Impact of Thiotepa-Based Autologous Hematopoietic Cell Transplantation in Primary Central Nervous System Lymphoma in First Complete Remission: A University of California Hematologic Malignancies Consortium Retrospective Analysis.

BACKGROUND: The choice between nonmyeloablative chemotherapy (NMA-C) or autologous hematopoietic cell transplantation (autoHCT) as consolidation in primary central nervous system lymphoma (PCNSL), and timing of autoHCT differs among centers. We aimed to clarify these points. METHODS: We retrospectively analyzed PCNSL adult patients who received consolidation in CR1 or underwent autoHCT during their treatment course. Cohort A included those who underwent autoHCT in CR1, cohort B included those who underwent NMA-C in CR1, and cohort C included patients who underwent autoHCT in CR2+. We compared cohorts A and B, and cohorts A and C. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), treatment-related mortality (TRM) and cumulative incidence of relapse (CIR). RESULTS: 36 patients were included in cohort A, 30 in cohort B, and 14 in cohort C. The 5-year OS for cohorts A vs B and vs C were 90.7% vs 62.8% (P = .045) and vs 77.9% (P = .32), respectively. The 5-year PFS from diagnosis for cohorts A vs B was 87.8% vs 37.3% (P < .001). The 5-year PFS from autoHCT for cohorts A vs C was 87.6% vs 58.4% (P = .023). The 5-year TRM and CIR in cohorts A vs B was 9.4% vs 9.5% (P = .674), and 2.9% vs 53.2% (P < .001), respectively. The 5-year TRM and CIR in cohorts A vs C from the time of autoHCT was 9.5% vs 22.1% (P = .188), and 2.9% vs 19.5% (P = .104), respectively. CONCLUSION: Despite the limitations, thiotepa-based autoHCT in CR1 appears to improve outcomes in eligible patients with PCNSL.

Fosmanogepix Therapy of Disseminated Fusarium Infection.

Invasive Fusarium infections cause high mortality. Fosmanogepix, a first-in-class antifungal agent, has potent activity against Fusarium. A patient with acute leukemia with invasive fusariosis, probably involving the central nervous system and caused by Fusarium lactis resistant to currently available antifungal agents, was cured of her infection with fosmanogepix. Fosmanogepix was well tolerated.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Investigation of Combination Treatment With an Aromatase Inhibitor Exemestane and Carboplatin-Based Therapy for Postmenopausal Women With Advanced NSCLC.

INTRODUCTION: Estrogen receptors (ER) (ERα, ERß) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single-center study evaluated the safety and tolerability of escalating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in postmenopausal women with stage IV nonsquamous NSCLC. METHODS: Patients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg × min/mL) and pemetrexed (500 mg/m2) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone. RESULTS: A total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to-treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associated with aromatase expression (p = 0.02). Circulating estrogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events. CONCLUSIONS: The combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy.

B-cell lymphomas associated with breast implants: Report of three cases and review of the literature.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen.

BACKGROUND: High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results. PATIENTS AND METHODS: A retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1). RESULTS: The 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL. CONCLUSION: HDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.

Cardiac Complications in the Adult Bone Marrow Transplant Patient.

PURPOSE OF REVIEW: Due to advancements in oncologic treatment strategies and techniques, the number of survivors who have undergone hematopoetic stem cell transplant (HCT) continues to increase in the United States; this number is projected to reach 502,000 by the year 2030. There is significant interest within the field of cardio-oncology to identify cardiotoxicity and cardiovascular disease in the HCT population. Epidemiologic studies analyzing both short- and long-term cardiovascular effects, risk stratification modeling, cardioprotective strategies, and expert consensus documents for cardiotoxicity surveillance recommendations are reviewed. RECENT FINDINGS: Patients who have undergone HCT are at increased risk of cardiovascular events and mortality compared to matched controls. The type of cardiotoxicity and the incidence rates vary based on specific therapeutic regimens and pre-existing cardiovascular risk factors. Life-threatening cardiotoxicity can present during HCT as acute heart failure, arrhythmias, pericardial tamponade, or cardiac arrest; or it can present late after treatment as cardiomyopathy, ischemic heart disease, vascular disease, stroke, or comorbid conditions, such as hypertension and diabetes mellitus that are associated with cardiac events. HCT is associated with excess cardiovascular risk partially due to exposure to cardiotoxic chemotherapy and radiation, as well as indirect and direct detrimental effects on cardiovascular reserve. This review discusses the epidemiology and the known cardiotoxic effects of historical chemoradiation agents in addition to newer targeted therapies. Recent expert consensus statements from cardiology and hematology/oncology societies are reviewed in regard to risk stratification of the cancer patient based on the type of treatments. Finally, gaps in knowledge are identified with proposed avenues of research that will allow for more accurate risk assessment, prediction, and potential treatment of the HCT patient in attenuating the risk of developing both short- and long-term cardiovascular comorbidities.

Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer.

OBJECTIVES: This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS). RESULTS: Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52-1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57-1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35-1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1-2 dermatologic and gastrointestinal adverse effects. CONCLUSION: Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.

Activity of Anti-CD19 Chimeric Antigen Receptor T Cells Against B Cell Lymphoma Is Enhanced by Antibody-Targeted Interferon-Alpha.

An important emerging form of immunotherapy targeting B cell malignancies is chimeric antigen receptor (CAR) T cell therapy. Despite encouraging response rates of anti-CD19 CAR T cell therapy in B cell lymphomas, limited durability of response necessitates further study to potentiate CAR T cell efficacy. Antibody-targeted interferon (IFN) therapy is a novel approach in immunotherapy. Given the ability of IFNs to promote T cell activation and survival, target cell recognition, and cytotoxicity, we asked whether antibody-targeted IFN could enhance the antitumor effects of anti-CD19 CAR T cells. We produced an anti-CD20-IFN fusion protein containing the potent type 1 IFN isoform alpha14 (α14), and demonstrated its ability to suppress proliferation and induce apoptosis of human B cell lymphomas. Indeed, with the combination of anti-CD20-hIFNα14 and CAR T cells, we found enhanced cell killing among B cell lymphoma lines. Importantly, for all cell lines pretreated with anti-CD20-hIFNα14, the subsequent cytokine production by CAR T cells was markedly increased regardless of the degree of cell killing. Thus, several activities of CD19 CAR T cells were enhanced in the presence of anti-CD20-hIFNα14. These data suggest that antibody-targeted IFN may be an important novel approach to improving the efficacy of CAR T cell therapy.

Revisiting Young Children's Understanding of the Psychological Causes of Behavior.

In 1989, Miller and Aloise challenged the prevailing belief that preschoolers tend to explain others' behavior in terms of external events or a person's physical attributes and have little understanding of psychological causes. That review documented preschoolers' understanding of, and even preference for, psychological causes as part of an emerging renaissance in developmental social-cognitive research. The present, updated review (97 articles, participant ages 3 months to 6 years) suggests the emergence of a transformative new perspective in which social-cognition is balanced between social and cognitive aspects rather than tilted toward cognition. Recent research on infants' awareness of mental states, young children's understanding of social categories and their judgments of the trustworthiness of informants, and cultural context reveals various ways in which preschoolers' social-causal reasoning is social.

A Longitudinal Examination of the Relation Between Internalizing Problem Behaviors and Early Adolescent Cigarette Smoking.

OBJECTIVE: The purpose of the present study was to investigate the longitudinal relation between internalizing problem behaviors (measured with the anxious/depressed and somatic complaints subscales of the Achenbach Teacher's Report Form) and self-reported cigarette smoking behavior and intentions during early adolescence. In addition, a possible mediating role of perceived harm was investigated. METHODS: Sixth graders and their teachers were surveyed in the sixth grade and students were surveyed again in the seventh grade. Smoking behavior and intentions were assessed with five items including lifetime use, 30-day use, tobacco user status (nonsmoker to heavy smoker), and two intentions/behavioral expectations items. In addition to perceived harm from smoking, reasons for smoking and reasons for not smoking were included on the survey. RESULTS: As hypothesized, teacher reports of sixth-grade internalizing problem behaviors were negatively related to seventh-grade smoking behavior and intentions. Moreover, perceived harm from smoking was negatively related to smoking and intentions. The hypothesized mediating role of perceived harm in the internalizing to smoking relationship was not supported. CONCLUSIONS: Potential differences in the relation between internalizing and smoking across adolescence are discussed. Specifically, the results of the present study and an examination of prior literature suggest that in early adolescence internalizing problems are negatively related to cigarette smoking, whereas in middle and late adolescence the opposite is true.

Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1): IDENTIFICATION OF CLUSTER IV ON LRP1 AS THE MAJOR BINDING SITE.

Hemophilia A is a bleeding disorder caused by a deficiency in coagulation factor VIII (fVIII) that affects 1 in 5,000 males. Current prophylactic replacement therapy, although effective, is difficult to maintain due to the cost and frequency of injections. Hepatic clearance of fVIII is mediated by the LDL receptor-related protein 1 (LRP1), a member of the LDL receptor family. Although it is well established that fVIII binds LRP1, the molecular details of this interaction are unclear as most of the studies have been performed using fragments of fVIII and LRP1. In the current investigation, we examine the binding of intact fVIII to full-length LRP1 to gain insight into the molecular interaction. Chemical modification studies confirm the requirement for lysine residues in the interaction of fVIII with LRP1. Examination of the ionic strength dependence of the interaction of fVIII with LRP1 resulted in a Debye-Hückel plot with a slope of 1.8 ± 0.5, suggesting the involvement of two critical charged residues in the interaction of fVIII with LRP1. Kinetic studies utilizing surface plasmon resonance techniques reveal that the high affinity of fVIII for LRP1 results from avidity effects mediated by the interactions of two sites in fVIII with complementary sites on LRP1 to form a bivalent fVIII·LRP1 complex. Furthermore, although fVIII bound avidly to soluble forms of clusters II and IV from LRP1, only soluble cluster IV competed with the binding of fVIII to full-length LRP1, revealing that cluster IV represents the major fVIII binding site in LRP1.

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation: CRITICAL ROLES OF LYSINES 60 AND 191.

The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor.

Sustaining the Effects of Gatekeeper Suicide Prevention Training.

Background: Gatekeeper training is a promising suicide prevention strategy that is growing in popularity. Although gatekeeper training programs have been found to improve trainee knowledge, self-efficacy, and perceived skills, researchers have found that the benefit of gatekeeper training may not last over time. Aims: The purpose of this study was to identify strategies for strengthening the long-term effects of suicide prevention gatekeeper training. Method: In-depth interviews and focus groups were conducted with gatekeepers (N = 44) and data were analyzed using a qualitative research approach. Results: The results of this study suggest that posttraining interventions may be more effective if they include the following seven themes: (a) social network - connecting with other gatekeepers; (b) continued learning - further education; (c) community outreach - building awareness; (d) accessibility - convenience; (e) reminders - ongoing communication; (f) program improvement -- enhancing previous training; and (g) certification - accreditation. Conclusion: Posttraining interventions that incorporate the themes from this study offer a promising direction in which to sustain the effects of gatekeeper suicide prevention training.

Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.

The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, ß, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results.

Using motives for smoking to distinguish between different college student smoker typologies.

Relatively little is known about how to categorize different types of smokers, especially occasional smokers. Because of the prevalence of occasional smoking among college students, the current study aimed to gain an understanding of the different typologies of smokers on campus. To accomplish this, a latent class analysis (LCA) was conducted using 17 motives for smoking items (N = 327). The LCA revealed that four smoker groups were present: (1) addicted smokers who endorsed smoking due to pleasure and habit/addiction; (2) stress smokers, who endorsed smoking to relax, to reduce levels of stress, and to regulate mood; (3) social smokers, who endorsed smoking because of social factors such as to fit in or because friends smoke; and (4) nonendorsing smokers, who had a low endorsement for all the items. An additional LCA with covariates revealed that age of initiation, current smoking patterns, smoker self-classification, and quit likelihood differentiated these groups of smokers whereas current age and alcohol use did not. These typologies should be considered when designing interventions for occasional smokers.

Using Peer Injunctive Norms to Predict Early Adolescent Cigarette Smoking Intentions.

The present study investigated the importance of the perceived injunctive norm to predict early adolescent cigarette smoking intentions. A total of 271 6th graders completed a survey that included perceived prevalence of friend smoking (descriptive norm), perceptions of friends' disapproval of smoking (injunctive norm), and future smoking intentions. Participants also listed their five best friends, in which the actual injunctive norm was calculated. Results showed that smoking intentions were significantly correlated with the perceived injunctive norm but not with the actual injunctive norm. Secondly, the perceived injunctive norm predicted an additional 3.4% of variance in smoking intentions above and beyond the perceived descriptive norm. These results demonstrate the importance of the perceived injunctive norm in predicting early adolescent smoking intentions.