Palliative care for older adults with cardiovascular disease.

Heart disease is the number one cause of death in the United States. Advanced cardiac conditions, such as heart failure, are characterized by severe symptoms, recurrent hospitalizations, limited/uncertain prognosis, decreased quality of life, and high levels of caregiver burden. The burden of heart failure is highest in older adults, for whom cardiovascular symptoms are layered on existing age-related problems such as geriatric syndromes, polypharmacy, depression, frailty, inadequate social support, decreased representation in clinical trials, and aging caregivers. Deliberate integration of outpatient and interdisciplinary geriatrics, palliative care, and cardiovascular care are essential for this special population. Life-prolonging and quality of life-focused approaches to managing cardiovascular disease are not mutually exclusive; many cardiology medications and treatments prolong life while also improving symptom burden. Symptom management, a cornerstone of palliative care, is therefore not only complementary to life-prolonging cardiology treatments, but also integral to optimized daily cardiovascular care. In this review, we aim to summarize relevant literature and provide practical tools that can be used by primary care clinicians, geriatricians, cardiologists and palliative care clinicians to optimize holistic outpatient care for adults who are aging with heart disease. While palliative care is appropriate for any age or stage of illness, we will focus on older adults with heart disease, and the nuances of managing their symptoms, goals of care, and quality of life.

Peripheral T-cell lymphoma: Are all patients high-risk?

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell neoplasms that represent approximately 10% of all non-Hodgkin Lymphoma (NHL). Outcomes for the majority of patients with PTCL are poor and treatment approaches have been relatively uniform using CHOP based therapy. For example, large registry studies consistently demonstrate 5-year overall survival (OS) of approximately 30-40%. However, as our understanding of the biology underpinning the heterogeneity of PTCL improves, and as treatments specifically for PTCL are developed, risk stratification has become a more relevant question. Tools including positron emission tomography-computed tomography (PET-CT) and minimal residual disease (MRD) monitoring offer the potential for dynamic risk stratification. In this review, we will first summarize registry data describing outcomes in the most common subtypes of PTCL - PTCL not otherwise specified (PTCL-NOS), nodal T-follicular helper cell lymphoma including angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). We will describe current clinically based prognostic indices validated in PTCL and then highlight emerging tools for prognostication including novel molecular biomarkers, imaging-based metrics, and MRD dynamics.

Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further.

Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study.

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.

Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.

Patterns of Utilization and Outcomes of Autologous Stem Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Diffuse Large B-cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements.

BACKGROUND: Patients with Diffuse Large Bcell Lymphoma (DLBCL) with MYC and BCL2 and/or BCL6 gene rearrangements [double-hit lymphoma/triple-hit lymphoma (DHL/THL)] have poor prognosis in the relapsed/refractory setting. METHODS: We utilized a real-world deidentified database of DLBCL patients and report patterns of therapy utilization in relapsed/refractory DLBCL. We used log-rank test to compare real-world overall survival (rwOS) among DHL and non-DHL subgroups for CAR Tcell therapy or ASCT respectively, stratified for prior lines of therapy. RESULTS: Of all 7,877 patients with DLBCL, 367 patients had DHL while 6113 had non-DHL. Second line chemotherapy was administered to 147 DHL patients and 1517 non-DHL. 1393 were excluded, including 934 with unknown DHL/THL status. Approximately 47% received salvage intent chemotherapy in the DHL subgroup, of which 19% patients eventually received ASCT, while 34% received salvage intent chemotherapy in the non-DHL/THL group with 32% receiving ASCT. DHL/THL status negatively influenced median rwOS for patients who underwent ASCT in the second-line while it was associated with numerically inferior but without statistically significant rwOS among patients that underwent CAR Tcell therapy on multivariable analysis. CONCLUSION: rwOS of relapsed DHL/THL is inferior to non-DHL/THL. Fewer patients with DHL/THL were able to proceed with ASCT after salvage chemotherapy compared to non-DHL/THL. ASCT as second-line therapy for relapsed DHL/THL had worse rwOS than for non-DHL/THL, consistent with the natural history of DHL/THL. This difference was not seen for CAR Tcell therapy, which combined with promising results from clinical trials, suggests a greater role for CAR T-cell therapy in relapsed/refractory DHL.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Evaluating real-world treatment patterns and outcomes of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is considered incurable with the available chemoimmunotherapy approaches, and therefore, newer effective targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors are increasingly used in MCL as chronic suppressive therapy, especially in the elderly. We aimed to describe the treatment patterns in MCL at different lines of therapy with a focus on BTK inhibitor use and compare outcomes with known prognostic factors using a nationwide Flatiron Health electronic health record-derived de-identified database. We analyzed patient-level data from the period of 2011 to 2021. In this study of 4336 patients with MCL, we found that bendamustine plus rituximab chemotherapy was the most commonly used frontline regimen (42%). Maintenance rituximab or consolidative autologous stem cell transplant (ASCT) was administered to 31% of all patients. Also, for patients who received ASCT as consolidation therapy, only 34% subsequently received rituximab maintenance. BTK inhibitors were the most preferred agents in second or later lines of therapy (n = 933, 57%), followed by bortezomib, lenalidomide, and venetoclax, respectively. Among patients treated with BTK inhibitors, the median real-world overall survival (rwOS) was 35 months (95% confidence interval [CI], 27-50), 24 months (95% CI, 22-30), and 18 months (95% CI, 14-21) for first line, second line, and third or later line of therapy, respectively. Patients with a deletion 17p/TP53 mutation and blastoid variant MCL had poor outcomes; however, BTK inhibitors appeared to mitigate the negative influence of del17p/TP53-mutated MCL with a hazard ratio of 1.17 (95% CI, 0.88-1.55) on multivariable analysis.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Enhanced Efficacy and Increased Long-Term Toxicity of CNS-Directed, AAV-Based Combination Therapy for Krabbe Disease.

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC) and the progressive accumulation of the toxic metabolite psychosine. We showed previously that central nervous system (CNS)-directed, adeno-associated virus (AAV)2/5-mediated gene therapy synergized with bone marrow transplantation and substrate reduction therapy (SRT) to greatly increase therapeutic efficacy in the murine model of Krabbe disease (Twitcher). However, motor deficits remained largely refractory to treatment. In the current study, we replaced AAV2/5 with an AAV2/9 vector. This single change significantly improved several endpoints primarily associated with motor function. However, nearly all (14/16) of the combination-treated Twitcher mice and all (19/19) of the combination-treated wild-type mice developed hepatocellular carcinoma (HCC). 10 out of 10 tumors analyzed had AAV integrations within the Rian locus. Several animals had additional integrations within or near genes that regulate cell growth or death, are known or potential tumor suppressors, or are associated with poor prognosis in human HCC. Finally, the substrate reduction drug L-cycloserine significantly decreased the level of the pro-apoptotic ceramide 18:0. These data demonstrate the value of AAV-based combination therapy for Krabbe disease. However, they also suggest that other therapies or co-morbidities must be taken into account before AAV-mediated gene therapy is considered for human therapeutic trials.

A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.

Brentuximab Vedotin in the Treatment of Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma.

PURPOSE OF REVIEW: The recent development of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30-positive cells, has led to therapeutic advances in the treatment of T cell lymphomas. In this review, we discuss key studies of BV in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) and highlight important questions for further investigation. RECENT FINDINGS: Monotherapy with BV has proven to be effective and well tolerated in patients with relapsed/refractory (R/R) CD30-positive CTCL. BV has shown significant activity in R/R PTCL as well, with particularly durable responses in patients with anaplastic large cell lymphoma (ALCL). In a landmark phase III study (ECHELON-2), BV + CHP demonstrated superior progression-free and overall survival relative to CHOP as frontline therapy for patients with CD30-expressing PTCL, representing the first randomized trial demonstrating an overall survival benefit in PTCL. Though BV is overall well tolerated, peripheral neuropathy remains a clinically significant adverse effect. BV is a major therapeutic advance in the treatment of patients with R/R CTCL and of those with PTCL in both the R/R and frontline settings. Key ongoing areas of investigation include optimization of CD30 expression as a predictive biomarker as well as the role of BV in consolidation therapy.

Choosing induction chemotherapy in therapy-related acute myeloid leukemia.

Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.

Primary Bone Marrow Diffuse Large B-cell Lymphoma Presenting as Transverse Myelitis.

Primary bone marrow diffuse large B-cell lymphoma (BM-DLBCL) is uncommon, with prior reports largely limited to small case series. Here we report the case of a patient who presented with neurologic deficits consistent with acute transverse myelitis and was found to have DLBCL isolated to the bone marrow. We follow this case with a review of the literature summarizing 107 reported cases of BM-DLBCL. Consistent with our case, literature review indicates that BM-DLBCL is characterized by (1) frequent presentation with cytopenias and B symptoms (2) predominant non-germinal center phenotype and (3) aggressive disease with high International Prognostic Index score and low overall survival, with a median survival of 10.0 months in our cohort.

Early-Life Diet Affects Host Microbiota and Later-Life Defenses Against Parasites in Frogs.

Food resources can affect the health of organisms by altering their symbiotic microbiota and affecting energy reserves for host defenses against parasites. Different diets can vary in their macronutrient content and therefore they might favor certain bacterial communities of the host and affect the development and maintenance of the immune system, such as the inflammatory or antibody responses. Thus, testing the effect of diet, especially for animals with wide diet breadths, on host-associated microbiota and defenses against parasites might be important in determining infection and disease risk. Here, we test whether the early-life diet of Cuban tree frogs (Osteopilus septentrionalis) affects early- and later-life microbiota as well as later-life defenses against skin-penetrating, gut worms (Aplectana hamatospicula). We fed tadpoles two ecologically common diets: a diet of conspecifics or a diet of algae (Arthrospira sp.). We then: (1) characterized the gut microbiota of tadpoles and adults; and (2) challenged adult frogs with parasitic worms and measured host resistance (including the antibody-mediated immune response) and tolerance of infections. Tadpole diet affected bacterial communities in the guts of tadpoles but did not have enduring effects on the bacterial communities of adults. In contrast, tadpole diet had enduring effects on host resistance and tolerance of infections in adult frogs. Frogs that were fed a conspecific-based diet as tadpoles were more resistant to worm penetration compared with frogs that were fed an alga-based diet as tadpoles, but less resistant to worm establishment, which may be related to their suppressed antibody response during worm establishment. Furthermore, frogs that were fed a conspecific-based diet as tadpoles were more tolerant to the effect of parasite abundance on host mass during worm establishment. Overall, our study demonstrates that the diet of Cuban tree frog tadpoles affects the gut microbiota and defenses against parasitic gut worms of frogs, but these effects depend on the stage of the host and infection, respectively.

Association of trainee participation with adenoma and polyp detection rates.

AIM: To investigate whether adenoma and polyp detection rates (ADR and PDR, respectively) in screening colonoscopies performed in the presence of fellows differ from those performed by attending physicians alone. METHODS: We performed a retrospective review of all patients who underwent a screening colonoscopy at Grady Memorial Hospital between July 1, 2009 and June 30, 2015. Patients with a history of colon polyps or cancer and those with poor colon preparation or failed cecal intubation were excluded from the analysis. Associations of fellowship training level with the ADR and PDR relative to attendings alone were assessed using unconditional multivariable logistic regression. Models were adjusted for sex, age, race, and colon preparation quality. RESULTS: A total of 7503 colonoscopies met the inclusion criteria and were included in the analysis. The mean age of the study patients was 58.2 years; 63.1% were women and 88.2% were African American. The ADR was higher in the fellow participation group overall compared to that in the attending group: 34.5% vs 30.7% (P = 0.001), and for third year fellows it was 35.4% vs 30.7% (aOR = 1.23, 95%CI: 1.09-1.39). The higher ADR in the fellow participation group was evident for both the right and left side of the colon. For the PDR the corresponding figures were 44.5% vs 40.1% (P = 0.0003) and 45.7% vs 40.1% (aOR = 1.25, 95%CI: 1.12-1.41). The ADR and PDR increased with increasing fellow training level (P for trend < 0.05). CONCLUSION: There is a stepwise increase in ADR and PDR across the years of gastroenterology training. Fellow participation is associated with higher adenoma and polyp detection.

Concomitant imatinib and ibrutinib in a patient with chronic myelogenous leukemia and chronic lymphocytic leukemia.

The availability of kinase and other small-molecule inhibitors to treat hematologic malignancies is increasing. Accordingly, novel regimens that employ these therapeutics are rapidly evolving. Herein we report the safe and effective administration of two targeted kinase inhibitors in a patient with concomitant chronic myelogenous leukemia and chronic lymphocytic leukemia.

Mechanism-based combination treatment dramatically increases therapeutic efficacy in murine globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations.