Publications by authors named "Donna Neuberg"

441 Publications

Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.

Blood Cancer Discov 2021 Jan 3;2(1):54-69. Epub 2020 Dec 3.

Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and post-therapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state, and a distinct expression profile together with MBL cells compared to normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically-driven growth dynamics and together with its persistent presence suggests a central role in the normal-to-cancer transition.
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http://dx.doi.org/10.1158/2643-3230.BCD-19-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888194PMC
January 2021

Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2021 Feb 9. Epub 2021 Feb 9.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1038/s41591-021-01253-5DOI Listing
February 2021

Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.

Nat Med 2021 Jan 21. Epub 2021 Jan 21.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
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http://dx.doi.org/10.1038/s41591-020-01206-4DOI Listing
January 2021

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Am J Hematol 2021 Jan 21. Epub 2021 Jan 21.

Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.
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http://dx.doi.org/10.1002/ajh.26102DOI Listing
January 2021

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis.

medRxiv 2021 Jan 15. Epub 2021 Jan 15.

Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, CT.

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain.

Research Question: How does in-hospital mortality compare with intermediate-versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19?

Study Design And Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death.

Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate-compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]).

Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Summary Conflict Of Interest Statements: No conflict of interest exists for any author on this manuscript.
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http://dx.doi.org/10.1101/2021.01.12.21249577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814841PMC
January 2021

Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.

Blood 2020 Dec;136(26):3070-3081

Division of Hematological Malignancies, Department of Medical Oncology, and.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.
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http://dx.doi.org/10.1182/blood.2020005397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770569PMC
December 2020

Cross-site concordance evaluation of tumor DNA and RNA sequencing platforms for the CIMAC-CIDC network.

Clin Cancer Res 2020 Dec 15. Epub 2020 Dec 15.

Department of Medical Oncology, Dana-Farber Cancer Institute

Purpose: Whole-exome (WES) and RNA-sequencing (RNA-seq) are key components of cancer immunogenomic analyses. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC) conducted a systematic harmonization study.

Experimental Design: DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling. In addition, two 10-plex HapMap cell-line pools with known mutations were used to evaluate the accuracy of the WES platforms.

Results: The WES platforms achieved high precision (> 0.98) and recall (> 0.87) on the HapMap pools when evaluated on loci using > 50X common coverage. Non-synonymous mutations clustered by tumor sample, achieving an Index of Specific Agreement above 0.67 among replicates, centers, and sample processing. A DV200 > 24% for RNA, as a putative pre-sequencing RNA quality control (QC) metric, was found to be a reliable threshold for generating consistent expression readouts in RNA-seq and NanoString data. MedTIN > 30 was likewise assessed as a reliable RNA-seq QC metric, above which samples from the same tumor across replicates, centers, and sample processing runs could be robustly clustered and HLA typing, immune infiltration, and immune repertoire inference could be performed.

Conclusions: The CIMAC collaborating laboratory platforms effectively generated consistent WES and RNA-seq data and enable robust cross-trial comparisons and meta-analyses of highly complex immuno-oncology biomarker data across the NCI CIMAC-CIDC Network.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3251DOI Listing
December 2020

Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub.

Blood Adv 2020 12;4(23):5966-5975

Division of Hematology/Oncology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada.

Coronavirus disease 2019 (COVID-19) is an illness resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019. Patients with cancer, and especially those with hematologic malignancies, may be at especially high risk of adverse outcomes, including mortality resulting from COVID-19 infection. The ASH Research Collaborative COVID-19 Registry for Hematology was developed to study features and outcomes of COVID-19 infection in patients with underlying blood disorders, such as hematologic malignancies. At the time of this report, data from 250 patients with blood cancers from 74 sites around the world had been entered into the registry. The most commonly represented malignancies were acute leukemia (33%), non-Hodgkin lymphoma (27%), and myeloma or amyloidosis (16%). Patients presented with a myriad of symptoms, most frequently fever (73%), cough (67%), dyspnea (50%), and fatigue (40%). Use of COVID-19-directed therapies, such as hydroxychloroquine (n = 76) or azithromycin (n = 59), was common. Overall mortality was 28%. Patients with a physician-estimated prognosis from the underlying hematologic malignancy of <12 months at the time of COVID-19 diagnosis and those with relapsed/refractory disease experienced a higher proportion of moderate/severe COVID-19 disease and death. In some instances, death occurred after a decision was made to forgo intensive care unit admission in favor of a palliative approach. Taken together, these data support the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection. Batch submissions from sites with high incidence of COVID-19 infection are planned to support future analyses.
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http://dx.doi.org/10.1182/bloodadvances.2020003170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724912PMC
December 2020

High throughput single-cell detection of multiplex CRISPR-edited gene modifications.

Genome Biol 2020 10 20;21(1):266. Epub 2020 Oct 20.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

CRISPR-Cas9 gene editing has transformed our ability to rapidly interrogate the functional impact of somatic mutations in human cancers. Droplet-based technology enables the analysis of Cas9-introduced gene edits in thousands of single cells. Using this technology, we analyze Ba/F3 cells engineered to express single or multiplexed loss-of-function mutations recurrent in chronic lymphocytic leukemia. Our approach reliably quantifies mutational co-occurrences, zygosity status, and the occurrence of Cas9 edits at single-cell resolution.
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http://dx.doi.org/10.1186/s13059-020-02174-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574538PMC
October 2020

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

Pediatr Blood Cancer 2021 Jan 7;68(1):e28719. Epub 2020 Oct 7.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Background/objectives: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy.

Design/methods: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes.

Results: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS.

Conclusions: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.
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http://dx.doi.org/10.1002/pbc.28719DOI Listing
January 2021

Pregnancy outcomes, risk factors, and cell count trends in pregnant women with essential thrombocythemia.

Leuk Res 2020 11 29;98:106459. Epub 2020 Sep 29.

Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

Pregnancy in essential thrombocythemia (ET) is associated with increased risk of obstetric complications. We retrospectively evaluated risk factors in 121 pregnancies in 52 ET women seen at 3 affiliate hospitals. Univariable and multivariable analyses were performed at the α = 0.10 level. Cell counts were characterized throughout pregnancy and correlated with outcomes using logistic modeling. The overall live birth rate was 69 %. 48.7 % of all women experienced a pregnancy complication, the most common being spontaneous abortion, which occurred in 26 % of all pregnancies. Maternal thrombosis and hemorrhage rates were 2.5 % and 5.8 %. On multivariable analysis, aspirin use (OR 0.29, p = 0.014, 90 % CI 0.118-0.658) and history of prior pregnancy loss (OR 3.86, p = 0.011, CI 1.49-9.15) were associated with decreased and increased pregnancy complications, respectively. A Markov model was used to analyze the probability of a future pregnancy complication based on initial pregnancy outcome. An ET woman who suffers a pregnancy complication has a 0.594 probability of a subsequent pregnancy complication, compared to a 0.367 probability if she didn't suffer a complication. However, despite this elevated risk, overall prognosis is good, with a >50 % probability of a successful pregnancy by the third attempt. Platelet counts decreased by 43 % in ET during pregnancy, with nadir at delivery and prompt recovery in the postpartum period. Women with larger declines in gestational platelet counts were less likely to suffer complications (p = 0.083). Our study provides important guidance to physicians treating ET women during pregnancy, including counseling information regarding risk assessment and expected trajectory of platelet levels.
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http://dx.doi.org/10.1016/j.leukres.2020.106459DOI Listing
November 2020

Analysis, identification and visualization of subgroups in genomics.

Brief Bioinform 2020 Sep 21. Epub 2020 Sep 21.

Institute of Medical Systems Biology, and head of Core Unit Bioinformatics, Ulm University, Ulm, Germany.

Motivation: Cancer is a complex and heterogeneous disease involving multiple somatic mutations that accumulate during its progression. In the past years, the wide availability of genomic data from patients' samples opened new perspectives in the analysis of gene mutations and alterations. Hence, visualizing and further identifying genes mutated in massive sets of patients are nowadays a critical task that sheds light on more personalized intervention approaches.

Results: Here, we extensively review existing tools for visualization and analysis of alteration data. We compare different approaches to study mutual exclusivity and sample coverage in large-scale omics data. We complement our review with the standalone software AVAtar ('analysis and visualization of alteration data') that integrates diverse aspects known from different tools into a comprehensive platform. AVAtar supplements customizable alteration plots by a multi-objective evolutionary algorithm for subset identification and provides an innovative and user-friendly interface for the evaluation of concurrent solutions. A use case from personalized medicine demonstrates its unique features showing an application on vaccination target selection.

Availability: AVAtar is available at: https://github.com/sysbio-bioinf/avatar.

Contact: hans.kestler@uni-ulm.de, phone: +49 (0) 731 500 24 500, fax: +49 (0) 731 500 24 502.
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http://dx.doi.org/10.1093/bib/bbaa217DOI Listing
September 2020

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect.

Sci Transl Med 2020 09;12(561)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.
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http://dx.doi.org/10.1126/scitranslmed.abb7661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829680PMC
September 2020

Endogenous Glucocorticoid Signaling Regulates CD8 T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.

Immunity 2020 Sep;53(3):658-671.e6

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

Identifying signals in the tumor microenvironment (TME) that shape CD8 T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8 tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8 TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8 TILs promotes dysfunction, with important implications for cancer immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682805PMC
September 2020

Spatial Signatures Identify Immune Escape via PD-1 as a Defining Feature of T-cell/Histiocyte-rich Large B-cell Lymphoma.

Blood 2020 Sep 1. Epub 2020 Sep 1.

Brigham and Women's Hospital, Boston, Massachusetts, United States.

T-cell/histiocyte-rich large B cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbor PD-L1/PD-L2 copy gain or amplification in 64% of cases, which is associated with increased PD-L1 expression (p = 0.0111). By directed and unsupervised spatial analyses of multi-parametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune 'neighborhoods' in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1-positive T cells. Further, unbiased clustering of spatially-resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in three of five patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies, including two complete responses and one partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL, and also support the potential utility of spatially-resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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http://dx.doi.org/10.1182/blood.2020006464DOI Listing
September 2020

A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma.

Nat Med 2020 09 10;26(9):1468-1479. Epub 2020 Aug 10.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274 (PD-L1) and PDC1LG2 (PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4, but not CD8, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3CD68CD4GrB subset. These studies highlight the roles of recently expanded, clonally diverse CD4 T cells and innate effectors in the efficacy of PD-1 blockade in cHL.
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http://dx.doi.org/10.1038/s41591-020-1006-1DOI Listing
September 2020

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
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http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
October 2020

Anticoagulation after intracranial hemorrhage in brain tumors: Risk of recurrent hemorrhage and venous thromboembolism.

Res Pract Thromb Haemost 2020 Jul 23;4(5):860-865. Epub 2020 Jun 23.

Division of Hemostasis and Thrombosis Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts USA.

Background: Intracranial hemorrhage (ICH) is a common and often devastating outcome in patients with brain tumors. Despite this, there is little evidence to guide anticoagulation management following an initial ICH event.

Objectives: To analyze the risk of recurrent hemorrhagic and thrombotic outcomes after an initial ICH event in patients with brain tumors and prior venous thromboembolism (VTE).

Patients And Methods: A retrospective cohort study was performed. Radiographic images obtained after initial ICH were reviewed for the primary outcomes of recurrent ICH and VTE.

Results And Conclusions: A total of 79 patients with brain tumors who developed ICH on anticoagulation for VTE were analyzed. Fifty-four patients (68.4%) restarted anticoagulation following ICH. The cumulative incidence of recurrent ICH at 1 year was 6.1% (95% confidence interval [CI], 1.5-15.3) following reinitiation of anticoagulation. Following a major ICH (defined as an ICH >10 mL in size, causing symptoms, or requiring intervention), the rate of recurrent ICH upon reexposure to anticoagulation was 14.5% (95% CI, 2.1-38.35), whereas the rate of recurrent ICH following smaller ICH was 2.6% (95% CI, 0.2%-12.0%). Mortality following a recurrent ICH on anticoagulation was 67% at 30 days. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to patients who did not restart anticoagulation (8.1% vs 35.3%;  = .003). We conclude that resumption of anticoagulation is lowest among patients with metastatic brain tumors with small initial ICH. Following an initial major ICH, resumption of anticoagulation was associated with a high rate of recurrent ICH.
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http://dx.doi.org/10.1002/rth2.12377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354400PMC
July 2020

Heparin induced thrombocytopenia antibodies in Covid-19.

Am J Hematol 2020 Jul 13. Epub 2020 Jul 13.

Division of Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/ajh.25935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405086PMC
July 2020

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Nat Commun 2020 06 12;11(1):2996. Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.
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http://dx.doi.org/10.1038/s41467-020-16805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293239PMC
June 2020

BCR selection and affinity maturation in Peyer's patch germinal centres.

Nature 2020 06 6;582(7812):421-425. Epub 2020 May 6.

Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.

The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs). Although most GCs are transient, those in intestinal Peyer's patches (PPs)-which depend on the gut microbiota-are chronic, and little is known about their BCR repertoires or patterns of somatic hypermutation. Here, using a high-throughput assay that analyses both V(D)J segment usage and somatic hypermutation profiles, we elucidate physiological BCR repertoires in mouse PP GCs. PP GCs from different mice expand public BCR clonotypes (clonotypes that are shared between many mice) that often have canonical CDR3s in the immunoglobulin heavy chain that, owing to junctional biases during V(D)J recombination, appear much more frequently than predicted in naive B cell repertoires. Some public clonotypes are dependent on the gut microbiota and encode antibodies that are reactive to bacterial glycans, whereas others are independent of gut bacteria. Transfer of faeces from specific-pathogen-free mice to germ-free mice restored germ-dependent clonotypes, directly implicating BCR selection. We identified somatic hypermutations that were recurrently selected in such public clonotypes, indicating that affinity maturation occurs in mouse PP GCs under homeostatic conditions. Thus, persistent gut antigens select recurrent BCR clonotypes to seed chronic PP GC responses.
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http://dx.doi.org/10.1038/s41586-020-2262-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478071PMC
June 2020

Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.

Nat Med 2020 06 29;26(6):909-918. Epub 2020 May 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8 T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8 T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.
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http://dx.doi.org/10.1038/s41591-020-0839-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499153PMC
June 2020

Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial.

Blood Adv 2020 05;4(10):2254-2260

Division of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Hospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dose low-molecular-weight heparin (LMWH) regimens in high-risk hospitalized patients with cancer. We conducted a randomized, double-blinded, phase 2 trial in hospitalized patients with active cancer at high risk of developing VTE based on Padua risk score. Patients were randomly assigned to fixed-dose enoxaparin (40 mg daily) vs weight-adjusted enoxaparin (1 mg/kg daily) during hospitalization. The primary objectives were to evaluate the safety of dose-adjusted enoxaparin and evaluate the incidence of VTE with fixed-dose enoxaparin. Blinded clinical assessments were performed at day 14, and patients randomly assigned to fixed-dose enoxaparin subsequently underwent a bilateral lower extremity ultrasound. A total of 50 patients were enrolled and randomized. The median weight of patients enrolled in weight-adjusted enoxaparin arm was 76 kg (range, 60.9-124.5 kg). There were no major hemorrhages or symptomatic VTE in either arm. At time of completion of the blinded clinical assessment, there was only 1 incidentally identified pulmonary embolus that occurred in the weight-adjusted arm. In the group randomly assigned to fixed-dose enoxaparin who subsequently underwent surveillance ultrasound, the cumulative incidence of DVT was 22% (90% binomial confidence interval, 0%-51.3%). This phase 2 trial confirms a high incidence of asymptomatic VTE among high-risk hospitalized patients with cancer and that weight-adjusted LMWH thromboprophylaxis is feasible and well-tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02706249.
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http://dx.doi.org/10.1182/bloodadvances.2020001804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252540PMC
May 2020

HLA alleles associated with asparaginase hypersensitivity in childhood ALL: a report from the DFCI Consortium.

Pharmacogenomics 2020 06 6;21(8):541-547. Epub 2020 May 6.

Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, H3T 1C5, Canada.

To evaluate the association between human leukocyte antigen (HLA) alleles and native asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. , and alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts. Two alleles in linkage disequilibrium ( and ) were associated with AH. Additional analyses, performed to distinguish between haplotypes with and without allele, showed that the association was dependent on the presence of . This study confirms the implication of , and alleles in developing AH in childhood ALL.
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http://dx.doi.org/10.2217/pgs-2019-0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299187PMC
June 2020

SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS.

Blood 2020 07;136(2):157-170

Department of Molecular Medicine, University of Pavia & Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement.
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http://dx.doi.org/10.1182/blood.2020004850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362582PMC
July 2020

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Clin Cancer Res 2020 06 13;26(11):2556-2564. Epub 2020 Mar 13.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.

Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).

Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654718PMC
June 2020

Mind the gap: Expediting gender parity in MD-PhD admissions.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Harvard/MIT MD-PhD Program and.

The 2018 National MD-PhD Program Outcomes Study highlighted the critical need to increase MD-PhD trainee diversity and close the gender gap in MD-PhD enrollment. This Association of American Medical Colleges imperative prompted us to evaluate trends in female matriculation from our institutional MD-PhD program compared with national data. Based on a 10-year review of Harvard/MIT Medical Scientist Training Program admissions, we observed a sharp and sustained increase in female matriculants for the past 5 years that is well above the national average. We report our experience with achieving gender parity among matriculants of our MD-PhD program, identify the specific stage of the admissions process where the gender balance acutely shifted, and attribute the increase in female matriculation to concrete administrative changes that were put into place just prior to the observed gender balance shift. These changes included increasing the number of faculty participants in application screening and awardee selection and establishing gender balance among faculty decision makers. We believe that adopting basic administrative practices geared toward increasing the diversity of perspectives among admissions faculty has the potential to expedite gender parity of MD-PhD matriculants nationwide and could eventually help achieve gender balance in the national physician-scientist workforce.
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http://dx.doi.org/10.1172/jci.insight.136037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101133PMC
February 2020

Automated Flow Synthesis of Tumor Neoantigen Peptides for Personalized Immunotherapy.

Sci Rep 2020 01 20;10(1):723. Epub 2020 Jan 20.

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.

High-throughput genome sequencing and computation have enabled rapid identification of targets for personalized medicine, including cancer vaccines. Synthetic peptides are an established mode of cancer vaccine delivery, but generating the peptides for each patient in a rapid and affordable fashion remains difficult. High-throughput peptide synthesis technology is therefore urgently needed for patient-specific cancer vaccines to succeed in the clinic. Previously, we developed automated flow peptide synthesis technology that greatly accelerates the production of synthetic peptides. Herein, we show that this technology permits the synthesis of high-quality peptides for personalized medicine. Automated flow synthesis produces 30-mer peptides in less than 35 minutes and 15- to 16-mer peptides in less than 20 minutes. The purity of these peptides is comparable with or higher than the purity of peptides produced by other methods. This work illustrates how automated flow synthesis technology can enable customized peptide therapies by accelerating synthesis and increasing purity. We envision that implementing this technology in clinical settings will greatly increase capacity to generate clinical-grade peptides on demand, which is a key step in reaching the full potential of personalized vaccines for the treatment of cancer and other diseases.
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http://dx.doi.org/10.1038/s41598-019-56943-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971261PMC
January 2020