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1. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function

Author

Aluri, Jahnavi, Bach, Alicia, Kaviany, Saara, Chiquetto Paracatu, Luana, Kitcharoensakkul, Maleewan, Walkiewicz, Magdalena A, Putnam, Christopher D, Shinawi, Marwan, Saucier, Nermina, Rizzi, Elise M, Harmon, Michael T, Keppel, Molly P, Ritter, Michelle, Similuk, Morgan, Kulm, Elaine, Joyce, Michael, de Jesus, Adriana A, Goldbach-Mansky, Raphaela, Lee, Yi-Shan, Cella, Marina, Kendall, Peggy L, Dinauer, Mary C, Bednarski, Jeffrey J, Bemrich-Stolz, Christina, Canna, Scott W, Abraham, Shirley M, Demczko, Matthew M, Powell, Jonathan, Jones, Stacie M, Scurlock, Amy M, De Ravin, Suk See, Bleesing, Jack J, Connelly, James A, Rao, V Koneti, Schuettpelz, Laura G, and Cooper, Megan A

Subjects
Stem Cell Research, Clinical Research, Genetics, Transplantation, Stem Cell Research - Nonembryonic - Human, Hematology, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Inflammatory and immune system, Good Health and Well Being, Adolescent, Adult, B-Lymphocytes, Bone Marrow Failure Disorders, Cell Differentiation, Child, Child, Preschool, Cytokines, Female, Follow-Up Studies, Gain of Function Mutation, Humans, Immunologic Deficiency Syndromes, Infant, Inflammation, Lymphocyte Activation, Male, Mosaicism, Pancytopenia, Pedigree, Prognosis, T-Lymphocytes, Toll-Like Receptor 8, Young Adult, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with

Published
2021

2. Pluripotent stem cell–derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity

Author

Zhu, Huang, Blum, Robert H, Bjordahl, Ryan, Gaidarova, Svetlana, Rogers, Paul, Lee, Tom Tong, Abujarour, Ramzey, Bonello, Gregory B, Wu, Jianming, Tsai, Pei-Fang, Miller, Jeffrey S, Walcheck, Bruce, Valamehr, Bahram, and Kaufman, Dan S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Immunology, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Women's Health, Stem Cell Research - Induced Pluripotent Stem Cell, Cancer, Lymphatic Research, Hematology, Immunization, Biotechnology, Lymphoma, Ovarian Cancer, Rare Diseases, Immunotherapy, 5.2 Cellular and gene therapies, 2.1 Biological and endogenous factors, Animals, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Antigens, CD20, Antineoplastic Agents, Immunological, Cell Line, Cell Line, Tumor, Female, Humans, Induced Pluripotent Stem Cells, Killer Cells, Natural, Lymphoma, B-Cell, Mice, Inbred NOD, Mice, SCID, Ovarian Neoplasms, Receptors, IgG, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation. We previously demonstrated that a point mutation of CD16a prevents this activation-induced surface cleavage. This noncleavable CD16a variant is now further modified to include the high-affinity noncleavable variant of CD16a (hnCD16) and was engineered into human induced pluripotent stem cells (iPSCs) to create a renewable source for human induced pluripotent stem cell-derived NK (hnCD16-iNK) cells. Compared with unmodified iNK cells and peripheral blood-derived NK (PB-NK) cells, hnCD16-iNK cells proved to be highly resistant to activation-induced cleavage of CD16a. We found that hnCD16-iNK cells were functionally mature and exhibited enhanced ADCC against multiple tumor targets. In vivo xenograft studies using a human B-cell lymphoma demonstrated that treatment with hnCD16-iNK cells and anti-CD20 mAb led to significantly improved regression of B-cell lymphoma compared with treatment utilizing anti-CD20 mAb with PB-NK cells or unmodified iNK cells. hnCD16-iNK cells, combined with anti-HER2 mAb, also mediated improved survival in an ovarian cancer xenograft model. Together, these findings show that hnCD16-iNK cells combined with mAbs are highly effective against hematologic malignancies and solid tumors that are typically resistant to NK cell-mediated killing, demonstrating the feasibility of producing a standardized off-the-shelf engineered NK cell therapy with improved ADCC properties to treat malignancies that are otherwise refractory.

Published
2020

3. Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma

Author

Ward, Jeffrey P., Berrien-Elliott, Melissa M., Gomez, Felicia, Luo, Jingqin, Becker-Hapak, Michelle, Cashen, Amanda F., Wagner-Johnston, Nina D., Maddocks, Kami, Mosior, Matthew, Foster, Mark, Krysiak, Kilannin, Schmidt, Alina, Skidmore, Zachary L., Desai, Sweta, Watkins, Marcus P., Fischer, Anne, Griffith, Malachi, Griffith, Obi L., Fehniger, Todd A., and Bartlett, Nancy L.

Published
2022
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4. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Author

Huffman, Jennifer E., Nicholas, Jayna, Hahn, Julie, Heath, Adam S., Raffield, Laura M., Yanek, Lisa R., Brody, Jennifer A., Thibord, Florian, Almasy, Laura, Bartz, Traci M., Bielak, Lawrence F., Bowler, Russell P., Carrasquilla, Germán D., Chasman, Daniel I., Chen, Ming-Huei, Emmert, David B., Ghanbari, Mohsen, Haessler, Jeffrey, Hottenga, Jouke-Jan, Kleber, Marcus E., Le, Ngoc-Quynh, Lee, Jiwon, Lewis, Joshua P., Li-Gao, Ruifang, Luan, Jian'an, Malmberg, Anni, Mangino, Massimo, Marioni, Riccardo E., Martinez-Perez, Angel, Pankratz, Nathan, Polasek, Ozren, Richmond, Anne, Rodriguez, Benjamin A. T., Rotter, Jerome I., Steri, Maristella, Suchon, Pierre, Trompet, Stella, Weiss, Stefan, Zare, Marjan, Auer, Paul, Cho, Michael H., Christofidou, Paraskevi, Davies, Gail, de Geus, Eco, Deleuze, Jean-François, Delgado, Graciela E., Ekunwe, Lynette, Faraday, Nauder, Gögele, Martin, Greinacher, Andreas, Gao, He, Howard, Tom, Joshi, Peter K., Kilpeläinen, Tuomas O., Lahti, Jari, Linneberg, Allan, Naitza, Silvia, Noordam, Raymond, Paüls-Vergés, Ferran, Rich, Stephen S., Rosendaal, Frits R., Rudan, Igor, Ryan, Kathleen A., Souto, Juan Carlos, van Rooij, Frank J. A., Wang, Heming, Zhao, Wei, Becker, Lewis C., Beswick, Andrew, Brown, Michael R., Cade, Brian E., Campbell, Harry, Cho, Kelly, Crapo, James D., Curran, Joanne E., de Maat, Moniek P. M., Doyle, Margaret, Elliott, Paul, Floyd, James S., Fuchsberger, Christian, Grarup, Niels, Guo, Xiuqing, Harris, Sarah E., Hou, Lifang, Kolcic, Ivana, Kooperberg, Charles, Menni, Cristina, Nauck, Matthias, O'Connell, Jeffrey R., Orrù, Valeria, Psaty, Bruce M., Räikkönen, Katri, Smith, Jennifer A., Soria, Jose Manuel, Stott, David J., van Hylckama Vlieg, Astrid, Watkins, Hugh, Willemsen, Gonneke, Wilson, Peter W. F., Ben-Shlomo, Yoav, Blangero, John, Boomsma, Dorret, Cox, Simon R., Dehghan, Abbas, Eriksson, Johan G., Fiorillo, Edoardo, Fornage, Myriam, Hansen, Torben, Hayward, Caroline, Ikram, M. Arfan, Jukema, J. Wouter, Kardia, Sharon L. R., Lange, Leslie A., März, Winfried, Mathias, Rasika A., Mitchell, Braxton D., Mook-Kanamori, Dennis O., Morange, Pierre-Emmanuel, Pedersen, Oluf, Pramstaller, Peter P., Redline, Susan, Reiner, Alexander, Ridker, Paul M., Silverman, Edwin K., Spector, Tim D., Völker, Uwe, Wareham, Nicholas J., Wilson, James F., Yao, Jie, Trégouët, David-Alexandre, Johnson, Andrew D., Wolberg, Alisa S., de Vries, Paul S., Sabater-Lleal, Maria, Morrison, Alanna C., and Smith, Nicholas L.

Abstract

•Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 distinct variants (20 novel).•Links to (1) liver enzyme, blood cell, and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

Published
2024
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5. Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice

Author

Kauppi, Maria, Hyland, Craig D., Viney, Elizabeth M., White, Christine A., de Graaf, Carolyn A., Welch, AnneMarie E., Yousef, Jumana, Dagley, Laura F., Emery-Corbin, Samantha J., Di Rago, Ladina, Kueh, Andrew J., Herold, Marco J., Hilton, Douglas J., Babon, Jeffrey J., Nicola, Nicos A., Behrens, Kira, and Alexander, Warren S.

Abstract

•Cul5 regulates production of megakaryocyte-committed stem cells to prevent excess megakaryopoiesis.•Cul5-deficient megakaryopoiesis is largely independent of TPO and involves signaling via the β-common and/or β-IL-3 receptors.

Published
2025
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6. Air pollution is associated with increased risk of venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis

Author

Lutsey, Pamela L., Misialek, Jeffrey R., Young, Michael T., Berman, Jesse, Leiser, Claire L., Pope, Zachary C., Cushman, Mary, Folsom, Aaron R., and Kaufman, Joel D.

Abstract

•Air pollution exposure is common, and may increase risk of developing blood clots.•Greater long-term exposure to air pollution (ie, PM2.5, NOxNO2) was associated with higher risk of developing venous thromboembolism.

Published
2025
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7. Outcomes in patients with ETV6::RUNX1or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies

Author

Purvis, Katelyn, Zhou, Yinmei, Karol, Seth E., Rubnitz, Jeffrey E., Ribeiro, Raul C., Lee, Shawn, Yang, Jun J., Bowman, W. Paul, Wang, Lu, Dixon, Stephanie B., Roberts, Kathryn G., Gao, Qingsong, Cheng, Cheng, Mullighan, Charles G., Jeha, Sima, Pui, Ching-Hon, and Inaba, Hiroto

Abstract

•Among NCI high-risk patients, 93% with ETV6::RUNX1and 54% with hyperdiploid B-ALL had excellent outcomes with low-intensity therapy.•NCI high-risk patients with hyperdiploid B-ALL and slow early MRD response had worse outcomes and, therefore, require new approaches.

Published
2025
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8. Refined ELN 2024 risk stratification improves survival prognostication following venetoclax-based therapy in AML

Author

Lachowiez, Curtis A., Ravikumar, Vishvaas I., Othman, Jad, O’Nions, Jenny, Peters, Daniel T., McMahon, Christine, Swords, Ronan, Cook, Rachel, Saultz, Jennifer N., Tyner, Jeffrey W., Dillon, Richard, Zeidner, Joshua F., and Pollyea, Daniel A.

Abstract

The European LeukemiaNet 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates reclassification and incorporation of new gene mutations in the present model can further improve and individualize prognostication.

Published
2024
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11. Unbalanced MYCbreak-apart FISH patterns indicate the presence of a MYCrearrangement in HGBCL-DH-BCL2

Author

Collinge, Brett, Ben-Neriah, Susana, Hilton, Laura K., Alduaij, Waleed, Tucker, Tracy, Slack, Graham W., Farinha, Pedro, Craig, Jeffrey W., Boyle, Merrill, Meissner, Barbara, Villa, Diego, Gerrie, Alina S., Sehn, Laurie H., Savage, Kerry J., Morin, Ryan D., Mungall, Andrew J., Steidl, Christian, and Scott, David W.

Abstract

•Unbalanced MYCbreak-apart FISH patterns, in which red or green signal is lost, are observed in ∼13% of HGBCL-DH-BCL2tumors.•Balanced and unbalanced MYCrearrangements have the same biological consequences and should be reported as positive for rearrangement.

Published
2024
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12. Interleukin-5–producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy

Author

Van Gool, Frédéric, Molofsky, Ari B, Morar, Malika M, Rosenzwajg, Michelle, Liang, Hong-Erh, Klatzmann, David, Locksley, Richard M, and Bluestone, Jeffrey A

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Antibodies, Cell Proliferation, Eosinophilia, Humans, Immunity, Innate, Interleukin-2, Interleukin-5, Lymphocytes, Mice, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract

Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal a novel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease.

Published
2014

13. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank

Author

Ryu, Justine, Rämö, Joel T., Jurgens, Sean J., Palotie, Aarno, Daly, Mark, Riley-Gills, Bridget, Jacob, Howard, Viollet, Coralie, Petrovski, Slavé, Chen, Chia-Yen, John, Sally, Okafo, George, Plenge, Robert, Maranville, Joseph, McCarthy, Mark, Pendergrass, Rion, Ehm, Margaret G., Auro, Kirsi, Longerich, Simonne, Mälarstig, Anders, Vlahiotis, Anna, Klinger, Katherine, Chatelain, Clement, Gossel, Matthias, Estrada, Karol, Graham, Robert, Waterworth, Dawn, O´Donnell, Chris, Renaud, Nicole, Mäkelä, Tomi P., Kaprio, Jaakko, Ruddock, Minna, Virolainen, Petri, Hakanen, Antti, Kilpi, Terhi, Perola, Markus, Partanen, Jukka, Raivio, Taneli, Tikkanen, Jani, Serpi, Raisa, Kristiansson, Kati, Kosma, Veli-Matti, Laukkanen, Jari, Hautalahti, Marco, Tuovila, Outi, Waring, Jeffrey, Riley-Gillis, Bridget, Rahimov, Fedik, Tachmazidou, Ioanna, Chen, Chia-Yen, Ding, Zhihao, Jung, Marc, Tuoken, Hanati, Biswas, Shameek, Pendergrass, Rion, Ehm, Margaret G., Pulford, David, Raghavan, Neha, Huertas-Vazquez, Adriana, Sul, Jae-Hoon, Mälarstig, Anders, Hu, Xinli, Hedman, Åsa, Klinger, Katherine, Graham, Robert, Waterworth, Dawn, Renaud, Nicole, Obeidat, Ma´en, Chung, Jonathan, Zierer, Jonas, Niemi, Mari, Ripatti, Samuli, Schleutker, Johanna, Perola, Markus, Arvas, Mikko, Carpén, Olli, Hinttala, Reetta, Kettunen, Johannes, Mannermaa, Arto, Aalto-Setälä, Katriina, Kähönen, Mika, Laukkanen, Jari, Mäkelä, Johanna, Kälviäinen, Reetta, Julkunen, Valtteri, Soininen, Hilkka, Remes, Anne, Hiltunen, Mikko, Peltola, Jukka, Raivio, Minna, Tienari, Pentti, Rinne, Juha, Kallionpää, Roosa, Partanen, Juulia, Ziemann, Adam, Smaoui, Nizar, Lehtonen, Anne, Eaton, Susan, Runz, Heiko, Lahdenperä, Sanni, Biswas, Shameek, Bowers, Natalie, Teng, Edmond, Pendergrass, Rion, Xu, Fanli, Pulford, David, Auro, Kirsi, Addis, Laura, Eicher, John, Li, Qingqin S., He, Karen, Khramtsova, Ekaterina, Raghavan, Neha, Färkkilä, Martti, Koskela, Jukka, Pikkarainen, Sampsa, Jussila, Airi, Kaukinen, Katri, Blomster, Timo, Kiviniemi, Mikko, Voutilainen, Markku, Daly, Mark, Waring, Jeffrey, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Lu, Tim, Bowers, Natalie, Pendergrass, Rion, McCarthy, Linda, Hart, Amy, Guan, Meijian, Miller, Jason, Kalpala, Kirsi, Miller, Melissa, Hu, Xinli, Eklund, Kari, Palomäki, Antti, Isomäki, Pia, Pirilä, Laura, Kaipiainen-Seppänen, Oili, Huhtakangas, Johanna, Mars, Nina, Waring, Jeffrey, Rahimov, Fedik, Lertratanakul, Apinya, Smaoui, Nizar, Lehtonen, Anne, Viollet, Coralie, Hochfeld, Marla, Bowers, Natalie, Pendergrass, Rion, Gordillo, Jorge Esparza, Auro, Kirsi, Waterworth, Dawn, Farias, Fabiana, Kalpala, Kirsi, Bing, Nan, Hu, Xinli, Laitinen, Tarja, Pelkonen, Margit, Kauppi, Paula, Kankaanranta, Hannu, Harju, Terttu, Lahesmaa, Riitta, Smaoui, Nizar, Viollet, Coralie, Eaton, Susan, Chen, Hubert, Pendergrass, Rion, Bowers, Natalie, Betts, Joanna, Auro, Kirsi, Mishra, Rajashree, Mouded, Majd, Ngo, Debby, Niiranen, Teemu, Vaura, Felix, Salomaa, Veikko, Metsärinne, Kaj, Aittokallio, Jenni, Kähönen, Mika, Hernesniemi, Jussi, Gordin, Daniel, Sinisalo, Juha, Taskinen, Marja-Riitta, Tuomi, Tiinamaija, Hiltunen, Timo, Laukkanen, Jari, Elliott, Amanda, Reeve, Mary Pat, Ruotsalainen, Sanni, Paul, Dirk, Bowers, Natalie, Pendergrass, Rion, Chu, Audrey, Auro, Kirsi, Reilly, Dermot, Mendelson, Mike, Parkkinen, Jaakko, Miller, Melissa, Meretoja, Tuomo, Joensuu, Heikki, Carpén, Olli, Mattson, Johanna, Salminen, Eveliina, Auranen, Annika, Karihtala, Peeter, Auvinen, Päivi, Elenius, Klaus, Schleutker, Johanna, Pitkänen, Esa, Mars, Nina, Daly, Mark, Popovic, Relja, Waring, Jeffrey, Riley-Gillis, Bridget, Lehtonen, Anne, Fabre, Margarete, Schutzman, Jennifer, Bowers, Natalie, Pendergrass, Rion, Kulkarni, Diptee, Auro, Kirsi, Porello, Alessandro, Loboda, Andrey, Lehtonen, Heli, McDonough, Stefan, Vuoti, Sauli, Kaarniranta, Kai, Turunen, Joni A., Ollila, Terhi, Uusitalo, Hannu, Karjalainen, Juha, Pitkänen, Esa, Liu, Mengzhen, Runz, Heiko, Loomis, Stephanie, Strauss, Erich, Bowers, Natalie, Chen, Hao, Pendergrass, Rion, Tasanen, Kaisa, Huilaja, Laura, Hannula-Jouppi, Katariina, Salmi, Teea, Peltonen, Sirkku, Koulu, Leena, Smaoui, Nizar, Rahimov, Fedik, Lehtonen, Anne, Choy, David, Pendergrass, Rion, Waterworth, Dawn, Kalpala, Kirsi, Wu, Ying, Pussinen, Pirkko, Salminen, Aino, Salo, Tuula, Rice, David, Nieminen, Pekka, Palotie, Ulla, Siponen, Maria, Suominen, Liisa, Mäntylä, Päivi, Gursoy, Ulvi, Anttonen, Vuokko, Sipilä, Kirsi, Pendergrass, Rion, Laivuori, Hannele, Kurra, Venla, Kotaniemi-Talonen, Laura, Heikinheimo, Oskari, Kalliala, Ilkka, Aaltonen, Lauri, Jokimaa, Varpu, Kettunen, Johannes, Vääräsmäki, Marja, Uimari, Outi, Morin-Papunen, Laure, Niinimäki, Maarit, Piltonen, Terhi, Kivinen, Katja, Widen, Elisabeth, Tukiainen, Taru, Reeve, Mary Pat, Daly, Mark, Välimäki, Niko, Laakkonen, Eija, Tyrmi, Jaakko, Silven, Heidi, Sliz, Eeva, Arffman, Riikka, Savukoski, Susanna, Laisk, Triin, Pujol, Natalia, Liu, Mengzhen, Riley-Gillis, Bridget, Pendergrass, Rion, Kumar, Janet, Auro, Kirsi, Hovatta, Iiris, Chen, Chia-Yen, Isometsä, Erkki, Ollila, Hanna, Suvisaari, Jaana, Mäkitie, Antti, Bizaki-Vallaskangas, Argyro, Toppila-Salmi, Sanna, Willberg, Tytti, Saarentaus, Elmo, Aarnisalo, Antti, Salminen, Eveliina, Rahikkala, Elisa, Kettunen, Johannes, Aittomäki, Kristiina, Åberg, Fredrik, Kurki, Mitja, Ripatti, Samuli, Daly, Mark, Karjalainen, Juha, Havulinna, Aki, Mehtonen, Juha, Palta, Priit, Hassan, Shabbeer, Della Briotta Parolo, Pietro, Zhou, Wei, Maasha, Mutaamba, Hassan, Shabbeer, Lemmelä, Susanna, Rivas, Manuel, Palotie, Aarno, Liu, Aoxing, Lehisto, Arto, Ganna, Andrea, Llorens, Vincent, Laivuori, Hannele, Tukiainen, Taru, Reeve, Mary Pat, Heyne, Henrike, Mars, Nina, Rämö, Joel, Saarentaus, Elmo, Ollila, Hanna, Rodosthenous, Rodos, Strausz, Satu, Palotie, Tuula, Palin, Kimmo, Garcia-Tabuenca, Javier, Siirtola, Harri, Kiiskinen, Tuomo, Lee, Jiwoo, Tsuo, Kristin, Elliott, Amanda, Kristiansson, Kati, Arvas, Mikko, Hyvärinen, Kati, Ritari, Jarmo, Carpén, Olli, Kettunen, Johannes, Pylkäs, Katri, Sliz, Eeva, Karjalainen, Minna, Mantere, Tuomo, Kangasniemi, Eeva, Heikkinen, Sami, Mannermaa, Arto, Laakkonen, Eija, Pitkänen, Nina, Lessard, Samuel, Chatelain, Clément, Kallio, Lila, Wahlfors, Tiina, Partanen, Jukka, Punkka, Eero, Serpi, Raisa, Siltanen, Sanna, Kosma, Veli-Matti, Kuopio, Teijo, Jalanko, Anu, Shen, Huei-Yi, Kajanne, Risto, Aavikko, Mervi, Cooper, Helen, Öller, Denise, Leinonen, Rasko, Palin, Henna, Linna, Malla-Maria, Kurki, Mitja, Karjalainen, Juha, Della Briotta Parolo, Pietro, Lehisto, Arto, Mehtonen, Juha, Zhou, Wei, Kanai, Masahiro, Maasha, Mutaamba, Zheng, Zhili, Laivuori, Hannele, Havulinna, Aki, Lemmelä, Susanna, Kiiskinen, Tuomo, Lahtela, L. Elisa, Kaunisto, Mari, Kilpeläinen, Elina, Sipilä, Timo P., Dada, Oluwaseun Alexander, Ghazal, Awaisa, Kytölä, Anastasia, Weldatsadik, Rigbe, Ruotsalainen, Sanni, Donner, Kati, Sipilä, Timo P., Loukola, Anu, Laiho, Päivi, Sistonen, Tuuli, Kaiharju, Essi, Laukkanen, Markku, Järvensivu, Elina, Lähteenmäki, Sini, Männikkö, Lotta, Wong, Regis, Toivola, Auli, Brunfeldt, Minna, Mattsson, Hannele, Kristiansson, Kati, Lemmelä, Susanna, Koskelainen, Sami, Hiekkalinna, Tero, Paajanen, Teemu, Palta, Priit, Luo, Shuang, Laitinen, Tarja, Reeve, Mary Pat, Padmanabhuni, Shanmukha Sampath, Niemi, Marianna, Siirtola, Harri, Gracia-Tabuenca, Javier, Helminen, Mika, Luukkaala, Tiina, Vähätalo, Iida, Tammerluoto, Jyrki, Hautalahti, Marco, Mäkelä, Johanna, Smith, Sarah, Southerington, Tom, Lehto, Petri, Niiranen, Teemu, Sanna-Cherchi, Simone, Bauer, Kenneth A., Haj, Amelia, Choi, Seung Hoan, Palotie, Aarno, Daly, Mark, Ellinor, Patrick T., and Bendapudi, Pavan K.

Abstract

•Population-scale genomics (N = 937 939) allowed assembly of a large FVL/PTGM double-heterozygous cohort while mitigating ascertainment bias.•FVL/PTGM DH appeared to be more common than FVL homozygosity and conferred a similar risk of venous thrombosis.

Published
2024
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14. Causal role for JAK2 V617F in thrombosis

Author

Fleischman, Angela G and Tyner, Jeffrey W

Subjects
Animals, Blood Platelets, Humans, Janus Kinase 2, Mutant Proteins, Mutation, Thrombocythemia, Essential, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

In this issue of Blood, Hobbs et al use a JAK2 V617F knock-in mouse model to interrogate the impact of JAK2 V617F on thrombosis and demonstrate altered function of megakaryocytes and platelets in the context of JAK2 V617F expression.

Published
2013

15. Transfusion-related acute lung injury: incidence and risk factors.

Author

Toy, Pearl, Gajic, Ognjen, Bacchetti, Peter, Looney, Mark R, Gropper, Michael A, Hubmayr, Rolf, Lowell, Clifford A, Norris, Philip J, Murphy, Edward L, Weiskopf, Richard B, Wilson, Gregory, Koenigsberg, Monique, Lee, Deanna, Schuller, Randy, Wu, Ping, Grimes, Barbara, Gandhi, Manish J, Winters, Jeffrey L, Mair, David, Hirschler, Nora, Sanchez Rosen, Rosa, Matthay, Michael A, and TRALI Study Group

Subjects
TRALI Study Group, Humans, Blood Transfusion, Population Surveillance, Incidence, Risk Factors, Case-Control Studies, Retrospective Studies, Adult, Aged, Middle Aged, Academic Medical Centers, Female, Male, Acute Lung Injury, Young Adult, Transfusion Reaction, Prevention, Clinical Research, Acute Respiratory Distress Syndrome, Rare Diseases, Lung, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology
Abstract

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

Published
2012

16. Impact of hematopoietic cell transplantation on myocardial fibrosis in young patients with sickle cell disease

Author

Sharma, Akshay, Selukar, Subodh, Bi, Yu, Merlocco, Anthony, Morin, Cara E., Goode, Chris, Rai, Parul, Towbin, Jeffrey A., Hankins, Jane S., Gottschalk, Stephen, Triplett, Brandon, and Johnson, Jason N.

Abstract

Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.govas #NCT04362293.

Published
2024
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18. Acute myeloid leukemias with UBTFtandem duplications are sensitive to menin inhibitors

Author

Barajas, Juan M., Rasouli, Milad, Umeda, Masayuki, Hiltenbrand, Ryan, Abdelhamed, Sherif, Mohnani, Rebecca, Arthur, Bright, Westover, Tamara, Thomas, Melvin E., Ashtiani, Minoo, Janke, Laura J., Xu, Beisi, Chang, Ti-Cheng, Rosikiewicz, Wojciech, Xiong, Emily, Rolle, Chandra, Low, Jonathan, Krishan, Reethu, Song, Guangchun, Walsh, Michael P., Ma, Jing, Rubnitz, Jeffrey E., Iacobucci, Ilaria, Chen, Taosheng, Krippner-Heidenreich, Anja, Zwaan, Christian M., Heidenreich, Olaf, and Klco, Jeffery M.

Abstract

•UBTF tandem duplications and KMT2A/menin complex co-occupy genomic targets dysregulated in UBTF-TD acute myeloid leukemias.•UBTF-TD acute myeloid leukemias are sensitive to menin inhibition.

Published
2024
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19. Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission

Author

Jabbour, Elias, Haddad, Fadi G., Short, Nicholas J., Senapati, Jayastu, Jain, Nitin, Sasaki, Koji, Jorgensen, Jeffrey, Wang, Sa A., Alvarado, Yesid, Wang, Xuemei, DiNardo, Courtney, Masarova, Lucia, Kadia, Tapan, Garris, Rebecca S., Ravandi, Farhad, and Kantarjian, Hagop

Abstract

•Inotuzumab ozogamicin was safe and effective in eradicating MRD in patients with B-cell ALL in CR.•The MRD conversion rate was 69%, which translated into a 2-year relapse-free survival of 54% and a 2-year overall survival of 60%.

Published
2024
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20. Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD

Author

Leiding, Jennifer W., Arnold, Danielle E., Parikh, Suhag, Logan, Brent, Marsh, Rebecca A., Griffith, Linda M., Wu, Ruizhe, Kidd, Sharon, Mallhi, Kanwaldeep, Chellapandian, Deepak, Si Lim, Stephanie J., Grunebaum, Eyal, Falcone, E. Liana, Murguia-Favela, Luis, Grossman, Debbi, Prasad, Vinod K., Heimall, Jennifer R., Touzot, Fabien, Burroughs, Lauri M., Bleesing, Jack, Kapoor, Neena, Dara, Jasmeen, Williams, Olatundun, Kapadia, Malika, Oshrine, Benjamin R., Bednarski, Jeffrey J., Rayes, Ahmad, Chong, Hey, Cuvelier, Geoffrey D. E., Forbes Satter, Lisa R., Martinez, Caridad, Vander Lugt, Mark T., Yu, Lolie C., Chandrakasan, Shanmuganathan, Joshi, Avni, Prockop, Susan E., Dávila Saldaña, Blachy J., Aquino, Victor, Broglie, Larisa A., Ebens, Christen L., Madden, Lisa M., DeSantes, Kenneth, Milner, Jordan, Rangarajan, Hemalatha G., Shah, Ami J., Gillio, Alfred P., Knutsen, Alan P., Miller, Holly K., Moore, Theodore B., Graham, Pamela, Bauchat, Andrea, Bunin, Nancy J., Teira, Pierre, Petrovic, Aleksandra, Chandra, Sharat, Abdel-Azim, Hisham, Dorsey, Morna J., Birbrayer, Olga, Cowan, Morton J., Dvorak, Christopher C., Haddad, Elie, Kohn, Donald B., Notarangelo, Luigi D., Pai, Sung-Yun, Puck, Jennifer M., Pulsipher, Michael A., Torgerson, Troy R., Malech, Harry L., and Kang, Elizabeth M.

Abstract

•Allogeneic HCT quickly and durably resolved disease manifestations in patients with CGD, with excellent survival.•HCT should be considered early for CGD before comorbidities affect the performance status.

Published
2023
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23. Molecular determinants of clinical outcomes in a real-world diffuse large B-cell lymphoma population

Author

Alduaij, Waleed, Collinge, Brett, Ben-Neriah, Susana, Jiang, Aixiang, Hilton, Laura K., Boyle, Merrill, Meissner, Barbara, Chong, Lauren, Miyata-Takata, Tomoko, Slack, Graham W., Farinha, Pedro, Craig, Jeffrey W., Lytle, Andrew, Savage, Kerry J., Villa, Diego, Gerrie, Alina S., Freeman, Ciara L., Gascoyne, Randy D., Connors, Joseph M., Morin, Ryan D., Sehn, Laurie H., Mungall, Andrew J., Steidl, Christian, and Scott, David W.

Abstract

•DHITsig expression extends beyond HGBCL-DH-BCL2to identify dark zone lymphomas and was thus renamed the “DZsig.”•DZsig refines cell-of-origin classification by identifying patients within GCB-DLBCL with inferior outcomes and shorter time to treatment.

Published
2023
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24. Macrophage NOX2 NADPH oxidase maintains alveolar homeostasis in mice

Author

Bhattacharya, Sourav, Idol, Rachel A., Yang, Wei, Rojas Márquez, Jorge David, Li, Yanan, Huang, Guangming, Beatty, Wandy L., Atkinson, Jeffrey J., Brumell, John H., Bagaitkar, Juhi, Magee, Jeffrey A., and Dinauer, Mary C.

Abstract

The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AMs) are the predominant immune cell in the airways at steady state, and limiting their activation is important, given the constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well understood. In this study, we showed a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, in CGD mice or mice with selective loss of NOX2 preferentially in macrophages. AMs lacking NOX2 had increased cytokine responses to Toll-like receptor-2 (TLR2) and TLR4 stimulation ex vivo. Moreover, between 4 and 12 week of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AMs with epigenetic and transcriptional profiles reflecting immune activation compared with WT AMs. The presence of CD11bhigh AMs in CGD mice correlated with an increased number of alveolar neutrophils and proinflammatory cytokines at steady state and increased lung inflammation after insults. Moreover, deletion of NOX2 preferentially in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying proinflammatory sequelae. In addition, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue specific, as those changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that the absence of NOX2 in alveolar macrophages leads to their proinflammatory remodeling and dysregulates alveolar homeostasis.

Published
2022
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25. CEBPB/IL-1β/TNF-α Feedback Loop Drives Drug Resistance to Venetoclax and MDM2 Inhibitors in Monocytic Leukemia

Author

Allen, Basil, Bottomly, Daniel, Köhnke, Thomas, Wang, Anthony, Lin, Hsin-yun, Johnson, Kara, Kenna, Isabel, Streltsova, Anastatia, Martin, Emma, Chen, Reid, Savoy, Lindsey, Long, Nicola, Ryabinin, Peter, Kurtz, Steve E., Eide, Chris, Carlos, Amy, Kaempf, Andy, Liu, Tingting, Tognon, Cristina, Searles, Robert, Piehowski, Paul D, Gosline, Sara J C, Agarwal, Anupriya, Chang, Bill H., Barton, Michelle, Druker, Brian J., Mcweeney, Shannon K., Majeti, Ravindra, Tyner, Jeffrey W., and Zhang, Haijiao

Abstract

IL-1 and TNF-α specifically increase CEBPB levels and protect M4/M5 cells from venetoclax and MDM2 inhibitors, but not M0/M1 leukemia cells.

Published
2025
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26. Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study

Author

Topp, Max S., Matasar, Matthew, Allan, John N., Ansell, Stephen M., Barnes, Jeffrey A., Arnason, Jon E., Michot, Jean-Marie, Goldschmidt, Neta, O’Brien, Susan M., Abadi, Uri, Avivi, Irit, Cheng, Yuan, Flink, Dina M., Zhu, Min, Brouwer-Visser, Jurriaan, Chaudhry, Aafia, Mohamed, Hesham, Ambati, Srikanth, and Crombie, Jennifer L.

Abstract

•In patients with diffuse large B-cell lymphoma progressing after CAR-T therapy, odronextamab showed a 48% ORR and 32% CR rate.•Odronextamab had a generally manageable safety profile, with 48% low-grade cytokine release syndrome and 20% grade ≥3 infections.

Published
2025
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29. FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation

Author

Li, Yanan, Yang, Wei, Patel, Riddhi M., Casey, Emily B., Denby, Elisabeth, Mendoza-Castrejon, Jonny, Rodriguez-Lopez, Priscilla, and Magee, Jeffrey A.

Abstract

Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3ITD) mutations cooperate with a variety of different initiating mutations to reprogram myeloid progenitor fate. These initiating mutations often skew toward either pediatric or adult AML patient populations, though FLT3ITD itself occurs at similar frequencies in both age groups. This raises the question of whether FLT3ITD might induce distinct transcriptional programs and unmask distinct therapeutic vulnerabilities when paired with pediatric, as opposed to adult AML-initiating mutations. To explore this possibility, we compared AML evolution in mice that carried Flt3ITD/NUP98-HOXD13 (NHD13) or Flt3ITD/Runx1DEL mutation pairs, which are respectively most common in pediatric and adult AML. Single-cell analyses and epigenome profiling revealed distinct interactions between Flt3ITD and its cooperating mutations. Whereas Flt3ITD and Flt3ITD/Runx1DEL caused aberrant expansion of myeloid progenitors, Flt3ITD/NHD13 drove the emergence of a pre-AML population that did not resemble normal hematopoietic progenitors. Differences between Flt3ITD/Runx1DEL and Flt3ITD/NHD13 cooperative target gene expression extended to fully transformed AML as well. Flt3ITD/NHD13 cooperative target genes were enriched in human NUP98-translocated AML. Flt3ITD/NHD13 selectively hijacked type I interferon signaling to drive expansion of the pre-AML population. Blocking interferon signaling delayed AML initiation and extended survival. Thus, common AML driver mutations, such as FLT3ITD, can coopt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence.

Published
2023
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30. FLT3ITDdrives context-specific changes in cell identity and variable interferon dependence during AML initiation

Author

Li, Yanan, Yang, Wei, Patel, Riddhi M., Casey, Emily B., Denby, Elisabeth, Mendoza-Castrejon, Jonny, Rodriguez-Lopez, Priscilla, and Magee, Jeffrey A.

Abstract

•Flt3ITDactivates distinct transcriptional programs via distinct enhancers when it cooperates with NUP98and Runx1mutations.•Flt3ITDand NUP98-HOXD13 selectively activate type I interferon signaling and thus create a context-specific pathway dependency.

Published
2023
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33. Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma

Author

Thomas, Nicole, Dreval, Kostiantyn, Gerhard, Daniela S., Hilton, Laura K., Abramson, Jeremy S., Ambinder, Richard F., Barta, Stefan, Bartlett, Nancy L., Bethony, Jeffrey, Bhatia, Kishor, Bowen, Jay, Bryan, Anthony C., Cesarman, Ethel, Casper, Corey, Chadburn, Amy, Cruz, Manuela, Dittmer, Dirk P., Dyer, Maureen A., Farinha, Pedro, Gastier-Foster, Julie M., Gerrie, Alina S., Grande, Bruno M., Greiner, Timothy, Griner, Nicholas B., Gross, Thomas G., Harris, Nancy L., Irvin, John D., Jaffe, Elaine S., Henry, David, Huppi, Rebecca, Leal, Fabio E., Lee, Michael S., Martin, Jean Paul, Martin, Marie-Reine, Mbulaiteye, Sam M., Mitsuyasu, Ronald, Morris, Vivian, Mullighan, Charles G., Mungall, Andrew J., Mungall, Karen, Mutyaba, Innocent, Nokta, Mostafa, Namirembe, Constance, Noy, Ariela, Ogwang, Martin D., Omoding, Abraham, Orem, Jackson, Ott, German, Petrello, Hilary, Pittaluga, Stefania, Phelan, James D., Ramos, Juan Carlos, Ratner, Lee, Reynolds, Steven J., Rubinstein, Paul G., Sissolak, Gerhard, Slack, Graham, Soudi, Shaghayegh, Swerdlow, Steven H., Traverse-Glehen, Alexandra, Wilson, Wyndham H., Wong, Jasper, Yarchoan, Robert, ZenKlusen, Jean C., Marra, Marco A., Staudt, Louis M., Scott, David W., and Morin, Ryan D.

Abstract

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Published
2023
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34. Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study

Author

Maese, Luke, Loh, Mignon L., Choi, Mi Rim, Lin, Tong, Aoki, Etsuko, Zanette, Michelle, Agarwal, Shirali, Iannone, Robert, Silverman, Jeffrey A., Silverman, Lewis B., Raetz, Elizabeth A., and Rau, Rachel E.

Abstract

AALL1931, a phase 2/3 study conducted in collaboration with the Children’s Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli–derived asparaginases. Each dose of a pegylated E coli–derived asparaginase remaining in patients’ treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

Published
2023
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35. Description of a novel subtype of acute myeloid leukemia defined by recurrent CBFB insertions

Author

Ryland, Georgina L., Umeda, Masayuki, Holmfeldt, Linda, Lehmann, Sören, Herlin, Morten Krogh, Ma, Jing, Khanlari, Mahsa, Rubnitz, Jeffrey E., Ries, Rhonda E., Kosasih, Hansen J., Ekert, Paul G., Goh, Hwee Ngee, Tiong, Ing S., Grimmond, Sean M., Haferlach, Claudia, Day, Ryan B., Ley, Timothy J., Meshinchi, Soheil, Ma, Xiaotu, Blombery, Piers, and Klco, Jeffery M.

Published
2023
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36. Recombinant Erwiniaasparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study

Author

Maese, Luke, Loh, Mignon L., Choi, Mi Rim, Lin, Tong, Aoki, Etsuko, Zanette, Michelle, Agarwal, Shirali, Iannone, Robert, Silverman, Jeffrey A., Silverman, Lewis B., Raetz, Elizabeth A., and Rau, Rachel E.

Abstract

•Intramuscular JZP458 at 25/25/50 mg/m2M/W/F was effective in patients with ALL/LBL, with a safety profile similar to other asparaginases.•JZP458 overcomes one of the most significant drug shortage issues facing patients with ALL/LBL.

Published
2023
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37. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need

Author

Pemmaraju, Naveen, Kantarjian, Hagop, Sweet, Kendra, Wang, Eunice, Senapati, Jayastu, Wilson, Nathaniel R., Konopleva, Marina, Frankel, Arthur E., Gupta, Vikas, Mesa, Ruben, Ulrickson, Matthew, Gorak, Edward, Bhatia, Sumeet, Budak-Alpdogan, Tulin, Mason, James, Garcia-Romero, Maria Teresa, Lopez-Santiago, Norma, Cesarman-Maus, Gabriela, Vachhani, Pankit, Lee, Sangmin, Bhatt, Vijaya Raj, Blum, William, Walter, Roland B., Bixby, Dale, Gojo, Ivana, Duvic, Madeleine, Rampal, Raajit K., de Lima, Marcos, Foran, James, Fathi, Amir T., Hall, Aric Cameron, Jacoby, Meagan A., Lancet, Jeffrey, Mannis, Gabriel, Stein, Anthony S., Mims, Alice, Rizzieri, David, Olin, Rebecca, Perl, Alexander, Schiller, Gary, Shami, Paul, Stone, Richard M., Strickland, Stephen, Wieduwilt, Matthew J., Daver, Naval, Ravandi, Farhad, Vasu, Sumithira, Guzman, Monica, Roboz, Gail J., Khoury, Joseph, Qazilbash, Muzaffar, Aung, Phyu P., Cuglievan, Branko, Madanat, Yazan, Kharfan-Dabaja, Mohamed A., Pawlowska, Anna, Taylor, Justin, Tallman, Martin, Dhakal, Prajwal, and Lane, Andrew A.

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Published
2023
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38. Intraocular involvement of mycosis fungoides associated with immunophenotypic switch from CD4+ to CD8+

Author

Jonathan A. Braue, John A. Zic, Stephen J. Kim, Anthony B. Daniels, and Jeffrey P. Zwerner

Subjects
Mycosis fungoides, medicine.medical_specialty, business.industry, Extramural, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, 030221 ophthalmology & optometry, Medicine, Stage (cooking), Letter to Blood, business, CD8
Abstract

TO THE EDITOR: Alibert first described mycosis fungoides (MF) in 1806, and Bazin later defined the natural evolution into the stages known today as patch, plaque, and tumor.[1][1] In the earliest stage, known as IA, MF is indolent. As progression ensues, extracutaneous invasion is not uncommon

Published
2018
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39. AML Cell Vaccines Co-Expressing CD80 and IL-15/IL-15 Receptor Alpha Induce Activation and Cytolytic Activity in Post Remission Autologous Patient PBMC Ex Vivo

Author

Xinyue Wang, Francesca M. Olguin, Karin L. Gaensler, Giulia Parisi, Kenneth I. Weinberg, Nathaniel Z. Rothschild, Jeffrey P. Fung, Donald B. Kohn, and William J. Murphy

Subjects
Chemistry, Immunology, Cell, Alpha (ethology), Cell Biology, Hematology, Biochemistry, Peripheral blood mononuclear cell, Cytolysis, medicine.anatomical_structure, Interleukin 15, medicine, Cancer research, Receptor, CD80, Ex vivo
Abstract

There is a critical need for more effective therapy for acute myelogenous leukemia (AML). Although many patients achieve remission, most relapse with poor outcomes. Even after allogeneic Stem Cell Transplantation (SCT), 30-50% of patients relapse due to the persistence of residual disease. To address the poor immunogenicity of AML cells and the diminished immune responsiveness of patients, our candidate autologous AML vaccine is lentivirally engineered, in each patient's leukemic cells, to express CD80, IL-15, and IL-15 Receptor alpha (IL-15Rα). In prior studies in a syngeneic 32Dp210 murine AML model, CD80-mediated co-stimulation of T-cells combined with immune activation by the IL-15/IL-15Rα heterodimer showed unprecedented synergy in induction of anti-leukemic cytolytic activity (Shi, Y. et al, 2018). This was observed in both ex vivo co-culture and in vivo where vaccinated leukemic mice had >80% cure rates. No local skin, organ, or systemic toxicity was observed, nor was there evidence of systemic cytokine release of IL-6 or TNFα after SC or IV injection of up to 10 8 transduced irradiated AML cells. We confirmed the feasibility of producing patient-derived AML vaccines by transduction of 16 independent AML samples with a tri-cistronic lentiviral vector (TLV) that contains human CD80, IL-15 and IL-15Rα. Transduction levels were 11-71% of cells (median 38.6%). To define the minimum transduction level required for PBMC activation and to assess synergy of co-expressed human CD80, IL-15, and IL-15Rα, allogenic U937 leukemia cells were initially used as stimulators. Transduced U937 (U937-TLV) had high-level surface expression of CD80 and IL-15, secreted IL-15 (7 ng/ml/24 hours from 2 x 10 6 cells/ml) and activated CD3+ T-cells from an AML patient (Fig.1). Mixtures of irradiated U937-TLV with non-transduced U937 were created at fixed ratios (100%, 80%, 40%, 20%, 10%, 5%, 0%) for overnight co-culture with patient PBMC. At 24 hours, the T-cells were analyzed for activation by measurement of the frequency of CD69+ CD4 or CD8 T cells (Fig. 1), normalized to expression of unstimulated PBMC (0%) and the percentage of maximal CD69 expression with 100% U937-TLV (100%). Background levels of activation due to the presence of allogenic U937 were negligible. Co-culture with as little as 10% transduced U937-TLV reliably activated patient T-cells. To assess the synergy of CD80, IL-15 and IL-15Rα expression, parallel experiments were performed with PBMC co-cultured in IL-15 containing supernatants from U937-TLV cells (Fig. 1). The frequencies of activated T-cells were significantly higher after co-culture with U937/U937-TLV cells than after stimulation with IL-15-containing supernatants from similar ratios of U937/U937-TLV, confirming the synergy of CD80 and IL-15/IL-15Rα in the transduced cells. To better, model the clinical setting, we assessed induction of immune responses of patient T cells to autologous transduced AML. PBMC were stimulated with transduced or non-transduced autologous AML cells vs stimulation with allogeneic U937-TLV, or with anti-CD3/CD28 beads to define maximal stimulation. Negative controls included culture of PBMC alone. All patients had T-cell activation, as measured by induction of CD69, HLA-DR and CD95 (Fas) expression, although there was heterogeneity in the nature of responses, e.g., disparate induction of the markers in individual patients (Fig. 2A and B). Induction of cytotoxic effector pathways was confirmed by detection of CD178 (FasL) and perforin expression (Figure 2C and D). Overall, all patients' PBMC had the capacity to mount T-cell responses of similar magnitude to both allogeneic U937-TLV and autologous vaccine. These studies establish that autologous AML cells transduced with CD80, IL-15 and IL-15Rα can elicit specific anti-leukemic T-cell responses, even in the face of prior lymphodepleting chemotherapy. A strength of this autologous vaccine strategy is that it is agnostic to which AML proteins are immunogenic for each patient. Although uniformly detected, there was heterogeneity in the induction of activation markers and effector pathways, which may reflect host and/or disease-related differences. The mechanisms underlying differences in the nature of responses in patients will be important to understand and will provide the basis for future immune correlative studies for our Phase 1 vaccine trial in transplant ineligible AML patients. Figure 1 Figure 1. Disclosures Kohn: Lyrik Therapeutics: Membership on an entity's Board of Directors or advisory committees; MyoGene Bio: Membership on an entity's Board of Directors or advisory committees; ImmunoVec: Membership on an entity's Board of Directors or advisory committees; Pluto Immunotherapeutics: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; UC Regents: Patents & Royalties; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sangamo Biosciences: Membership on an entity's Board of Directors or advisory committees.

Published
2021
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41. IL-13/IL-4 signaling contributes to fibrotic progression of the myeloproliferative neoplasms

Author

Melo-Cardenas, Johanna, Bezavada, Lavanya, Crawford, Jeremy Chase, Gurbuxani, Sandeep, Cotton, Anitria, Kang, Guolian, Gossett, Jeffrey, Marinaccio, Christian, Weinberg, Rona, Hoffman, Ronald, Migliaccio, Anna Rita, Zheng, Yan, Derecka, Marta, Rinaldi, Ciro R., and Crispino, John D.

Abstract

Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK inhibitors are generally effective for only 2 to 3 years and do not delay disease progression. MF is characterized by dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence that the inflammatory milieu in MF contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after the development of fibrosis, coupled with the analysis of bone marrow populations using single-cell RNA sequencing. We found high interleukin 13 (IL-13) levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced surface expression of transforming growth factor β and collagen biosynthesis. Similarly, analysis of samples from patients with MF revealed elevated levels of IL-13 in the plasma and increased IL-13 receptor expression in marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression, whereas reducing IL-13/IL-4 signaling reduced several features of the disease, including fibrosis. Finally, we observed an increase in the number of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.

Published
2022
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42. Dual antigen–targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia

Author

Cichocki, Frank, Goodridge, Jodie P., Bjordahl, Ryan, Mahmood, Sajid, Davis, Zachary B., Gaidarova, Svetlana, Abujarour, Ramzey, Groff, Brian, Witty, Alec, Wang, Hongbo, Tuininga, Katie, Kodal, Behiye, Felices, Martin, Bonello, Greg, Huffman, Janel, Dailey, Thomas, Lee, Tom T., Walcheck, Bruce, Valamehr, Bahram, and Miller, Jeffrey S.

Abstract

Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19− lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.

Published
2022
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43. Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation

Author

Thompson, Meghan C., Coombs, Catherine C., Roeker, Lindsey E., Jensen, Jeffrey L., Shah, Nirav N., Luo, Thomas, Patel, Krish, Bailey, Neil, Fakhri, Bita, Eyre, Toby A., Ghione, Paola, Rhodes, Joanna M., Zelenetz, Andrew D., Taylor, Justin, Palomba, Maria Lia, Meyer, Kendall, Rao, Danielle, Fox, Yehudit, Aronson, Julia H., Court, Sarah, Abdel-Wahab, Omar, and Mato, Anthony R.

Published
2022
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44. Improved Outcomes with Low-Dose Inotuzumab and Mini-Hyper-CVD Followed By Blinatumomab Consolidation in Relapsed-Refractory Acute Lymphoblastic Leukemia: Results of a Phase II Study

Author

Haddad, Fadi, Jabbour, Elias, Short, Nicholas, Jain, Nitin, Almanza Huante, Emmanuel, Sasaki, Koji, Nasnas, Patrice, Ravandi, Farhad, Kebriaei, Partow, Huang, Xuelin, Konopleva, Marina, Garcia-Manero, Guillermo, Champlin, Richard E, Kadia, Tapan M., Takahashi, Koichi, Daver, Naval, Khoury, Joseph D., Jorgensen, Jeffrey L., Wang, Sa A, Jacob, Jovitta, Garris, Rebecca, and Kantarjian, Hagop

Published
2022
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45. Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Author

Jain, Nitin, Keating, Michael J., Thompson, Philip A., Ferrajoli, Alessandra, Senapati, Jayastu, Burger, Jan A., Borthakur, Gautam, Takahashi, Koichi, Estrov, Zeev E., Konopleva, Marina, Sasaki, Koji, Kadia, Tapan M., Pemmaraju, Naveen, Daver, Naval, Jabbour, Elias, DiNardo, Courtney D., Alvarado, Yesid, Yilmaz, Musa, Bose, Prithviraj, Ohanian, Maro, Kanagal-Shamanna, Rashmi, Patel, Keyur, Jorgensen, Jeffrey L., Wang, Sa A, Nassar, Sameh, Garg, Naveen, Hwang, Hyunsoo, Wang, Xuemei, Cruz, Nichole, Ayala, Ana, Plunkett, William, Kantarjian, Hagop, Gandhi, Varsha, and Wierda, William G.

Published
2022
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46. Multivariable Analyses of Prognostic Factors for Progression-Free Survival (PFS) and Complete Response (CR) with Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone Versus Rvd Plus Autologous Stem Cell Transplantation (ASCT) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) in the Determination Phase 3 Trial

Author

Hassoun, Hani, Jacobus, Susanna J., Richardson, Paul G., Zonder, Jeffrey A., Voorhees, Peter M., Kaufman, Jonathan L., Yee, Andrew J., Scott, Emma C., Torka, Pallawi, Libby, Edward, Reeves, Brandi, Wang, Michael L., Anderson, Larry D., Milner, Carter, Gasparetto, Cristina J., Agha, Mounzer, Khan, Abdullah, Hurd, David Duane, Avigan, David, Costello, Caitlin, Jakubowiak, Andrzej, Lonial, Sagar, Raje, Noopur, Medvedova, Eva, McCarthy, Philip L., Orlowski, Robert Z., Nadeem, Omar, Laubach, Jacob P., Pasquini, Marcelo C., Giralt, Sergio A., Masone, Kelly, Samur, Mehmet K., Perrot, Aurore, Moreau, Philippe, Avet-Loiseau, Herve, Weller, Edie A., Munshi, Nikhil C., and Anderson, Kenneth C.

Published
2022
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47. Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia

Author

Laukkanen, Saara, Veloso, Alexandra, Yan, Chuan, Oksa, Laura, Alpert, Eric J., Do, Daniel, Hyvärinen, Noora, McCarthy, Karin, Adhikari, Abhinav, Yang, Qiqi, Iyer, Sowmya, Garcia, Sara P., Pello, Annukka, Ruokoranta, Tanja, Moisio, Sanni, Adhikari, Sadiksha, Yoder, Jeffrey A., Gallagher, Kayleigh, Whelton, Lauren, Allen, James R., Jin, Alex H., Loontiens, Siebe, Heinäniemi, Merja, Kelliher, Michelle, Heckman, Caroline A., Lohi, Olli, and Langenau, David M.

Abstract

Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.

Published
2022
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49. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

Author

Campo, Elias, Jaffe, Elaine S., Cook, James R., Quintanilla-Martinez, Leticia, Swerdlow, Steven H., Anderson, Kenneth C., Brousset, Pierre, Cerroni, Lorenzo, de Leval, Laurence, Dirnhofer, Stefan, Dogan, Ahmet, Feldman, Andrew L., Fend, Falko, Friedberg, Jonathan W., Gaulard, Philippe, Ghia, Paolo, Horwitz, Steven M., King, Rebecca L., Salles, Gilles, San-Miguel, Jesus, Seymour, John F., Treon, Steven P., Vose, Julie M., Zucca, Emanuele, Advani, Ranjana, Ansell, Stephen, Au, Wing-Yan, Barrionuevo, Carlos, Bergsagel, Leif, Chan, Wing C., Cohen, Jeffrey I., d’Amore, Francesco, Davies, Andrew, Falini, Brunangelo, Ghobrial, Irene M., Goodlad, John R., Gribben, John G., Hsi, Eric D., Kahl, Brad S., Kim, Won-Seog, Kumar, Shaji, LaCasce, Ann S., Laurent, Camille, Lenz, Georg, Leonard, John P., Link, Michael P., Lopez-Guillermo, Armando, Mateos, Maria Victoria, Macintyre, Elizabeth, Melnick, Ari M., Morschhauser, Franck, Nakamura, Shigeo, Narbaitz, Marina, Pavlovsky, Astrid, Pileri, Stefano A., Piris, Miguel, Pro, Barbara, Rajkumar, Vincent, Rosen, Steven T., Sander, Birgitta, Sehn, Laurie, Shipp, Margaret A., Smith, Sonali M., Staudt, Louis M., Thieblemont, Catherine, Tousseyn, Thomas, Wilson, Wyndham H., Yoshino, Tadashi, Zinzani, Pier-Luigi, Dreyling, Martin, Scott, David W., Winter, Jane N., and Zelenetz, Andrew D.

Abstract

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Published
2022
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50. Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC

Author

Cuvelier, Geoffrey D. E., Logan, Brent R., Prockop, Susan E., Buckley, Rebecca H., Kuo, Caroline Y., Griffith, Linda M., Liu, Xuerong, Yip, Alison, Hershfield, Michael S., Ayoub, Paul G., Moore, Theodore B., Dorsey, Morna J., O’Reilly, Richard J., Kapoor, Neena, Pai, Sung-Yun, Kapadia, Malika, Ebens, Christen L., Forbes Satter, Lisa R., Burroughs, Lauri M., Petrovic, Aleksandra, Chellapandian, Deepak, Heimall, Jennifer, Shyr, David C., Rayes, Ahmad, Bednarski, Jeffrey J., Chandra, Sharat, Chandrakasan, Shanmuganathan, Gillio, Alfred P., Madden, Lisa, Quigg, Troy C., Caywood, Emi H., Dávila Saldaña, Blachy J., DeSantes, Kenneth, Eissa, Hesham, Goldman, Frederick D., Rozmus, Jacob, Shah, Ami J., Vander Lugt, Mark T., Thakar, Monica S., Parrott, Roberta E., Martinez, Caridad, Leiding, Jennifer W., Torgerson, Troy R., Pulsipher, Michael A., Notarangelo, Luigi D., Cowan, Morton J., Dvorak, Christopher C., Haddad, Elie, Puck, Jennifer M., and Kohn, Donald B.

Abstract

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

Published
2022
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