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2. HCT: Historical Perspective

Author

Granot, Noa, Storb, Rainer, Sureda, Anna, editor, Corbacioglu, Selim, editor, Greco, Raffaella, editor, Kröger, Nicolaus, editor, and Carreras, Enric, editor

Published
2024
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10. Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation.

Author

Oshima, Masumi Ueda, Higgins, Jacob, Jenkins, Isaac, Randolph, Timothy, Smith, Thomas, Valentine III, Charles, Salk, Jesse, Yeung, Cecilia, Beppu, Lan, Campbell, Judy, Carpenter, Paul A., Lee, Stephanie J., Flowers, Mary E., Radich, Jerald P., and Storb, Rainer

Subjects
HEMATOPOIETIC stem cell transplantation, HEMATOPOIETIC system, STEM cell donors, GENE frequency, HEMATOPOIESIS
Abstract

After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system. Editor's summary: Donor-associated clonal hematopoiesis (CH) has been reported in recipients of allogeneic hematopoietic cell transplantation (HCT); however, an inability to detect ultralow-frequency variants has prevented a better understanding of the impact of HCT on clonal dynamics. Here, Ueda Oshima and colleagues used ultrasensitive duplex sequencing to characterize blood samples from a unique cohort of 16 donor-recipient pairs, collected up to 46 years after allogeneic HCT. The average mutation rate per year was similar between donors and recipients after HCT, and only 5.6% of variants shared between paired donors and recipients were substantially expanded in the recipient compared with the donor. Although larger studies with more time points are needed, the data from this unique cohort suggest that preferential expansion of donor CH variants in recipients of HCT is low. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

Published
2024
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13. HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide

Author

Mallhi, Kanwaldeep K., Srikanthan, Meera A., Baker, Kelsey K., Frangoul, Haydar A., Torgerson, Troy R., Petrovic, Aleksandra, Geddis, Amy E., Carpenter, Paul A., Baker, K. Scott, Sandmaier, Brenda M., Thakar, Monica S., Skoda-Smith, Suzanne, Kiem, Hans-Peter, Storb, Rainer, Woolfrey, Ann E., and Burroughs, Lauri M.

Published
2020
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14. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

Author

Crews, Leslie A, Balaian, Larisa, Santos, Nathaniel P Delos, Leu, Heather S, Court, Angela C, Lazzari, Elisa, Sadarangani, Anil, Zipeto, Maria A, La Clair, James J, Villa, Reymundo, Kulidjian, Anna, Storb, Rainer, Morris, Sheldon R, Ball, Edward D, Burkart, Michael D, and Jamieson, Catriona HM

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cancer, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Genetics, Rare Diseases, Aging, Stem Cell Research, Pediatric, Hematology, Stem Cell Research - Nonembryonic - Human, Orphan Drug, Clinical Research, Pediatric Cancer, Childhood Leukemia, 2.1 Biological and endogenous factors, Blood, Animals, Cell Survival, Cellular Senescence, Coculture Techniques, HEK293 Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Myelodysplastic Syndromes, Neoplastic Stem Cells, Protein Isoforms, RNA Splicing, Spliceosomes, Stromal Cells, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.

Published
2016

19. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial

Author

Sandmaier, Brenda M, Kornblit, Brian, Storer, Barry E, Olesen, Gitte, Maris, Michael B, Langston, Amelia A, Gutman, Jonathan A, Petersen, Soeren L, Chauncey, Thomas R, Bethge, Wolfgang A, Pulsipher, Michael A, Woolfrey, Ann E, Mielcarek, Marco, Martin, Paul J, Appelbaum, Fred R, Flowers, Mary E D, Maloney, David G, and Storb, Rainer

Published
2019
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28. Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience

Author

Shadman, Mazyar, Maloney, David G., Storer, Barry, Sandmaier, Brenda M., Chauncey, Thomas R., Smedegaard Andersen, Niels, Niederwieser, Dietger, Shizuru, Judith, Bruno, Benedetto, Pulsipher, Michael A., Maziarz, Richard T., Agura, Edward D., Hari, Parameswaran, Langston, Amelia A., Maris, Michael B., McSweeney, Peter A., Storb, Rainer, and Sorror, Mohamed L.

Published
2020
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34. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.

Author

Luznik, Leo, O'Donnell, Paul V, Symons, Heather J, Chen, Allen R, Leffell, M Susan, Zahurak, Marianna, Gooley, Ted A, Piantadosi, Steve, Kaup, Michele, Ambinder, Richard F, Huff, Carol Ann, Matsui, William, Bolaños-Meade, Javier, Borrello, Ivan, Powell, Jonathan D, Harrington, Elizabeth, Warnock, Sandy, Flowers, Mary, Brodsky, Robert A, Sandmaier, Brenda M, Storb, Rainer F, Jones, Richard J, and Fuchs, Ephraim J

Subjects
Humans, Hematologic Neoplasms, Hemoglobinuria, Paroxysmal, Graft vs Host Disease, Postoperative Complications, Mycophenolic Acid, Cyclophosphamide, Tacrolimus, Filgrastim, Granulocyte Colony-Stimulating Factor, Recombinant Proteins, Vidarabine, Immunosuppressive Agents, Disease-Free Survival, Blood Component Transfusion, Transplantation Conditioning, Postoperative Care, Whole-Body Irradiation, Bone Marrow Transplantation, Transplantation, Homologous, Drug Administration Schedule, Histocompatibility, Graft Survival, Adult, Aged, Middle Aged, Female, Male, bone marrow transplantation, cyclophosphamide, histocompatibility antigens, conditioning regimens, leukemia, lymphoma, Hemoglobinuria, Paroxysmal, Transplantation, Homologous, Immunology, Clinical Sciences
Abstract

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/microL) and platelet recovery (>20,000/microL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.

Published
2008

44. Supplementary Methods from Biodistributions, Myelosuppression, and Toxicities in Mice Treated with an Anti-CD45 Antibody Labeled with the α-Emitting Radionuclides Bismuth-213 or Astatine-211

Author

Nakamae, Hirohisa, primary, Wilbur, D. Scott, primary, Hamlin, Donald K., primary, Thakar, Monica S., primary, Santos, Erlinda B., primary, Fisher, Darrell R., primary, Kenoyer, Aimee L., primary, Pagel, John M., primary, Press, Oliver W., primary, Storb, Rainer, primary, and Sandmaier, Brenda M., primary

Published
2023
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45. Data from Biodistributions, Myelosuppression, and Toxicities in Mice Treated with an Anti-CD45 Antibody Labeled with the α-Emitting Radionuclides Bismuth-213 or Astatine-211

Author

Nakamae, Hirohisa, primary, Wilbur, D. Scott, primary, Hamlin, Donald K., primary, Thakar, Monica S., primary, Santos, Erlinda B., primary, Fisher, Darrell R., primary, Kenoyer, Aimee L., primary, Pagel, John M., primary, Press, Oliver W., primary, Storb, Rainer, primary, and Sandmaier, Brenda M., primary

Published
2023
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46. Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation

Author

Vaughn, Jennifer E., Storer, Barry E., Armand, Philippe, Raimondi, Roberto, Gibson, Christopher, Rambaldi, Alessandro, Ciceri, Fabio, Oneto, Rosi, Bruno, Benedetto, Martin, Paul J., Sandmaier, Brenda M., Storb, Rainer, and Sorror, Mohamed L.

Published
2015
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47. In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Author

Tefferi, Ayalew, Kantarjian, Hagop, Rajkumar, S. Vincent, Baker, Lawrence H., Abkowitz, Jan L., Adamson, John W., Advani, Ranjana Hira, Allison, James, Antman, Karen H., Bast, Robert C., Jr., Bennett, John M., Benz, Edward J., Jr., Berliner, Nancy, Bertino, Joseph, Bhatia, Ravi, Bhatia, Smita, Bhojwani, Deepa, Blanke, Charles D., Bloomfield, Clara D., Bosserman, Linda, Broxmeyer, Hal E., Byrd, John C., Cabanillas, Fernando, Canellos, George Peter, Chabner, Bruce A., Chanan-Khan, Asher, Cheson, Bruce, Clarkson, Bayard, Cohn, Susan L., Colon-Otero, Gerardo, Cortes, Jorge, Coutre, Steven, Cristofanilli, Massimo, Curran, Walter J., Jr., Daley, George Q., DeAngelo, Daniel J., Deeg, H. Joachim, Einhorn, Lawrence H., Erba, Harry P., Esteva, Francisco J., Estey, Elihu, Fidler, Isaiah J., Foran, James, Forman, Stephen, Freireich, Emil, Fuchs, Charles, George, James N., Gertz, Morie A., Giralt, Sergio, Golomb, Harvey, Greenberg, Peter, Gutterman, Jordan, Handin, Robert I., Hellman, Samuel, Hoff, Paulo Marcelo, Hoffman, Ronald, Hong, Waun Ki, Horowitz, Mary, Hortobagyi, Gabriel N., Hudis, Clifford, Issa, Jean Pierre, Johnson, Bruce Evan, Kantoff, Philip W., Kaushansky, Kenneth, Khayat, David, Khuri, Fadlo R., Kipps, Thomas J., Kripke, Margaret, Kyle, Robert A., Larson, Richard A., Lawrence, Theodore S., Levine, Ross, Link, Michael P., Lippman, Scott M., Lonial, Sagar, Lyman, Gary H., Markman, Maurie, Mendelsohn, John, Meropol, Neal J., Messinger, Yoav, Mulvey, Therese M., O’Brien, Susan, Perez-Soler, Roman, Pollock, Raphael, Prchal, Josef, Press, Oliver, Radich, Jerald, Rai, Kanti, Rosenberg, Saul A., Rowe, Jacob M., Rugo, Hope, Runowicz, Carolyn D., Sandmaier, Brenda M., Saven, Alan, Schafer, Andrew I., Schiffer, Charles, Sekeres, Mikkael A., Silver, Richard T., Siu, Lillian L., Steensma, David P., Stewart, F. Marc, Stock, Wendy, Stone, Richard, Storb, Rainer, Strong, Louise C., Tallman, Martin S., Thompson, Michael, Ueno, Naoto T., Van Etten, Richard A., Vose, Julie M., Wiernik, Peter H., Winer, Eric P., Younes, Anas, Zelenetz, Andrew D., and LeMaistre, Charles A.

Published
2015
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