Anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study.

Chimeric antigen receptor T-cell (CAR-T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B-cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR-T therapy in older patients with RR LBCL in the real-world setting. Patients aged ≥65 years with RR LBCL, treated with anti-CD19 CAR-T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65-89). Best objective and complete response rates were 86% and 62%, respectively. Median follow-up after infusion was 18.3 months. The median progression-free survival (PFS) was 6.9 months, with 6- and 12-month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR-T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR-T in older patients, including those aged ≥80 years. The age at CAR-T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR-T therapy solely based on their chronological age.

Impact of the COVID-19 pandemic on internal medicine training in the United States: results from a national survey.

BACKGROUND: Internal medicine (IM) residency is a notoriously challenging time generally characterized by long work hours and adjustment to new roles and responsibilities. The COVID-19 pandemic has led to multiple emergent adjustments in training schedules to accommodate increasing needs in patient care. The physician training period, in itself, has been consistently shown to be associated with vulnerability with respect to mental well-being. The impact of the COVID-19 pandemic on the experience of IM trainees is not well established. OBJECTIVE: Characterize the impact of the COVID-19 pandemic on trainee clinical education, finances, and well-being. METHODS: We developed a survey composed of 25 multiple choice questions, 6 of which had an optional short-answer component. The survey was distributed by the American College of Physicians (ACP) to 23,289 IM residents and subspecialty fellows. We received 1,128 complete surveys and an additional 269 partially completed surveys. RESULTS: The majority of respondents reported a disruption in their clinical schedule (76%) and a decrease in both didactic conferences (71%) and protected time for education (56%). A majority of respondents (81%) reported an impact on their well-being with an increase in their level of burnout and 41% of respondents reported a decrease in level of direct supervision. Despite these changes, the majority of trainee respondents (78%) felt well prepared for clinical practice after graduation. CONCLUSIONS: These results outline the vulnerable position of internal medicine physicians in training. Preserving educational experiences, adequate supervision, and humane work hours are essential in protecting trainees from mental illness and burnout during global emergencies.

Humoral Immunity After COVID-19 Vaccination in Chronic Lymphocytic Leukemia and Other Indolent Lymphomas: A Single-Center Observational Study.

BACKGROUND: Chronic lymphocytic leukemia (CLL) and other non-Hodgkin's lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers. METHODS: In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab. RESULTS: Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton's tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination. CONCLUSION: Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.

Phase I study of novel SYK inhibitor TAK-659 (mivavotinib) in combination with R-CHOP for front-line treatment of high-risk diffuse large B-cell lymphoma.

Background: TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We report results of a phase I single-institution escalation study of front-line treatment with R-CHOP and TAK-659 in treatment-naïve high-risk DLBCL. Methods: Patients with high-risk DLBCL were treated with R-CHOP for 1 cycle, followed by combined R-CHOP and TAK-659 for an additional five cycles, with TAK-659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK-659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow-up of 21 months, 92% of patients achieved complete response (CR). The most common treatment-emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) is one of the three US FDA-approved chimeric antigen receptor T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). TRANSCEND is the landmark trial that led to the approval of liso-cel in the third-line setting for R/R diffuse LBCL, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B and transformed lymphoma. The TRANSFORM and PILOT studies evaluated the use of liso-cel in the second-line treatment of R/R LBCL. This review details the structure and manufacturing process of liso-cel that make it distinct from other approved chimeric antigen receptor constructs, outlines results from landmark trials of liso-cel in LBCL and discusses liso-cel toxicity.

Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment for large B-cell lymphoma (LBCL). CAR T involves modifying a patient's immune cells (T cells, specifically), so that they can attack cancer cells and destroy them. Lisocabtagene maraleucel (liso-cel) is a type of CAR T-cell therapy that has been approved to treat patients with LBCL who have already received at least one line of treatment for their lymphoma. This article outlines the structure and manufacturing process of liso-cel and discusses how it differs from other approved CAR T-cell therapies. It also summarizes the clinical data for liso-cel in the treatment of LBCL, as well as its safety and expected side effects.

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has changed significantly since the development of oral Bruton's tyrosine kinase (BTK) inhibitors. While chemoimmunotherapy was previously the standard of care for first-line treatment, BTK inhibitors have proven to be a highly effective and safe therapeutic option for CLL/SLL, and now constitute one of the preferred first-line options. Ibrutinib, the first approved covalent BTK inhibitor in CLL/SLL, has the most long-term data supporting its efficacy in CLL/SLL treatment although is associated with increased risk of cardiovascular and hemorrhage adverse events due to off-target kinase inhibition. The second-generation covalent BTK inhibitors, including acalabrutinib and zanubrutinib, are more selective to BTK with less off-target effects. Resistance to covalent BTK inhibitors may emerge over time due to mutations in BTK and downstream kinases. Novel non-covalent BTK inhibitors currently being studied are showing promising activities to overcome such resistance. In this review, we discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.

CAR T-cell therapy for relapsed/refractory non-Hodgkin's lymphoma: a comprehensive review.

Non-Hodgkin lymphoma (NHL) is the seventh most common type of malignancy worldwide, with approximately 544,000 cases diagnosed in 2020.[1-3] The vast majority of NHLs are derived from B cells. The more than 80 subtypes of B-cell NHL are categorized according to their typical clinical course: indolent or aggressive.[4] Aggressive B-cell NHLs that are refractory to first-line therapy or that relapse following initial treatment are historically associated with a poor prognosis, despite the use of salvage chemotherapy and autologous stem cell transplant.[5] The advent of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment paradigm for patients who have relapsed/refractory aggressive B-cell NHL, with impressive response rates and the possibility for a durable remission in those whose disease has progressed despite multiple prior treatments.[6-8] This review outlines current indications for CAR T-cell therapy, major toxicities, novel CARs under investigation, and future directions.

The Matilda Effect: Underrecognition of Women in Hematology and Oncology Awards.

BACKGROUND: The proportion of women in the field of hematology and oncology (H&O) has increased over recent decades, but the representation of women in leadership positions remains poor. In an effort to close the gender gap in academia, it is important to report on such inequities in hopes to close these gaps and improve career development. MATERIALS AND METHODS: We conducted a retrospective, observational study of published award recipients from 1994 to 2019 from the seven major H&O societies in the world. Gender was determined based on publicly available data. The χ2 and Cochran-Armitage tests were used for data analysis. RESULTS: Of the 1,642 awardees over the past 26 years, 915 met inclusion criteria. Award recipients were overwhelmingly men (77.9%) and non-Hispanic White (84.7%). Women awardees received 30.3% of the humanistic and education-related awards, whereas only receiving 16.0% of basic science awards (p < .01). Women represent 35.6% of all hematologists and oncologists but only received 24.0% of awards given to these physicians (p = .004). Black, Hispanic, and Asian awardees represented 3.7%, 3.3%, and 6.8% of the total awardees, respectively. CONCLUSION: From 1994 to 2019, women were less likely to receive recognition awards from the seven major H&O societies studied compared with men. We also observed a considerably low proportion of minority awardees across all oncology subspecialties. Further studies examining how selection criteria favor either gender would be warranted in order to achieve equal representation in academic awards. IMPLICATIONS FOR PRACTICE: In this study, women and minority groups were found to be underrepresented amongst award recipients. Significant disparities were seen in disciplines that have been historically male predominant, such as basic sciences. As awards on an international level enhance academic resumes and assist with career advancement, it is important that awards are being given in an equitable manner. First steps to promote diversity and inclusion in academic medicine is reporting of gender and racial disparities in various areas of academia.

Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies.

Natural killer (NK) cells are lymphocytes that are integral to the body's innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related factors and is critical to subsequent adaptive immune responses against tumor antigens. The aim of this review is to discuss mechanisms by which tumor cells evade NK cells and to outline strategies that harness NK cells for cancer immunotherapy. We discuss strategies to relieve the exhausted state of NK cells, recent therapies focused on targeting NK-cell-specific activating and inhibitory receptors, the use of cytokines IL-2 and IL-15 to stimulate autologous or allogeneic NK cells, and ongoing trials exploring the use of genetically modified NK cells and chimeric antigen-receptor-modified NK (CAR-NK) cells.

Fluorodeoxyglucose-Positron Emission Tomography Predicts Bone Marrow Involvement in the Staging of Follicular Lymphoma.

BACKGROUND: Standard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard. MATERIALS AND METHODS: A total of 548 patients with newly diagnosed grade 1-3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report. RESULTS: Excluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%. CONCLUSION: In newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (<2.0 SUVmax and < 1.4 SUVmean ) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET. IMPLICATIONS FOR PRACTICE: Predicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Nuances of the Female Nurse-Physician Relationship: An Evolution Across Time.

Gender bias in academic medicine is increasingly recognized as a widespread phenomenon and has generated substantial research and discussion in recent years. Gender bias goes beyond leadership positions and financial compensation and extends to interprofessional relationships, including relationships with allied staff. Few studies have examined the female nurse-physician relationship, and the goal of this review is to consolidate the existing evidence and gaps in the literature with regard to this dyad. A literature search was conducted through MEDLINE, EMBASE, CINAHL, PubMed, and Google Scholar, and 13 pertinent articles were identified for inclusion in this review. Earlier studies found that female physicians and nurses generally reported improved communication and increased satisfaction when both parties were female. Over the years, several studies have emerged suggesting that the female nurse-physician relationship in fact presents with some challenges. Recent studies have found that female physicians often feel they do not receive the same level of assistance or respect from female nurses and have more difficulty communicating with them compared with male physicians. These results were reproduced in several quantitative and qualitative studies across multiple countries. The reported female nurse perspective of this relationship has been overall more positive, but recent studies have had a stronger focus on the physician perspective. Several hypotheses are discussed as to why such an evolution has occurred in the female nurse-physician relationship. There continue to be important gaps in the literature, including more in-depth evaluations of the female nurse perspective and investigation of the male perspective of the nurse-physician relationship.

Diagnosis of hypothenar hammer syndrome in a patient with acute ulnar artery occlusion.

A 56-year-old truck driver with a history of tobacco use presented with acute onset digital ischaemia in the ulnar distribution of his dominant hand, associated with severe pain. Occupational exposures included extensive manual labour and prolonged vibratory stimuli. Workup with Doppler and angiography confirmed the diagnosis of hypothenar hammer syndrome (HHS). After the failure of medical management, he underwent ulnar artery thrombectomy with reconstruction and arterial bypass grafting. His pain improved significantly postsurgically, and he was able to return to a normal routine. This case illustrates the classic presentation, examination, imaging findings and management options of HHS. HHS should be considered in patients with digital ischaemia and associated occupational exposures. Diagnosing the condition appropriately allows for optimal management, aiming at minimising symptoms and maximising quality of life.

Detection of extranodal and spleen involvement by FDG-PET imaging predicts adverse survival in untreated follicular lymphoma.

Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. This study aimed to determine the incidence and patterns of extranodal (EN) and spleen disease using PET/CT, and assess their utility in predicting early clinical failure. PET/CT images from 613 cases of untreated FL (2003-2016) were reviewed. The location and number of EN sites, patterns of bone involvement, and splenic involvement were recorded. Outcomes were assessed using event-free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24). So, 49% (301/613) of patients had PET/CT-detected EN involvement, and 28% (171/613) had spleen involvement. The presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. Presence of ≥2 EN sites and bone involvement pattern were also predictive of OS in a univariate analysis. In a multivariate analysis with FLIPI-2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (HR 1.49 (1.11-2.00), P = .007; HR 1.71 (1.10-2.65), P = .017; and HR 1.67 (1.06-2.62), P = .026, respectively). When the multivariate analysis was performed using PRIMA-PI factors (marrow and B2M), the number of EN sites was an independent prognostic factor for inferior OS (HR 2.28; P = .05). Baseline PET/CT identifies EN involvement in nearly half of patients with untreated FL. The presence of ≥2 EN sites, bone, soft tissue, or splenic involvement predicts early clinical failure. These results, when combined with other factors, may better identify high-risk patients and guide therapy.

Gestational diabetes and risk of cardiovascular disease up to 25 years after pregnancy: a retrospective cohort study.

AIMS: The risk of cardiovascular disease in women with gestational diabetes is poorly understood. We sought to determine whether gestational diabetes increases the risk of cardiovascular disease more than two decades after pregnancy. METHODS: We carried out a retrospective cohort study of 1,070,667 women who delivered infants in hospitals within Quebec, Canada, between 1989 and 2013. We followed 67,356 women with gestational diabetes and 1,003,311 without gestational diabetes for a maximum of 25.2 years after the index delivery. The main outcome measures were hospitalization for ischemic heart disease, myocardial infarction, coronary angioplasty, coronary artery bypass graft, and other cardiovascular disorders. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) comparing women with gestational diabetes to no gestational diabetes, adjusted for age, parity, socioeconomic deprivation, time period, and preeclampsia. RESULTS: Women with gestational diabetes had a higher cumulative incidence of hospitalization for cardiovascular disease 25 years after delivery (190.8 per 1000 women) compared with no gestational diabetes (117.8 per 1000 women). Gestational diabetes was associated with a higher risk of ischemic heart disease (HR 1.23, 95% CI 1.12-1.36), myocardial infarction (HR 2.14, 95% CI 1.15-2.47), coronary angioplasty (HR 2.23, 95% CI 1.87-2.65), and coronary artery bypass graft (HR 3.16, 95% CI 2.24-4.47). CONCLUSIONS: In this population of pregnant women, gestational diabetes was associated with an increased risk of heart disease 25 years after delivery. Women with gestational diabetes may merit closer monitoring for cardiovascular disease prevention after pregnancy.