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Article

Comparison of Patient-Reported Outcomes in 5-Year Survivors Who Received Bone Marrowvs Peripheral Blood Unrelated Donor Transplantation Long-term Follow-up of a Randomized Clinical Trial

by Stephanie J Lee; Brent Logan; Peter Westervelt; Corey Cutler; Ann Woolfrey; Shakila P. Khan; Edmund K Waller; Richard T. Maziarz; Juan Wu; Bronwen Shaw; Dennis Confer; Mary M. Horowitz; Claudio Anasetti

2016

Subjects
  • Health Sciences, Public Health
  • Health Sciences, Medicine and Surgery
  • File Download
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Abstract:Close

IMPORTANCE Bone marrow or peripheral blood from unrelated donors may be used for hematopoietic cell transplantation. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. OBJECTIVE To compare patient-reported outcomes between patients randomized to receive 1 of 2 graft types for unrelated donor transplantation. DESIGN, SETTING, AND PARTICIPANTS This follow-up of a randomized clinical trial included English- or Spanish-speaking patients 16 years or older participating in a multicenter randomized clinical trial of unrelated donor bone marrow (BM) vs peripheral blood (PB) (N = 551) in hematopoietic cell transplantation for hematologic neoplasms. Patient-reported outcomes were collected from patients at enrollment and 0.5, 1, 2, and 5 years after transplantation. INTERVENTIONS Unrelated donor BM or PB hematopoietic cell transplantation. MAIN OUTCOMES AND MEASURES Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Mental Health Inventory, occupational functioning, Lee Chronic Graft-vs-Host Disease Symptom Scale. RESULTS At 5 years after transplantation, 102 BMand 93 PB participants were alive and eligible for assessment (age-40 years or older: 104 [53.5%] male: 101 [51.8%] ). The mean (SE) Mental Health Inventory PsychologicalWell-Being scores (78.9 [1.7] vs 72.2 [1.9] P = .01 higher better) and Lee chronic graft-vs-host disease symptom scores (13.1 [1.5] vs 19.3 [1.6] P = .004 lower better) were significantly better for BMrecipients, adjusting for baseline scores and missing data. Recipients of BM were also more likely to be working full or part-time than recipients of PB (odds ratio, 1.5 95%CI, 1.2-2.0 P = .002), adjusting for work status before transplantation. With a median follow-up of 73 months (range, 30-121 months) for survivors, no differences in survival (40% vs 39% P = .84), relapse (32%vs 29% P = .47), or treatment-related mortality (29% vs 32% P = .44) between BM and PB were observed. CONCLUSIONS AND RELEVANCE Recipients of unrelated donor BM had better psychological well-being, less burdensome chronic GVHD symptoms, and were more likely to return to work than recipients of PB at 5 years after transplantation. Bone marrow should be the standard of care for these types of transplant procedures.

Article

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors

by Michael A. Pulsipher; Brent R. Logan; Deidre M. Kiefer; Pintip Chitphakdithai; Marcie L. Riches; J.Douglas Rizzo; Paolo Anderlini; O'Susan F. Leitman; Hati Kobusingye; RaeAnne M. Besser; John P. Miller; Rebecca J. Drexler; Aly Abdel-Mageed; Ibrahim A. Ahmed; Luke P. Akard; Andrew S. Artz; Edward D. Ball; Ruthee-Lu Bayer; Carolyn Bigelow; Brian J. Bolwell; E.Randolph Broun; David C. Delgado; Katharine Duckworth; Christopher C. Dvorak; Theresa E. Hahn; Ann E Haight; Parameswaran N. Hari; Brandon M. Hayes-Lattin; David A. Jacobsohn; Ann A. Jakubowski; Kimberly A. Kasow; Hillard M. Lazarus; Jane L. Liesveld; Micheal Linenberger; Mark R. Litzow; Walter Longo; Margarida Magalhaes-Silverman; John M. McCarty; Joseph P. McGuirk; Shahram Mori; Vinod Parameswaran; Vinod K. Prasad; Scott D. Rowley; Witold B. Rybka; Indira Sahdev; Jeffrey R. Schriber; George B. Selby; Paul J. Shaughnessy; Shalini Shenoy; Thomas Spitzer; William T. Tse; Joseph P. Uberti; Madhuri Vusirikala; Edmund K Waller; Daniel J. Weisdorf; Gregory A. Yanik; Willis H. Navarro; Mary M. Horowitz; Galen E. Switzer; Dennis L. Confer; Bronwen E. Shaw

2019

Subjects
  • Health Sciences, Medicine and Surgery
  • File Download
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Abstract:Close

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier: 00948636.

Article

The Potential of CAR T Cell Therapy in Pancreatic Cancer

by Mehmet Akce; Mohammad Y. Zaidi; Edmund K Waller; Bassel El-Rayes; Gregory Lesinski

2018

Subjects
  • Health Sciences, Immunology
  • Health Sciences, Oncology
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Pancreatic cancer has a dismal prognosis and effective treatment options are limited. It is projected to be the second most common cause of cancer related mortality in the United States by 2030 and there is urgent unmet need for novel systemic treatment options. Immunotherapy with antibodies targeting PD-1, PD-L1, CTLA-4 has not shown clinical activity in unselected pancreatic cancer, emphasizing the need for combination immunotherapy approaches or other therapeutic strategies. As such, chimeric antigen receptor (CAR) T cell therapy represents an emerging therapeutic option for pancreatic cancer. This modality utilizes genetically engineered T cells that are redirected to specific cancer-associated antigens to elicit potent cytotoxic activity. This review summarizes the available preclinical data and highlights early phase clinical trials using CAR T cell approaches in pancreatic cancer, a disease state that is gaining attention as a conduit for cell therapy. Future directions in application of CAR T cell therapy are also considered including its ability to be directed against novel epitopes and combined with other therapeutic regimens.

Article

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study

by Sven de Vos; LJ Swinnen; D Wang; E Reid; N Fowler; J Cordero; M Dunbar; SH Enschede; C Nolan; AM Petrich; JA Ross; AH Salem; M Verdugo; S Agarwal; L Zhou; M Kozloff; LJ Nastoupil; Christopher Flowers

2018

Subjects
  • Health Sciences, Oncology
  • File Download
  • View Abstract

Abstract:Close

Background Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7 months (95% CI 4.3-21.0), respectively. Conclusions This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered Clinicaltrials.gov, NCT01594229.

Article

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

by Anupama Reddy; Jenny Zhang; Nicholas S. Davis; Andrea B. Moffitt; Cassandra L. Love; Alexander Waldrop; Sirpa Leppa; Annika Pasanen; Leo Meriranta; Marja-Liisa Karjalainen-Lindsberg; Peter Norgaard; Mette Pedersen; Anne O. Gang; Estrid Hogdall; Tayla B. Heavican; Waseem Lone; Leon Bernal-Mizrachi; Jean Koff; Ashley D. Staton; Christopher Flowers

2017

Subjects
  • Biology, Cell
  • Biology, Molecular
  • Health Sciences, Oncology
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Abstract:Close

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.

Article

Bioactive Lipids and Circulating Progenitor Cells in Patients with Cardiovascular Disease

by Salim S. Hayek; Yuri Klyachkin; Ahmed Asfour; Nima Ghasemzadeh; Mosaab Awad; Iraj Hesaroieh; Hina Ahmed; Brandon Gray; Jonathan Kim; Edmund Waller; Arshed Quyyumi; Ahmed K. Abdel-Latif

2017

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Medicine and Surgery
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  • View Abstract

Abstract:Close

Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD341, CD341/CD1331, and CD341/CXCR41CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated.

Article

Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling

by Jian-Ming Li; Christopher T. Petersen; Jing-Xia Li; Christopher T. Panjwani; Reema Chandra; Daniel J Giver; Cynthia R Giver; Bruce R. Blazar

2016

Subjects
  • Health Sciences, Immunology
  • Health Sciences, Medicine and Surgery
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The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versushost disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates coinhibitory pathways; its role in allo-BMT has not been studied. We found VIP transiently expressed in donor NK, NK-T, dendritic cells, and T cells after allo transplant, as well as host leukocytes. A peptide antagonist of VIP signaling (VIPhyb) increased T-cell proliferation in vitro and reduced IL10 expression in donor T cells. Treatment of allo-BMT recipients with VIPhyb, or transplanting donor grafts lacking VIP (VIP-KO), activated donor T-cells in lymphoid organs, reduced T-cell homing to GvHD target organs, and enhanced GvL without increasing GvHD in multiple allo-BMT models. Genetic or ex vivo depletion of donor NK cells or CD8 + T cells from allografts abrogated the VIPhyb-enhanced GvL activity. VIPhyb treatment led to downregulation of PD-1 and PD-L1 expression on donor immune cells, increased effector molecule expression, and expanded oligoclonal CD8 + T cells that protected secondary allo transplant recipients from leukemia. Blocking VIP signaling thus represents a novel pharmacologic approach to separate GvL from GvHD and enhance adaptive T-cell responses to leukemia-associated antigens in allo-BMT.

Article

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci

by Kristin A. Rand; Chi Song; Eric Dean; Daniel J. Serie; Karen Curtin; Xin Sheng; Donglei Hu; Carol Ann Huff; Leon Bernal-Mizrachi; Michael H. Tomasson; Sikander Ailawadhi; Seema Singhal; Karen Pawlish; Edward S. Peters; Cathryn H. Bock; Alex Stram; David J. Van den Berg; Christopher K. Edlund; David V. Conti; Todd Zimmerman; Amie E. Hwang; Scott Huntsman; John Graff; Ajay Nooka; Yinfei Kong; Silvana L. Pregja; Sonja Berndt; William J. Blot; John Carpten; Graham Casey; Lisa Chu; W. Ryan Diver; Victoria L. Stevens; Michael R. Lieber; Phyllis J. Goodman; Anselm J.M. Hennis; Ann W. Hsing; Jayesh Mehta; Rick A. Kittles; Suzanne Kolb; Eric A. Klein; Cristina Leske; Adam B. Murphy; Barbara Nemesure; Christine Neslund-Dudas; Sara S. Strom; Ravi Vij; Benjamin A. Rybicki; Janet L. Stanford; Lisa B. Signorello; John S. Witte; Christine B. Ambrosone; Parveen Bhatti; Esther M. John; Leslie Bernstein; Wei Zheng; Andrew F. Olshan; Jennifer J. Hu; Regina C. Ziegler; Sarah J. Nyante; Elisa V. Bandera; Brenda M. Birmann; Sue A. Ingles; Michael F. Press; Djordje Atanackovic; Martha J. Glenn; Lisa A. Cannon-Albright; Brandt Jones; Guido Tricot; Thomas G. Martin; Shaji K. Kumar; Jeffrey L. Wolf; Sandra L. Halverson; Nathaniel Rothman; Angela R. Brooks-Wilson; S. Vincent Rajkumar; Laurence N. Kolonel; Stephen J. Chanock; Susan L. Slager; Richard K. Severson; Nalini Janakiraman; Howard R. Terebelo; Elizabeth E. Brown; Anneclaire J. De Roos; Ann F. Mohrbacher; Graham A. Colditz; Graham G. Giles; John J. Spinelli; Brian C. Chiu; Nikhil C. Munshi; Kenneth C. Anderson; Joan Levy; Jeffrey A. Zonder; Robert Z. Orlowski; Sagar Lonial; Nicola J. Camp; Celine M. Vachon; Elad Ziv; Daniel O. Stram; Dennis J. Hazelett; Christopher A. Haiman; Wendy Cozen

2016

Subjects
  • Health Sciences, Oncology
  • Health Sciences, General
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Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry- European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional.

Article

Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention

by Scott N. Furlan; Benjamin Watkins; Victor Tkachev; Ryan Flynn; Sarah Cooley; Swetha Ramakrishnan; Karnail Singh; Cynthia Giver; Kelly Hamby; Linda Stempora; Aneesah Garrett; Jingyang Chen; Kayla M. Betz; Carly G.K. Ziegler; Gregory K. Tharp; Steven Bosinger; Daniel E.L. Promislow; Jeffrey S. Miller; Edmund Waller; Bruce R. Blazar; Leslie Kean

2015

Subjects
  • Biology, Cell
  • Health Sciences, Medicine and Surgery
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Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3+ T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD.

Article

De novo CD5+diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort

by Lapo Alinari; Alejandro Gru; Carl Quinion; Ying Huang; Arletta Lozanski; Gerard Lozanski; Jacqueline Poston; Girish Venkataraman; Eunhye Oak; Freiderike Kreisel; Steven I. Park; Stephanie Matthews; Jeremy S. Abramson; Hana Iris Lim; Peter Martin; Jonathon Cohen; Andrew Evens; Zeina Al-Mansour; Arun Singavi; Timothy S. Fenske; Kristie A. Blum

2016

Subjects
  • Health Sciences, Pathology
  • Health Sciences, Medicine and Surgery
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De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m2. The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.
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