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Background: The majority of patients with Hodgkin lymphoma (HL) achieve disease remission after primary therapy. To the best of the authors' knowledge, no consensus exists for postremission surveillance imaging. Methods: Retrospectively analyzed were 192 adult patients with classic HL in first remission. Events were defined as recurrent HL or secondary malignancies. Primary outcome was positive predictive value (PPV) of surveillance positron emission tomography/computed tomography (PET/CT) and CT scans in event detection. Secondary outcomes were costs and radiation exposures of surveillance scans. Results: Sixteen events (12 recurrent HL cases and 4 secondary malignancies) were detected during a median follow-up of 31 months. The PPV of surveillance PET/CT was 22.9% compared with 28.6% for CT (P=.73). Factors that were found to significantly improve the PPV of scans in detecting recurrent HL included PET and CT concordance, involvement of a prior disease site, or the occurrence of a radiographic abnormality within 12 months. There were too few events to determine whether event detection by PET/CT versus CT or the presence of symptoms at the time of event detection affected overall outcomes. The cost to detect a single event was approximately $100,000. Radiation exposure to detect a single event was 146.6 millisieverts per patient for each of 9 patients. Conclusions: For patients with HL in first disease remission, surveillance radiography appears to be expensive, with limited clinical impact. Surveillance CT is generally adequate. [ABSTRACT FROM AUTHOR]

STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily ( n  = 55) or placebo ( n  = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p  = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.

Abstract: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited., Methods: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period., Results: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010)., Conclusions: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use., Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction., Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022., Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months., Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months., Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups., Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use., Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Background: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows., Methods: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network., Results: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network., Conclusion: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology., (© The Author(s) 2022. Published by Oxford University Press.)

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, β, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Although up to half of patients receiving chemotherapeutic agents develop hypersensitivity reactions to the same, desensitization protocols can induce temporary tolerance to allow patients to continue to receive first-line treatment. Approximately 25% of patients develop cutaneous hypersensitivity reactions to ibrutinib, but there are no published management guidelines., Case Report: We describe the case of a 71-year-old woman with chronic lymphocytic leukemia who developed a delayed maculopapular rash with lip tingling and swelling following ibrutinib therapy., Management and Outcome: We performed a novel 11-step desensitization procedure to ibrutinib allowing us to successfully induce tolerance against IgE-mediated symptoms in this patient., Discussion: As indications for ibrutinib use expand and more patients present with IgE-mediated symptoms, we expect that this protocol will provide benefit for many such patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted health care systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied, and the frequency of nosocomial spread to patients with cancer is not well understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in patients with cancer admitted at a large academic center., Materials and Methods: Medical records of patients with cancer diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID-19 (January 2019 to February 2020), COVID-19 (March to May 2020), and post-COVID-19 surge (June to August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed., Results: Overall, the daily inpatient census was steady in 2019 (median, 103; range, 92-118) and until February 2020 (median, 112; range, 102-114). However, there was a major decline from March to May 2020 (median, 68; range, 57-104), with 45.4% lower admissions during April 2020. As the COVID-19 surge eased, the daily inpatient census over time returned to the pre-COVID-19 baseline (median, 103; range, 99-111). One patient (1/231, 0.004%) tested positive for SARS-CoV-2 13 days after hospitalization, and it is unclear if it was nosocomial or community spread., Conclusion: In this study, inpatient oncology admissions decreased substantially during the COVID-19 surge but over time returned to the pre-COVID-19 baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary., Implications for Practice: The COVID-19 pandemic has had a major impact on the health care system, and cancer patients are a vulnerable population. This study observes a significant decline in the daily inpatient oncology census from March to May 2020 compared with the same time frame in the previous year and examines the potential reasons for this decline. In addition, nosocomial rates of COVID-19 were investigated, and rates were found to be very low. These findings suggest that aggressive infection control measures can mitigate the nosocomial infection risk among cancer patients and the inpatient setting is a safe environment, providing reassurance., (© 2021 AlphaMed Press.)

Background: As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials., Material and Methods: We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality., Results: During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy., Conclusion: The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality., Implications for Practice: Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies., (© 2020 AlphaMed Press.)

Background: Inpatient supportive care programs often target patients with advanced solid tumors. To the authors' knowledge, few studies to date have characterized symptom burden in hospitalized patients with potentially curable cancers. The objective of the current study was to compare symptom burden, palliative care consultation, and readmission rates in hospitalized patients by cancer type and treatment intent., Methods: The authors conducted a single-center study of hospitalized patients with cancer between 2014 and 2017. They assessed physical symptoms using the Edmonton Symptom Assessment System and psychological distress using the Patient Health Questionnaire-4 and the Primary Care PTSD (Posttraumatic Stress Disorder) Screen. Multivariate linear regression models were used to assess symptom burden, logistic regression was used to assess palliative care use, and competing risk regression was used to compare 90-day readmission risk., Results: A total of 1549 patients were enrolled and surveyed. The majority of patients reported moderate to severe fatigue, poor well-being, and drowsiness with no significant differences noted by cancer type and treatment intent. Compared with other groups, patients with incurable solid cancer reported higher physical symptoms (beta coefficient [B], 4.73; P < .01) and symptoms of depression (B, 0.44; P < .01) and anxiety (B, 0.39; P < .01), but no difference in posttraumatic stress disorder. Among patients in the top quartile symptom burden according to the Edmonton Symptom Assessment System, the palliative care service was consulted in 14.7%, 7.9%, 25.0%, and 49.6%, respectively, of patients with potentially curable hematologic, potentially curable solid, incurable hematologic, and incurable solid cancers (P < .001). Compared with patients with potentially curable solid cancer, patients in each group experienced a higher risk of readmission within 90 days., Conclusions: Hospitalized patients with cancer experience substantial physical and psychological symptoms. Palliative care rarely is consulted for highly symptomatic patients with potentially curable cancers. Supportive care interventions should target the needs of symptomatic patients regardless of treatment intent., (© 2020 American Cancer Society.)

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Bendamustine-rituximab (BR) is a standard therapy in CLL, and lenalidomide has single-agent activity. This phase 1 study evaluated lenalidomide-BR as initial CLL therapy. Thirteen patients were treated at three dose levels (DL), and an additional 10 were treated at the MTD. The MTD was DL3: lenalidomide 5 mg daily D8-21 of C1, then 10 mg D1-21 of C2-6. One DLT occurred at DL2 (pulmonary embolus). Grade ≥3 toxicities included neutropenia (52.2%), rash (26.1%), anemia (21.7%), thrombocytopenia (21.7%), and febrile neutropenia (13.0%). Of 13, 9 treated at the MTD required dose modification, most for neutropenia (5). OR and CR rates were 87% and 39%, respectively. Lenalidomide-BR could be safely administered and was active as initial CLL therapy, although frequent dose modification at the MTD suggests that lenalidomide 10 mg is too high for most patients. Given the current treatment landscape, lenalidomide combinations warrant evaluation in CLL patients who are chemonaïve but have been failed by the approved targeted therapies.

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation is standard therapy for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin-induced lung injury and radiation toxicity. Brentuximab vedotin is highly active in relapsed HL and was recently approved with doxorubicin, vinblastine, and dacarbazine (AVD) for previously untreated stage III/IV HL. We evaluated brentuximab-AVD for nonbulky stage I/II HL in a multicenter phase 2 study. Patients received a lead-in cycle of brentuximab vedotin monotherapy on days 1 and 15, followed by an exploratory positron emission tomography/computed tomography scan. Patients then received brentuximab-AVD for 4 to 6 cycles based on interim positron emission tomography/computed tomography scanning after cycle 2. Thirty-four patients were enrolled with a median age of 36 years (range, 20-75 years). Risk was early favorable in 62% and unfavorable in 38%. The best complete response rate was 100%. At a median follow-up of 38 months, the progression-free survival and overall survival were 94% and 97%, respectively. The most common adverse events were peripheral sensory neuropathy (79%), neutropenia (76%), fatigue (74%), and nausea (71%). The most common grade 3/4 toxicities were neutropenia (62%), febrile neutropenia (35%), and peripheral sensory neuropathy (24%). One elderly patient died of neutropenic sepsis in the first brentuximab-AVD cycle. Brentuximab dose reductions were required in 38% of patients, most for peripheral neuropathy. In conclusion, brentuximab-AVD without bleomycin or radiation produced a high complete response rate, with most patients requiring only 4 total cycles of therapy. Because toxicity was higher than would be expected from AVD alone, this method may not be appropriate for early-stage patients with a highly favorable prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01534078., (© 2019 by The American Society of Hematology.)

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia., Methods: We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m 2 , days 1-3), cyclophosphamide (250 mg/m 2 , days 1-3), and rituximab (375 mg/m 2 day 1 of cycle 1; 500 mg/m 2 day 1 of cycles 2-6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing., Findings: Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50-58). At data cutoff, median follow-up was 16·5 months (IQR 10·6-34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%)., Interpretation: The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients., Funding: Pharmacyclics and the Leukemia & Lymphoma Society., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity ( P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) ( P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival ( P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials., (© 2019 by The American Society of Hematology.)

Purpose: Patients with cancer often prefer to avoid time in the hospital; however, data are lacking on the prevalence and predictors of potentially avoidable readmissions (PARs) among those with advanced cancer., Methods: We enrolled patients with advanced cancer from September 2, 2014, to November 21, 2014, who had an unplanned hospitalization and assessed their patient-reported symptom burden (Edmonton Symptom Assessment System) at the time of admission. For 1 year after enrollment, we reviewed patients' health records to determine the primary reason for every hospital readmission and we classified readmissions as PARs using adapted Graham's criteria. We examined predictors of PARs using nonlinear mixed-effects models with binomial distribution., Results: We enrolled 200 (86.2%) of 232 patients who were approached. For these 200 patients, we reviewed 277 total hospital readmissions and identified 108 (39.0%) of these as PARs. The most common reasons for PARs were premature discharge from a prior hospitalization (30.6%) and failure of timely follow-up (28.7%). PAR hospitalizations were more likely than non-PAR hospitalizations to experience symptoms as the primary reason for admission (28.7% v 13.0%; P = .001). We found that married patients were less likely to experience PARs (odds ratio, 0.30; 95% CI, 0.15 to 0.57; P < .001) and that those with a higher physical symptom burden were more likely to experience PARs (odds ratio, 1.03; 95% CI, 1.01 to 1.05; P = .012)., Conclusion: We observed that a substantial proportion of hospital readmissions are potentially avoidable and found that patients' symptom burdens predict PARs. These findings underscore the need to assess and address the symptom burden of hospitalized patients with advanced cancer in this highly symptomatic population.

Background: Hospitalized patients with cancer experience a high symptom burden, which is associated with poor health outcomes and increased health care utilization. However, studies investigating symptom monitoring interventions in this population are lacking. We conducted a pilot randomized trial to assess the feasibility and preliminary efficacy of a symptom monitoring intervention to improve symptom management in hospitalized patients with advanced cancer., Patients and Methods: We randomly assigned patients with advanced cancer who were admitted to the inpatient oncology service to a symptom monitoring intervention or usual care. Patients in both arms self-reported their symptoms daily (Edmonton Symptom Assessment System and Patient Health Questionnaire-4). Patients assigned to the intervention had their symptom reports presented graphically with alerts for moderate/severe symptoms during daily team rounds. The primary end point of the study was feasibility. We defined the intervention as feasible if >75% of participants hospitalized >2 days completed >2 symptom reports. We observed daily rounds to determine whether clinicians discussed and developed a plan to address patients' symptoms. We used regression models to assess intervention effects on patients' symptoms throughout their hospitalization, readmission risk, and hospital length of stay (LOS)., Results: Among 150 enrolled patients (81.1% enrollment), 94.2% completed >2 symptom reports. Clinicians discussed 60.4% of the symptom reports and developed a plan to address the symptoms highlighted by the symptom reports 20.8% of the time. Compared with usual care, intervention patients had a greater proportion of days with lower psychological distress (B = 0.12, P = 0.008), but no significant difference in the proportion of days with improved Edmonton Symptom Assessment System-physical symptoms (B = 0.07, P = 0.138). Intervention patients had lower readmission risk (hazard ratio = 0.68, P = 0.224), although this difference was not significant. We found no significant intervention effects on hospital LOS (B = 0.16, P = 0.862)., Conclusions: This symptom monitoring intervention is feasible and demonstrates encouraging preliminary efficacy for improving patients' symptoms and readmission risk.ClinicalTrials.gov identifier NCT02891993., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Among patients with cancer, depressive symptoms are associated with worse clinical outcomes, including greater health care utilization. As use of antidepressant medications can improve depressive symptoms, we sought to examine relationships among depressive symptoms, antidepressant medications, and hospital length of stay (LOS) in patients with advanced cancer., Materials and Methods: From September 2014 to May 2016, we prospectively enrolled patients with advanced cancer who had an unplanned hospitalization. We performed chart review to obtain information regarding documented depressive symptoms in the 3 months prior to admission and use of antidepressant medications at the time of admission. We compared differences in hospital LOS by presence or absence of depressive symptoms and used adjusted linear regression to examine if antidepressant medications moderated these outcomes., Results: Of 1,036 patients, 126 (12.2%) had depressive symptoms documented prior to admission, and 288 (27.8%) were taking antidepressant medications at the time of admission. Patients with depressive symptoms experienced longer hospital LOS (7.25 vs. 6.13 days; p = .036). Use of antidepressant medications moderated this relationship; among patients not on antidepressant medications, depressive symptoms were associated with longer hospital LOS (7.88 vs. 6.11 days; p = .025), but among those on antidepressant medications, depressive symptoms were not associated with hospital LOS (6.57 vs. 6.17 days; p = .578)., Conclusion: Documented depressive symptoms prior to hospital admission were associated with longer hospital LOS. This effect was restricted to patients not on antidepressant medications. Future studies are needed to investigate if use of antidepressant medications decreases LOS for patients hospitalized with advanced cancer and the mechanisms by which this may occur., Implications for Practice: This study investigated the prevalence of documented depressive symptoms in patients with advanced cancer in the 3 months prior to an unplanned hospitalization and the prevalence of use of antidepressant medications at time of hospital admission. The relationship of these variables with hospital length of stay was also examined, and it was found that documented depressive symptoms were associated with prolonged hospital length of stay. Interestingly, antidepressant medications moderated the relationship between depressive symptoms and hospital length of stay. These findings support the need to recognize and address depressive symptoms among patients with advanced cancer, with potential implications for optimizing health care utilization., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

This is a phase II study of panobinostat, an oral pan-HDAC inhibitor, combined with rituximab in patients with relapsed diffuse large B cell lymphoma. Panobinostat was administered orally 3 times a week every other week on a 28-day cycle. Rituximab was administered weekly during the first cycle, then on Day 1 of cycles 2 to 6. Patients without disease progression after 6 cycles continued panobinostat monotherapy for up to 6 additional cycles in the absence of disease progression. Eighteen eligible subjects were enrolled, and 18 were evaluable for response. The overall response rate was 11% (90% CI [2%-34%]) with 2 subjects having a partial response. The duration of response in these subjects was 51 and 60 days. Five additional subjects had stable disease with 3 subjects having tumor reduction between 27 and 44%, not meeting criteria for partial response. One subject with stable disease remained on therapy a total of 12 cycles. The most common toxicities while on study were thrombocytopenia (14 patients, 78%); fatigue (11, 61%); anemia (10, 56%); diarrhea (8, 44%); and nausea, lymphopenia, anorexia, and hypophosphatemia (5 each, 28% of patients), the majority of which was grade 2 or less. These data indicate that the combination of panobinostat with rituximab is able to induce responses in a limited number of subjects with relapsed diffuse large B cell lymphoma., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Patients with cancer experience many stressors placing them at risk for posttraumatic stress disorder (PTSD) symptoms, yet little is known about factors associated with PTSD symptoms in this population. This study explored relationships among patients' PTSD symptoms, physical and psychological symptom burden, and risk for hospital readmissions., Methods: We prospectively enrolled patients with cancer admitted for an unplanned hospitalization from August 2015-April 2017. Upon admission, we assessed patients' PTSD symptoms (Primary Care PTSD Screen), as well as physical (Edmonton Symptom Assessment System [ESAS]) and psychological (Patient Health Questionnaire 4 [PHQ-4]) symptoms. We examined associations between PTSD symptoms and patients' physical and psychological symptom burden using linear regression. We evaluated relationships between PTSD symptoms and unplanned hospital readmissions within 90-days using Cox regression., Results: We enrolled 954 of 1,087 (87.8%) patients approached, and 127 (13.3%) screened positive for PTSD symptoms. The 90-day hospital readmission rate was 38.9%. Younger age, female sex, greater comorbidities, and genitourinary cancer type were associated with higher PTSD scores. Patients' PTSD symptoms were associated with physical symptoms (ESAS physical: B = 3.41; P < .001), the total symptom burden (ESAS total: B = 5.97; P < .001), depression (PHQ-4 depression: B = 0.67; P < .001), and anxiety symptoms (PHQ-4 anxiety: B = 0.71; P < .001). Patients' PTSD symptoms were associated with a lower risk of hospital readmissions (hazard ratio, 0.81; P = .001)., Conclusions: A high proportion of hospitalized patients with cancer experience PTSD symptoms, which are associated with a greater physical and psychological symptom burden and a lower risk of hospital readmissions. Interventions to address patients' PTSD symptoms are needed and should account for their physical and psychological symptom burden. Cancer 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

White-blood-cell (WBC) assessment is employed for innumerable clinical procedures as one indicator of immune status. Currently, WBC determinations are obtained by clinical laboratory analysis of whole blood samples. Both the extraction of blood and its analysis limit the accessibility and frequency of the measurement. In this study, we demonstrate the feasibility of a non-invasive device to perform point-of-care WBC analysis without the need for blood draws, focusing on a chemotherapy setting where patients' neutrophils-the most common type of WBC-become very low. In particular, we built a portable optical prototype, and used it to collect 22 microcirculatory-video datasets from 11 chemotherapy patients. Based on these videos, we identified moving optical absorption gaps in the flow of red cells, using them as proxies to WBC movement through nailfold capillaries. We then showed that counting these gaps allows discriminating cases of severe neutropenia (<500 neutrophils per µL), associated with increased risks of life-threatening infections, from non-neutropenic cases (>1,500 neutrophils per µL). This result suggests that the integration of optical imaging, consumer electronics, and data analysis can make non-invasive screening for severe neutropenia accessible to patients. More generally, this work provides a first step towards a long-term objective of non-invasive WBC counting.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Purpose Patients with advanced cancer experience potentially burdensome transitions of care after hospitalizations. We examined predictors of discharge location and assessed the relationship between discharge location and survival in this population. Methods We conducted a prospective study of 932 patients with advanced cancer who experienced an unplanned hospitalization between September 2014 and March 2016. Upon admission, we assessed patients' physical symptoms (Edmonton Symptom Assessment System) and psychological distress (Patient Health Questionnaire-4). The primary outcome was discharge location (home without hospice, postacute care [PAC], or hospice [any setting]). The secondary outcome was survival. Results Of 932 patients, 726 (77.9%) were discharged home without hospice, 118 (12.7%) were discharged to PAC, and 88 (9.4%) to hospice. Those discharged to PAC and hospice reported high rates of severe symptoms, including dyspnea, constipation, low appetite, fatigue, depression, and anxiety. Using logistic regression, patients discharged to PAC or hospice versus home without hospice were more likely to be older (odds ratio [OR], 1.03; 95% CI, 1.02 to 1.05; P < .001), live alone (OR, 1.95; 95% CI, 1.25 to 3.02; P < .003), have impaired mobility (OR, 5.08; 95% CI, 3.46 to 7.45; P < .001), longer hospital stays (OR, 1.15; 95% CI, 1.11 to 1.20; P < .001), higher Edmonton Symptom Assessment System physical symptoms (OR, 1.02; 95% CI, 1.003 to 1.032; P < .017), and higher Patient Health Questionnaire-4 depression symptoms (OR, 1.13; 95% CI, 1.01 to 1.25; P < .027). Patients discharged to hospice rather than PAC were more likely to receive palliative care consultation (OR, 4.44; 95% CI, 2.12 to 9.29; P < .001) and have shorter hospital stays (OR, 0.84; 95% CI, 0.77 to 0.91; P < .001). Patients discharged to PAC versus home had lower survival (hazard ratio, 1.53; 95% CI, 1.22 to 1.93; P < .001). Conclusion Patients with advanced cancer who were discharged to PAC facilities and hospice had substantial physical and psychological symptom burden, impaired physical function, and inferior survival compared with those discharged to home. These patients may benefit from interventions to enhance their quality of life and care.

Background: Although hospitalized patients with advanced cancer have a low chance of surviving cardiopulmonary resuscitation (CPR), the processes by which they change their code status from full code to do not resuscitate (DNR) are unknown., Methods: We conducted a mixed-methods study on a prospective cohort of hospitalized patients with advanced cancer. Two physicians used a consensus-driven medical record review to characterize processes that led to code status order transitions from full code to DNR., Results: In total, 1047 hospitalizations were reviewed among 728 patients. Admitting clinicians did not address code status in 53% of hospitalizations, resulting in code status orders of "presumed full." In total, 275 patients (26.3%) transitioned from full code to DNR, and 48.7% (134 of 275 patients) of those had an order of "presumed full" at admission; however, upon further clarification, the patients expressed that they had wished to be DNR before the hospitalization. We identified 3 additional processes leading to order transition from full code to DNR acute clinical deterioration (15.3%), discontinuation of cancer-directed therapy (17.1%), and education about the potential harms/futility of CPR (15.3%). Compared with discontinuing therapy and education, transitions because of acute clinical deterioration were associated with less patient involvement (P = .002), a shorter time to death (P < .001), and a greater likelihood of inpatient death (P = .005)., Conclusions: One-half of code status order changes among hospitalized patients with advanced cancer were because of full code orders in patients who had a preference for DNR before hospitalization. Transitions due of acute clinical deterioration were associated with less patient engagement and a higher likelihood of inpatient death. Cancer 2017;123:4895-902. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Patients with advanced cancer often experience frequent and prolonged hospitalizations; however, the factors associated with greater health care utilization have not been described. We sought to investigate the relation between patients' physical and psychological symptom burden and health care utilization., Methods: We enrolled patients with advanced cancer and unplanned hospitalizations from September 2014-May 2016. Upon admission, we assessed physical (Edmonton Symptom Assessment System [ESAS]) and psychological symptoms (Patient Health Questionnaire 4 [PHQ-4]). We examined the relationship between symptom burden and healthcare utilization using linear regression for hospital length of stay (LOS) and Cox regression for time to first unplanned readmission within 90 days. We adjusted all models for age, sex, marital status, comorbidity, education, time since advanced cancer diagnosis, and cancer type., Results: We enrolled 1,036 of 1,152 (89.9%) consecutive patients approached. Over one-half reported moderate/severe fatigue, poor well being, drowsiness, pain, and lack of appetite. PHQ-4 scores indicated that 28.8% and 28.0% of patients had depression and anxiety symptoms, respectively. The mean hospital LOS was 6.3 days, and the 90-day readmission rate was 43.1%. Physical symptoms (ESAS: unstandardized coefficient [B], 0.06; P < .001), psychological distress (PHQ-4 total: B, 0.11; P = .040), and depression symptoms (PHQ-4 depression: B, 0.22; P = .017) were associated with longer hospital LOS. Physical (ESAS: hazard ratio, 1.01; P < .001), and anxiety symptoms (PHQ-4 anxiety: hazard ratio, 1.06; P = .045) were associated with a higher likelihood for readmission., Conclusions: Hospitalized patients with advanced cancer experience a high symptom burden, which is significantly associated with prolonged hospitalizations and readmissions. Interventions are needed to address the symptom burden of this population to improve health care delivery and utilization. Cancer 2017;123:4720-4727. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Atrial fibrillation (AF) is frequently observed in patients being treated for cancer and can lead to increased morbidity and mortality in this population. With the use of newer, targeted cancer therapies, several drug-drug interactions have emerged that complicate the use of antiarrhythmic drugs (AADs) in patients with active malignancy. Moreover, specific targeted therapies such as ibrutinib may contribute directly to the development of AF. The decision to pursue systemic anticoagulation can be challenging in patients with malignancy due to a number of factors, including the need for frequent procedures, the presence of malignancy-related risk factors for bleeding, and limited data regarding the safety of the novel oral anticoagulants (NOACs) in cancer patients. This review describes the challenges associated with AF management in patients with cancer and highlights a number of important drug-drug interactions that can impact patient management., (© The Author(s). 2017.)

Purpose: To determine the impact of the establishment of a dedicated oncofertility clinic on the frequency of patient referrals for fertility preservation (FP) consultation and the time from patient referral to consultation., Methods: A retrospective chart review of all women aged 21 to 44 years with an active cancer diagnosis who were referred for FP consultation from 2011 to 2015., Results: A total of 6895 female patients eligible for FP were seen at the Massachusetts General Hospital (MGH) Cancer Center. Of those eligible, a total of 209 patients were referred for FP consultation with 150 included in the final analysis. Since the establishment of the oncofertility clinic, the mean time to nonemergent consultation with a reproductive endocrinologist decreased by 27%, from 10.4 to 7.6 days ( P = .03). Furthermore, the proportion of reproductive-aged females seen at the MGH Cancer Center referred for FP consultation increased from 1.7% to 3.0% ( P < .01)., Conclusion: A dedicated oncofertility clinic increases physician referrals for FP and decreases the mean time to consultation, improving access to FP consultation for reproductive-aged women with cancer., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ephraim Hochberg reports owning stock in Flatiron and Insight and has served as a consultant to those 2 companies, which are unrelated to the subject of this manuscript.

Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers., (© 2016 by The American Society of Hematology.)

Unlabelled: B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We used a novel approach called "pinpointing enhancer-associated rearrangements by chromatin immunoprecipitation," or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a "pseudo-double-hit" t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma., Significance: We demonstrate a novel approach for simultaneous detection of genomic rearrangements and enhancer activity in tumor biopsies. We identify novel mechanisms of enhancer-driven regulation of the oncogenes MYC and BCL6, and show that the BCL6 locus can serve as an enhancer donor in an "enhancer hijacking" translocation., (©2015 American Association for Cancer Research.)

Anthracyclines are an important component of cancer treatments; however, their use is limited by the occurrence of cardiotoxicity. There are limited data on the occurrence of heart failure and the value of baseline and follow-up measurements of left ventricular (LV) ejection fraction (EF) in the current era. Therefore, the objectives of the present study were twofold: (1) to characterize the occurrence of and risk factors for major adverse cardiac events (MACEs: symptomatic heart failure and cardiac death) in a large contemporaneous population of adult patients treated with anthracyclines and (2) to test the value of LVEF and LV dimensions obtained using echocardiography in the prediction of MACE. Five thousand fifty-seven patients were studied, of whom 124 (2.4%) developed MACE. Of the total cohort, 2,285 patients had an available echocardiogram pre-chemotherapy. Patients with MACE were older (p <0.0001), predominantly men (p = 0.03), and with a higher incidence of cardiovascular risk factors and cardiac treatments. Patients with hematologic cancers had a higher incidence of cardiac events than patients with breast cancer (4.2% vs 0.7%, p <0.0001). Baseline LVEF, LVEF ≤5 points above the lower limits of normal, and LV internal diameter were predictive of the rate of occurrence of MACE. In conclusion, older patients with hematologic cancers and patients with a baseline LVEF ≤5 points above the lower limit of normal have higher incidence of MACE and should be closely monitored., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Molecular profiling of central nervous system lymphomas in cerebrospinal fluid (CSF) samples can be challenging due to the paucicellular and limited nature of the samples. Presented herein is a microfluidic platform for complete CSF lymphoid cell analysis, including single cell capture in sub-nanoliter traps, and molecular and chemotherapeutic response profiling via on-chip imaging, all in less than one hour. The system can detect scant lymphoma cells and quantitate their kappa/lambda immunoglobulin light chain restriction patterns. The approach can be further customized for measurement of additional biomarkers, such as those for differential diagnosis of lymphoma subtypes or for prognosis, as well as for imaging exposure to experimental drugs.

Objective: Pathology reports are rich in narrative statements that encode a complex web of relations among medical concepts. These relations are routinely used by doctors to reason on diagnoses, but often require hand-crafted rules or supervised learning to extract into prespecified forms for computational disease modeling. We aim to automatically capture relations from narrative text without supervision., Methods: We design a novel framework that translates sentences into graph representations, automatically mines sentence subgraphs, reduces redundancy in mined subgraphs, and automatically generates subgraph features for subsequent classification tasks. To ensure meaningful interpretations over the sentence graphs, we use the Unified Medical Language System Metathesaurus to map token subsequences to concepts, and in turn sentence graph nodes. We test our system with multiple lymphoma classification tasks that together mimic the differential diagnosis by a pathologist. To this end, we prevent our classifiers from looking at explicit mentions or synonyms of lymphomas in the text., Results and Conclusions: We compare our system with three baseline classifiers using standard n-grams, full MetaMap concepts, and filtered MetaMap concepts. Our system achieves high F-measures on multiple binary classifications of lymphoma (Burkitt lymphoma, 0.8; diffuse large B-cell lymphoma, 0.909; follicular lymphoma, 0.84; Hodgkin lymphoma, 0.912). Significance tests show that our system outperforms all three baselines. Moreover, feature analysis identifies subgraph features that contribute to improved performance; these features agree with the state-of-the-art knowledge about lymphoma classification. We also highlight how these unsupervised relation features may provide meaningful insights into lymphoma classification., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.

Purpose: Breast implant-associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown., Patients and Methods: We reviewed the literature for all published cases of breast implant-associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up., Results: The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively)., Conclusion: Most patients with breast implant-associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.

We conducted a phase 1 trial evaluating the oral nucleoside analog clofarabine in patients with relapsed/refractory non-Hodgkin lymphoma. Patients were treated once daily on days 1 through 21 of a 28-day cycle for a maximum of six cycles. The study was conducted with a 3 + 3 design with 10 additional patients treated at the recommended phase 2 dose. Thirty patients were enrolled including indolent B-cell lymphomas (n = 21), mantle cell lymphoma (n = 6) and diffuse large B-cell lymphoma (n = 3). The primary toxicities were hematologic including grade 3-4 neutropenia (53%) and thrombocytopenia (27%). Three milligrams was determined to be the recommended phase 2 dose. Tumor volume was reduced in 70% of patients, and the overall response rate was 47% including 27% complete remissions. Responses were seen in indolent B-cell lymphomas and mantle cell lymphoma. At a median follow-up of 17 months, 68% of responding patients remain in ongoing remission. Oral clofarabine was well tolerated with encouraging efficacy in indolent B-cell lymphomas and mantle cell lymphomas, warranting further investigation.

This pilot study investigates the value of baseline total lesion glycolysis (TLG) in (18)F-FDG PET/CT scans for prediction of progression-free survival (PFS) in patients with Diffuse Large B-Cell Lymphoma (DLBCL). We also evaluate the role of other quantitative parameters measured at baseline and interim PET/CT for prediction of PFS. A retrospective review (2003-2010) of patients with DLBCL who underwent (18)F-FDG PET/CT before, after cycle two, and after completion of R-CHOP treatment, identified 84 patients. Twenty patients fulfilled the inclusion criteria. Standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), and TLG were measured in baseline and interim PET/CT. Relationship between quantitative parameters and PFS was statistically analyzed using Log-rank test and univariate Cox-regression analysis. Of 20 patients (F/M: 7/13, range: 20-73 years), six patients (30%) developed recurrence after chemotherapy (mean follow-up: 51.35±17.05 months, range: 12-81 months). Results of statistical analysis showed TLG as the only discriminator of recurrence at baseline (cut-point: 704.77 g, HR: 11.21, CI: 1.29-97, P=0.02). Among the interim PET/CT parameters, SUVmean (cut -point: 2.07, HR: 6.31, CI: 1.25-31.61), SUVmax (cut-point: 2.3, HR: 6.31, CI: 1.25-31.61), and TLG (cut-point: 96.5 g, HR: 6.38, CI: 1.29 - 31.61) could all help predict PFS (P<0.05). Although not routinely reported, high baseline TLG may be a useful index to identify patients with DLBCL who are at increased risk for relapse after conventional R-CHOP. If confirmed in larger prospective studies, this may allow the selection of alternate therapeutic choices at the onset of treatment.

Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted.