ganguly, Siddhartha, Hamadani, Mehdi, Hayashi, Robert J., Hematti, Peiman, Inamoto, Yoshihiro, Khera, Nandita, Kindwall-Keller, Tamila, Landau, Heather, Lazarus, Hillard, Majhail, Navneet S., Marks, David I., Olsson, Richard F., Seo, Sachiko, Steinberg, Amir, William, Basem M., Wirk, Baldeep, Yared, Jean A., Aljurf, Mahmoud, Abidi, Muneer H., Allewelt, Heather, Beitinjaneh, Amer, Cook, Rachel, Cornell, Robert F., Fay, Joseph W., Hale, Gregory, Chakrabarty, Jennifer Holter, Jodele, Sonata, Kasow, Kimberly A., Mahindra, Anuj, Malone, Adriana K., Popat, Uday, Rizzo, J. Douglas, Schouten, Harry C., Warwick, Anne B., Wood, William A., Sekeres, Mikkael A., Litzow, Mark R., Gale, Robert P., Hashmi, Shahrukh K., Radivoyevitch, Tomas, Dean, Robert M., Shaw, Bronwen E., Brazauskas, Ruta, Tecca, Heather R., Molenaar, Remco J., Battiwalla, Minoo, Savani, Bipin N., Flowers, Mary E. D., Cooke, Kenneth R., Hamilton, Betty K., Kalaycio, Matt, Maciejewski, Jaroslaw P., Ahmed, Ibrahim, Akpek, Gorgun, Bajel, Ashish, Buchbinder, David, Cahn, Jean-Yves, D'Souza, Anita, Daly, Andrew, DeFilipp, Zachariah, Ganguly, Siddhartha, Hamadani, Mehdi, Hayashi, Robert J., Hematti, Peiman, Inamoto, Yoshihiro, Khera, Nandita, Kindwall-Keller, Tamila, Landau, Heather, Lazarus, Hillard, Majhail, Navneet S., Marks, David I., Olsson, Richard F., Seo, Sachiko, Steinberg, Amir, William, Basem M., Wirk, Baldeep, Yared, Jean A., Aljurf, Mahmoud, Abidi, Muneer H., Allewelt, Heather, Beitinjaneh, Amer, Cook, Rachel, Cornell, Robert F., Fay, Joseph W., Hale, Gregory, Chakrabarty, Jennifer Holter, Jodele, Sonata, Kasow, Kimberly A., Mahindra, Anuj, Malone, Adriana K., Popat, Uday, Rizzo, J. Douglas, Schouten, Harry C., Warwick, Anne B., Wood, William A., Sekeres, Mikkael A., Litzow, Mark R., Gale, Robert P., and Hashmi, Shahrukh K.

Abstract

Background: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n=916), non-Hodgkin lymphoma (NHL; n=3546) and plasma cell myeloma (PCM; n=4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. Results: 335 MDS/ AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR=4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR=2.5 [1.1, 2.5]); (2) >= 3 versus 1 line of chemotherapy for NHL (HR=1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR=2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/ MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort. Conclusions: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Published
2018
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7. Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia

Author

Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, Acute Leukemia Committee of the CIBMTR, Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, and Acute Leukemia Committee of the CIBMTR

Published
2018

8. Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia

Author

Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, Acute Leukemia Committee of the CIBMTR, Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, and Acute Leukemia Committee of the CIBMTR

Published
2018

9. Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia

Author

CTI Nierkens, Child Health, Regenerative Medicine and Stem Cells, Haematologie, Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, Acute Leukemia Committee of the CIBMTR, CTI Nierkens, Child Health, Regenerative Medicine and Stem Cells, Haematologie, Kebriaei, Partow, Anasetti, Claudio, Zhang, Mei Jie, Wang, Hai Lin, Aldoss, Ibrahim, de Lima, Marcos, Khoury, H. Jean, Sandmaier, Brenda M., Horowitz, Mary M., Artz, Andrew, Bejanyan, Nelli, Ciurea, Stefan, Lazarus, Hillard M., Gale, Robert Peter, Litzow, Mark, Bredeson, Christopher, Seftel, Matthew D., Pulsipher, Michael A., Boelens, Jaap Jan, Alvarnas, Joseph, Champlin, Richard, Forman, Stephen, Pullarkat, Vinod, Weisdorf, Daniel, Marks, David I., Hogan, William, Battiwalla, Minoo, Copelan, Edward, Hildebrandt, Gerhard, Ganguly, Sid, Majhail, Navneet, Woolfrey, Ann, Nivison-Smith, Ian, Hertzberg, Mark, Diaz, Miguel Angel, Jakubowski, Ann, Ustun, Celalettin, Yong, Agnes, Freytes, Cesar, DeFilipp, Zachariah, Inamoto, Yoshi, Cahn, Jean Yves, Savani, Bipin, Yared, Jean, Bajel, Ashish, Bacher, Ulrike, Uy, Geoffrey, Rizzieri, David, Wieduwilt, Matthew, Bierings, Marc, and Acute Leukemia Committee of the CIBMTR

Published
2018

10. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States

Author

Muffly, Lori, Pasquini, Marcelo C., Martens, Michael, Brazauskas, Ruta, Zhu, Xiaochun, Adekola, Kehinde, Aljurf, Mahmoud, Ballen, Karen K., Bajel, Ashish, Baron, Frederic, Battiwalla, Minoo, Beitinjaneh, Amer, Cahn, Jean-Yves, Carabasi, Mathew, Chen, Yi-Bin, Chhabra, Saurabh, Ciurea, Stefan, Copelan, Edward, D'Souza, Anita, Edwards, John, Foran, James, Freytes, Cesar O., Fung, Henry C., Gale, Robert Peter, Giralt, Sergio, Hashmi, Shahrukh K., Hildebrandt, Gerhard C., Ho, Vincent, Jakubowski, Ann, Lazarus, Hillard, Luskin, Marlise R., Martino, Rodrigo, Maziarz, Richard, McCarthy, Philip, Nishihori, Taiga, Olin, Rebecca, Olsson, Richard F., Pawarode, Attaphol, Peres, Edward, Rezvani, Andrew R., Rizzieri, David, Savani, Bipin N., Schouten, Harry C., Sabloff, Mitchell, Seftel, Matthew, Seo, Sachiko, Sorror, Mohamed L., Szer, Jeff, Wirk, Baldeep M., Wood, William A., Artz, Andrew, Muffly, Lori, Pasquini, Marcelo C., Martens, Michael, Brazauskas, Ruta, Zhu, Xiaochun, Adekola, Kehinde, Aljurf, Mahmoud, Ballen, Karen K., Bajel, Ashish, Baron, Frederic, Battiwalla, Minoo, Beitinjaneh, Amer, Cahn, Jean-Yves, Carabasi, Mathew, Chen, Yi-Bin, Chhabra, Saurabh, Ciurea, Stefan, Copelan, Edward, D'Souza, Anita, Edwards, John, Foran, James, Freytes, Cesar O., Fung, Henry C., Gale, Robert Peter, Giralt, Sergio, Hashmi, Shahrukh K., Hildebrandt, Gerhard C., Ho, Vincent, Jakubowski, Ann, Lazarus, Hillard, Luskin, Marlise R., Martino, Rodrigo, Maziarz, Richard, McCarthy, Philip, Nishihori, Taiga, Olin, Rebecca, Olsson, Richard F., Pawarode, Attaphol, Peres, Edward, Rezvani, Andrew R., Rizzieri, David, Savani, Bipin N., Schouten, Harry C., Sabloff, Mitchell, Seftel, Matthew, Seo, Sachiko, Sorror, Mohamed L., Szer, Jeff, Wirk, Baldeep M., Wood, William A., and Artz, Andrew

Abstract

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults >= 70 years with hematologic malignancies across the United States. Adults >= 70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients >= 70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index >= 3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients >= 70 years. Select adults >= 70 years with hematologic malignancies should be considered for transplant.

Published
2017
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11. Allogeneic Hematopoietic Cell Transplantation for Adult Chronic Myelomonocytic Leukemia

Author

Liu, Hien Duong, Ahn, Kwang Woo, Hu, Zhen-Huan, Hamadani, Mehdi, Nishihori, Taiga, Wirk, Baldeep, Beitinjaneh, Amer, Rizzieri, David, Grunwald, Michael R., Sabloff, Mitchell, Olsson, Richard F., Bajel, Ashish, Bredeson, Christopher, Daly, Andrew, Inamoto, Yoshihiro, Majhail, Navneet, Saad, Ayman, Gupta, Vikas, Gerds, Aaron, Malone, Adriana, Tallman, Martin, Reshef, Ran, Marks, David I., Copelan, Edward, Gergis, Usama, Savoie, Mary Lynn, Ustun, Celalettin, Litzow, Mark R., Cahn, Jean-Yves, Kindwall-Keller, Tamila, Akpek, Gorgun, Savani, Bipin N., Aljurf, Mahmoud, Rowe, Jacob M., Wiernik, Peter H., Hsu, Jack W., Cortes, Jorge, Kalaycio, Matt, Maziarz, Richard, Sobecks, Ronald, Popat, Uday, Alyea, Edwin, Saber, Wael, Liu, Hien Duong, Ahn, Kwang Woo, Hu, Zhen-Huan, Hamadani, Mehdi, Nishihori, Taiga, Wirk, Baldeep, Beitinjaneh, Amer, Rizzieri, David, Grunwald, Michael R., Sabloff, Mitchell, Olsson, Richard F., Bajel, Ashish, Bredeson, Christopher, Daly, Andrew, Inamoto, Yoshihiro, Majhail, Navneet, Saad, Ayman, Gupta, Vikas, Gerds, Aaron, Malone, Adriana, Tallman, Martin, Reshef, Ran, Marks, David I., Copelan, Edward, Gergis, Usama, Savoie, Mary Lynn, Ustun, Celalettin, Litzow, Mark R., Cahn, Jean-Yves, Kindwall-Keller, Tamila, Akpek, Gorgun, Savani, Bipin N., Aljurf, Mahmoud, Rowe, Jacob M., Wiernik, Peter H., Hsu, Jack W., Cortes, Jorge, Kalaycio, Matt, Maziarz, Richard, Sobecks, Ronald, Popat, Uday, Alyea, Edwin, and Saber, Wael

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with chronic myelomonocytic leukemia (CMML); however, few data exist regarding prognostic factors and transplantation outcomes. We performed this retrospective study to identify prognostic factors for post-transplantation outcomes. The CMML-specific prognostic scoring system (CPSS) has been validated in subjects receiving nontransplantation therapy and was included in our study. From 2001 to 2012, 209 adult subjects who received HCT for CMML were reported to the Center for International Blood and Marrow Transplant Research. The median age at transplantation was 57 years (range, 23 to 74). Median follow-up was 51 months (range, 3 to 122). On multivariate analyses, CPSS scores, Karnofsky performance status (KPS), and graft source were significant predictors of survival (P = .004, P = .01, P = .01, respectively). Higher CPSS scores were not associated with disease-free survival, relapse, or transplantation-related mortality. In a restricted analysis of subjects with relapse after HCT, those with intermediate-2/high risk had a nearly 2-fold increased risk of death after relapse compared to those with low/intermediate-1 CPSS scores. Respective 1-year, 3-year, and 5-year survival rates for low/intermediate-1 risk subjects were 61% (95% confidence interval [CI], 52% to 72%), 48% (95% CI, 37% to 59%), and 44% (95% CI, 33% to 55%), and for intermediate-2/high risk subjects were 38% (95% CI, 28% to 49%), 32% (95% CI, 21% to 42%), and 19% (95% CI, 8% to 29%). We conclude that higher CPSS score at time of transplantation, lower KPS, and a bone marrow graft are associated with inferior survival after HCT. Further investigation of CMML disease-related biology may provide insights into other risk factors predictive of post-transplantation outcomes. (C) 2017 American Society for Blood and Marrow Transplantation.

Published
2017
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12. The natural history of NPM1MUT Measurable Residual Disease (MRD) positivity after completion of chemotherapy in Acute Myeloid Leukemia (AML)

Author

Tiong, Ing Soo, Dillon, Richard, Ivey, Adam, Kok, Chung Hoow, Kuzich, James Anton, Thiagarajah, Nisha, Bajel, Ashish, Potter, Nicola, Smith, Matthew, Hemmaway, Claire, Thomas, Abin, Gilkes, Amanda, Russell, Nigel H., Wei, Andrew H., Tiong, Ing Soo, Dillon, Richard, Ivey, Adam, Kok, Chung Hoow, Kuzich, James Anton, Thiagarajah, Nisha, Bajel, Ashish, Potter, Nicola, Smith, Matthew, Hemmaway, Claire, Thomas, Abin, Gilkes, Amanda, Russell, Nigel H., and Wei, Andrew H.

Abstract

Molecular MRD assays targeting NPM1 mutant (mut) transcripts have an established role for monitoring treatment efficacy in patients with NPM1mut AML. Approximately 25% of NPM1mut patients show persistent MRD level in the bone marrow (BM) at the end of treatment (EOT), which is associated with a higher risk of relapse (Ivey, NEJM 2016; Kronke, JCO 2011). Molecular persistence at low copy number (MP-LCN) is defined by the European LeukemiaNet (ELN) as MRD positivity in patients in morphological complete remission (CR) with <1000-2000 transcripts per 105ABL and a relative increase of <1 log between any two positive samples collected after EOT (Schuurhuis, Blood 2018). The UK NCRI working group recently reported the impact of NPM1mut MRD burden and FLT3-ITD status on risk of relapse after allogeneic stem cell transplantation (Dillon, Blood 2020), however the clinical relevance of NPM1mut MP-LCN in patients who are not transplanted is unknown. We aimed to characterize the natural history of persistent NPM1mut MRD after chemotherapy and to identify factors associated with subsequent disease progression.

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