The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Romiplostim for Treatment of Children and Young Adults With Severe Aplastic Anemia and Myelodysplastic Syndrome.

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.

Recurrent MSC E116K mutations in ALK-negative anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK-, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSC E116K, exclusively in ALK- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC E116K for ALK- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin-bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30-IRF4-MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSC E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

The utility of prognostic indices, early events, and histological subtypes on predicting outcomes in non-follicular indolent B-cell lymphomas.

Indolent B-cell lymphomas other than follicular lymphoma account for up to 10% of all B-cell neoplasms. While they typically follow a slowly progressive course, some patients experience rapid progression and early mortality. Prognostic scoring systems have not been adopted, hindering the ability of clinicians or researchers to predict outcomes, or risk-stratify patients during clinical trials. To address this, we evaluated the utility of existing prognostic indices and novel, early disease-related outcomes, to predict subsequent long term survival. Baseline characteristics and outcomes data were generated from a longitudinal cohort study that prospectively enrolled 632 patients newly diagnosed with marginal zone lymphoma, lymphoplasmacytic lymphomas, or B-cell lymphomas not otherwise specified, beginning in 2002. The International Prognostic Index (IPI), Follicular Lymphoma International Prognostic Index (FLIPI), and MALT International prognostic index (MALT-IPI) demonstrated c-statistics that ranged from 0.593-0.612 for event-free survival (EFS), and 0.683-0.714 for overall survival (OS). Patients who attained event-free survival at 12 months (EFS12) experienced similar mortality to the US general population (standardized mortality ratio [SMR] 1.19; 95% CI 0.95-1.46). Patients who did not attain EFS12 had subsequent worse morality (SMR 3.14 (95% CI 2.05-4.59). The MALT-IPI demonstrated utility in predicting subsequent long-term outcomes among patients with non-follicular indolent B-cell lymphomas. This index should be used by clinicians giving guidance to patients at the time of initial diagnosis, and risk stratification during clinical studies. The divergent long-term outcomes experienced by patients who do or do not attain EFS12 suggest there exists a subset of patients who harbor high-risk disease. Future research efforts should focus on methods to identify these patients at the time of diagnosis, in order to enable risk-tailored therapy.

Outcomes among North American patients with diffuse large B-cell lymphoma are independent of tumor Epstein-Barr virus positivity or immunosuppression.

The prevalence, presenting clinical and pathological characteristics, and outcomes for patients with diffuse large B-cell lymphoma that is Epstein-Barr virus positive remain uncertain as does the impact of congenital or iatrogenic immunosuppression. Patients with newly diagnosed diffuse large B-cell lymphoma with available tissue arrays were identified from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource. Patients infected with human immunodeficiency virus or who had undergone a prior organ transplant were excluded. Epstein-Barr virus-associated ribonucleic acid testing was performed on all tissue arrays. A history of significant congenital or iatrogenic immunosuppression was determined for all patients. At enrollment, 16 of the 362 (4.4%) biopsies were positive for Epstein-Barr virus. Thirty-nine (10.8%) patients had a significant history of immunosuppression. Patients with Epstein-Barr-positive diffuse large B-cell lymphoma had no unique clinical characteristics but on pathology exhibited a higher frequency of CD30 positivity (25.0% versus 8.1%, respectively; P<0.01), and non-germinal-center subtype (62.5% versus 34.1%, respectively; P<0.01). No baseline clinical characteristics were associated with a history of immunosuppression. With a median follow up of 59 months, and after adjustment for International Prognostic Index, there was no association of Epstein-Barr virus positivity or immunosuppression with event-free survival at 24 months (odds ratio=0.49; 95% confidence interval: 0.13-1.84 and odds ratio=0.81; 95% confidence interval: 0.37-1.77) or overall survival (hazard ratio=0.86; 95% confidence interval: 0.38-1.97 and hazard ratio=1.00; 95% confidence interval: 0.57-1.74). In contrast to non-Western populations, our North American population had a low prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma that did not convey an adverse prognosis. A history of immunosuppression, while known to be a risk factor for the development of diffuse large B-cell lymphoma, did not affect subsequent prognosis.

Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy.

This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline-based immunochemotherapy (IC). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B-cell lymphoma (PMBL) patients treated with front-line anthracycline-based IC were followed for relapse. Patients with relapse on follow-up and subsequently retreated were included in this analysis. 1039 patients received anthracycline-based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL.

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma.

Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL). To determine whether the addition of these biological factors may further refine prognostication, 30 cytokines and chemokines were measured in pretreatment serum specimens from newly diagnosed FL patients (n = 209) and from 400 matched controls. Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy. Correlations with outcome in chemotherapy treated patients were further examined in a separate cohort of 183 South West Oncology Group (SWOG) patients and all patients were then included in a meta-analysis. Six cytokines were associated with outcome in the Molecular Epidemiology Resource (MER) after adjusting for the FL international prognostic index. In patients who were observed or treated with rituximab alone, increased serum IL-12 and interleukin 1 receptor antagonist (IL-1RA) (P = .005 and .02) were associated with a shorter event-free survival. In patients receiving chemotherapy, hepatocyte growth factor, IL-8, IL-1RA, and CXCL9 (P = .015, .048, .004, and .0005) predicted a shorter EFS. When the MER chemotherapy treated patients and SWOG patients were combined in a meta-analysis, IL-2R, IL-1RA, and CXCL9 (P = .013, .042, and .0012) were associated with a poor EFS.

Direct catalytic arylation of heteroarenes with meso-bromophenyl-substituted porphyrins.

The arylation of mono-, di- and tetra-meso-bromophenyl-substituted porphyrins with the heteroarenes containing "acidic" C-H bonds, such as benzoxazole, benzothiazole and N-methylimidazole was studied in the presence of three alternative catalytic systems: Pd(dba)2/DavePhos/Cs2CO3, Pd(PPh3)4/PivOH/K2CO3 and Pd(OAc)2/Cu(OAc)2/PPh3/K2CO3. The first catalytic system was found to be successful in the reaction with benzoxazole, the second one was less efficient for our purpose, while the third system proved to be most versatile and afforded corresponding mono-, di-, tri- and even tetraarylated derivatives of porphyrins.

Early event status informs subsequent outcome in newly diagnosed follicular lymphoma.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc.

Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma.

We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12-88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps.

Primary Cutaneous Polymorphic EBV-Associated Posttransplant Lymphoproliferative Disorder After a Renal Transplant and Review of the Literature.

IMPORTANCE: Posttransplant lymphoproliferative disorder (PTLD) is an uncommon complication after solid organ transplants and hematopoietic stem cell transplants. Extranodal involvement in PTLD can involve several organ systems, including the central nervous system, bone marrow, lungs, gastrointestinal tract, and skin. Isolated involvement of the skin without systemic involvement in PTLD is rare. Primary cutaneous PTLD is generally categorized as either cutaneous T-cell lymphomas or cutaneous B-cell lymphomas, with variable Epstein-Barr virus (EBV) positivity. Herein, we describe an exceedingly uncommon case of a polymorphic variant of primary cutaneous PTLD. OBSERVATIONS: A woman in her 30s, who received an EBV+ deceased donor kidney transplant, presented with a 2-week history of 2 indurated patches over the lower abdomen. A skin biopsy revealed an atypical lymphoid proliferation with immunohistochemical stains demonstrating a mixed population of both B and T cells that stained strongly positive for EBV-encoded RNA. A bone marrow biopsy and positron emission tomography/computed tomography were negative for systemic involvement. The patient was treated with immunosuppression reduction and rituximab infusions. CONCLUSIONS AND RELEVANCE: This case highlights a rare polymorphic variant of primary cutaneous EBV-associated PTLD and increases awareness of this uncommon posttransplant complication. Cutaneous PTLD is reviewed, therefore dermatologists are aware of this uncommon disorder.

Missing the target: characterization of bullous pemphigoid patients who are negative using the BP180 enzyme-linked immunosorbant assay.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies specific for the 180-kd BP antigen-2 (BP180) (also termed "type XVII collagen") protein. The BP180 enzyme-linked immunosorbent assay (ELISA) is specific for the immunodominant NC16A domain of the protein. However, we and others have observed patients whose reactivity to BP180 is exclusive of the NC16A domain (referred to henceforth as non-NC16A BP). OBJECTIVE: We sought to determine the incidence of non-NC16A BP and identify regions of reactivity within the BP180 protein. METHODS: Sera from 51 patients who met the clinical and histologic criteria for BP were screened for NC16A reactivity by ELISA. Sera that were negative by ELISA were screened for IgG reactivity to an epidermal extract, recombinant BP180 protein, and subregions of BP180, by immunoblot. Demographic and clinical data were also collected on all patients. RESULTS: Four sera (7.8%) were negative using the BP180 ELISA but positive for IgG reactivity to the extracellular domain of BP180. Further mapping identified 4 regions outside of NC16A recognized by these sera: amino acid (AA) 1280 to 1315, AA 1080 to 1107, AA 1331 to 1404, and AA 1365 to 1413. One of these sera also had IgE specific for NC16A. One patient had an atypical presentation with lesions limited to the lower aspect of the legs and scarring of the nail beds. LIMITATIONS: The small total number of patients with non-NC16A BP limits the identification of demographic or clinical correlates. CONCLUSION: It is significant that 7.8% of sera from patients with new BP react to regions of BP180 exclusively outside of NC16A and, thus, would not be identified using the currently available BP180 ELISA.

Utilizing digital pathology and immunohistochemistry of p53 as an adjunct to molecular testing in myeloid disorders.

TP53 mutation status guides early therapeutic decisions in the treatment of clonal myeloid disorders and serves as a simple means of monitoring response to treatment. We aim here to develop a standardized protocol for evaluating TP53 mutation status in myeloid disorders using immunohistochemistry assisted by digital image analysis and further compare this approach to manual interpretation alone. To accomplish this, we obtained 118 bone marrow biopsies from patients with hematologic malignancy and molecular testing for mutations associated with acute myeloid leukemia was performed. Clot or core biopsy slides were stained for p53 and digitally scanned. Overall mutation burden was assessed digitally using two different metrics to determine positivity, compared to the results of manual review, and correlated with molecular results. Using this approach, we found that digital analysis of immunohistochemistry stained slides performed worse than manual categorization alone in predicting TP53 mutation status in our cohort (PPV 91%, NPV 100% vs. PPV 100%, NPV 98%). While digital analysis reduced inter- and intraobserver variability when assessing mutation burden, there was poor correlation between the quantity and intensity of p53 staining and molecular analysis (R2 = 0.204). Therefore, digital image analysis of p53 immunohistochemistry accurately predicts TP53 mutation status as confirmed by molecular testing but does not offer a significant advantage over manual categorization alone. However, this approach offers a highly standardized methodology for monitoring disease status or response to treatment once a diagnosis has been made.

Evolving frontline immunochemotherapy for mantle cell lymphoma and the impact on survival outcomes.

Because there have been a dvances in frontline treatment for mantle cell lymphoma (MCL) over the last 2 decades, we sought to characterize the changes in frontline treatment patterns and their association with outcomes. Patients with newly diagnosed MCL from September 2002 through June 2015 were enrolled in a prospective cohort study, and clinical characteristics, treatment, and clinical outcomes were compared between patients diagnosed from 2002 to 2009 (Era 1) compared with 2010 to 2015 (Era 2). Patient age, sex, and simplified MCL International Prognostic Index (sMIPI) score were similar between the 2 groups. In patients age 65 years or younger, there was less use of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-Hyper-CVAD) (16.1% vs 8.8%) but more use of rituximab plus maximum-strength cyclophosphamide, doxorubicin, vincristine, and prednisone (R-maxi-CHOP) alternating with rituximab plus high-dose cytarabine (R-HiDAC), also known as the Nordic regimen, and R-CHOP alternating with rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) (1.1% vs 26.4%) and less use of R-CHOP or R-CHOP-like regimens (64.5% vs 35.2%) but more use of R-bendamustine (0% vs 12.1%) in Era 2 (P < .001). These changes were associated with improved event-free survival (EFS; 5-year EFS, 34.3% vs 50.0%; P = .010) and overall survival (OS; 5-year OS, 68.8% vs 81.6%; P = .017) in Era 2. In patients older than age 65 years, there was less use of R-CHOP or R-CHOP-like therapy (39.0% vs 14.3%) and nonstandard systemic therapy (36.6% vs 13.0%) but more use of R-bendamustine (0% vs 49.4%). These changes were associated with a trend for improved EFS (5-year EFS, 25.4% vs 37.5%; P = .051) in Era 2. The shift from R-CHOP or R-CHOP-like regimens to R-bendamustine was associated with improved EFS (5-year EFS, 25.0% vs 44.6%; P = .008) in Era 2. Results from this prospective cohort study provide critical real-world evidence for improved outcomes with evolving frontline patterns of care in patients with MCL.

Causes of death in low-grade B-cell lymphomas in the rituximab era: a prospective cohort study.

Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non-lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P < .001), whereas the rates for non-lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

Markers of Follicular Helper T Cells Are Occasionally Expressed in T-Cell or Histiocyte-Rich Large B-Cell Lymphoma, Classic Hodgkin Lymphoma, and Atypical Paracortical HyperplasiaA Diagnostic Pitfall For T-Cell Lymphomas of T Follicular Helper Origin.

OBJECTIVES: Follicular helper T cell (TFH) markers are expressed in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma of the TFH phenotype (PTCL-TFH). However, differential expression and coexpression of these markers in benign and other malignant lymphoid proliferations have not been well studied. METHODS: We performed programmed death-1 (PD-1), C-X-C motif chemokine ligand 13 (CXCL13), inducible costimulator (ICOS), CD10, and B-cell lymphoma 6 protein (BCL-6) immunohistochemistry on AITL, PTCL not otherwise specified (PTCL-NOS), PTCL-TFH, T-cell or histiocyte-rich large B-cell lymphoma (THRLBCL), classic Hodgkin lymphoma (CHL), atypical paracortical hyperplasia (PCH), progressive transformation of germinal centers (PTGC), and reactive follicular hyperplasia (RFH). RESULTS: CXCL13 and ICOS were more sensitive but less specific for AITL than PD-1, CD10, and BCL-6. Moreover, 74% of AITL (none of PTCL-NOS or PTCL-TFH) coexpressed more than 2 TFH markers. In background T cells of THRLBCL, 70% of cases coexpressed more than 1 marker. The background T cells of CHL expressed all TFH markers except CD10 in all cases. In addition, 13% of PCH cases coexpressed more than 1 marker. In RFH and PTGC, all markers were expressed mainly in germinal centers with rare extrafollicular staining. CONCLUSIONS: AITL, PTCL-NOS, and PTCL-TFH show differential expression of TFH markers. AITL frequently coexpresses more than 2 TFH markers. TFH markers can be expressed in PCH and in background T cells of THRLBCL and CHL. Consequently, caution should be used before a diagnosis of AITL is established, particularly with limited samples.

Utility of Flow Cytometry and Fluorescence In Situ Hybridization in Follow-up Monitoring of Plasma Cell Myeloma.

OBJECTIVES: We sought to investigate the clinical utility of flow cytometry (FC) and fluorescence in situ hybridization (FISH) in the workup of myeloma. METHODS: We retrospectively reviewed the reports of bone marrow biopsies received for myeloma evaluation between October 2015 and January 2019. RESULTS: A total of 1,708 biopsy specimens from 469 myeloma patients (mean age, 64.5 years [SD, 9.3]; female, 41.4%) were reviewed. Both FC and FISH had comparable detection rates at the time of initial diagnosis (97.6% vs 98.8%) and for follow-up cases (28.6% vs 28.2%). FC and FISH results were concordant in 98.8% of the initial diagnosis cases and 89.6% of the follow-up cases. The FISH-positive (FISH+)/FC-negative (FC-) discordance and FISH-/FC+ discordance occurred among 81 (5.0%) and 87 (5.4%) follow-up cases. In comparison with all concordant cases, FISH+/FC- discordant cases were more likely to have received treatment with daratumumab (P < .05). CONCLUSIONS: Plasma cell-enriched FISH and FC have comparable abnormal plasma cell detection rates, and approximately 10% of the follow-up cases have discordant FISH and FC results in which residual disease is detected by only one of these modalities. FISH testing should be considered for cases with negative FC, especially in patients who have received treatment with daratumumab or in cases in which there is concern about specimen adequacy.