Novel Approaches to Managing Patients with Relapsed and Refractory Waldenström Macroglobulinemia.

PURPOSE OF REVIEW: Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents. RECENT FINDINGS: Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course.

Multi-omics analysis in IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation.

Currently, the role of DNA methylation in the IgM-monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multi-omics prospective analysis was conducted integrating DNA methylation, RNA-seq and WES data in 34 subjects [23 WM, 6 IgM-MGUS, 5 normal controls]. Analysis was focused on defining differences between IgM-gammopathies (WM/IgM-MGUS) compared to controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions which were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of CXCR4 signaling pathway along with several interleukin (IL-6, IL-8, IL15) signaling pathways in WM compared to IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM-gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

Clinical implications of frailty assessed in hospitalized patients with acute-exacerbation of interstitial lung disease.

BACKGROUND: Approximately 50% of patients with interstitial lung disease (ILD) experience frailty, which remains unexplored in acute exacerbations of ILD (AE-ILD). A better understanding may help with prognostication and resource planning. We evaluated the association of frailty with clinical characteristics, physical function, hospital outcomes, and post-AE-ILD recovery. METHODS: Retrospective cohort study of AE-ILD patients (01/2015-10/2019) with frailty (proportion ≥0.25) on a 30-item cumulative-deficits index. Frail and non-frail patients were compared for pre- and post-hospitalization clinical characteristics, adjusted for age, sex, and ILD diagnosis. One-year mortality, considering transplantation as a competing risk, was analysed adjusting for age, frailty, and Charlson Comorbidity Index (CCI). RESULTS: 89 AE-ILD patients were admitted (median: 67 years, 63% idiopathic pulmonary fibrosis). 31 were frail, which was associated with older age, greater CCI, lower 6-min walk distance, and decreased independence pre-hospitalization. Frail patients had more major complications (32% vs 10%, p = .01) and required more multidisciplinary support during hospitalization. Frailty was not associated with 1-year mortality (HR: 0.97, 95%CI: [0.45-2.10]) factoring transplantation as a competing risk. CONCLUSIONS: Frailty was associated with reduced exercise capacity, increased comorbidities and hospital complications. Identifying frailty may highlight those requiring additional multidisciplinary support, but further study is needed to explore whether frailty is modifiable with AE-ILD.

MicroRNA and long non-coding RNA analysis in IgM monoclonal gammopathies reveals epigenetic influence on cellular functions and oncogenesis.

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BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma-Directed Therapy.

INTRODUCTION: BRCA1-associated ataxia-telangiectasia-mutated activator-1 (BRAT1) is responsible for cell cycle surveillance and mitochondrial function. The implications of adult-onset BRAT1-variant and the resulting phenotypic neurocognitive and imaging features have not been previously described. CASE REPORT: A 66-year-old man with a recent diagnosis of classic Hodgkin lymphoma was referred to neuro-oncology for cognitive and motor decline, and progressive cerebral white matter changes noted on magnetic resonance imaging (MRI). A neurological examination revealed global weakness, broad-based gait, and bilateral extensor plantar responses. Brain MRI demonstrated periventricular, deep, and subcortical white matter T2/FLAIR hyperintensities without contrast enhancement. Cerebral spinal fluid studies were unremarkable. A GeneDX genetic leukodystrophy panel conduction revealed a pathogenic variant (c.294dupA; p.L99TfsX92) resulting in a truncated protein of BRAT1, along with a variant of uncertain significance (c.746A>G;p.E249G). A presumptive diagnosis of late-onset leukoencephalopathy secondary to the BRAT1 variant was made. In an attempt to combat his mitochondrial dysfunction, he was initiated on a mitochondrial cocktail, including B-100 complex and coenzyme Q10. He began lymphoma-directed combination chemotherapy and developed precipitous functional decline after 2 cycles of therapy. Compared with prechemotherapy imaging, repeat positron emission tomography/computed tomography metabolic imaging showed a response after 3 cycles of chemotherapy; however, repeat brain MRI showed worsening diffuse white matter hyperintensities and cerebral atrophy. CONCLUSION: Given the variability in phenotypes and clinical onset, leukodystrophies can be a diagnostic challenge. This case demonstrated progressive BRAT1-associated leukodystrophy exacerbated by chemotherapy-induced toxic leukoencephalopathy. Mitochondrial energy deficiency in the context of multiple metabolic insults was likely underlying the progressive neurological decline observed in this case of genetic leukodystrophy.

SOHO State of the Art Updates and Next Questions | From Biology to Therapy: Progress in Hodgkin Lymphoma.

Classic Hodgkin lymphoma (HL) is a unique lymphoid malignancy where the malignant cells comprise only 1% to 2% of the total tumor cellularity. Over the past 2 decades, the treatment of HL has evolved drastically based on the advent of novel targeted therapies. Novel agents including programmed death-1 (PD-1) inhibitors, antibody-drug conjugates such as brentuximab vedotin, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapies have served to shape the management of HL in the frontline as well as the relapsed and refractory (R/R) setting. Some of these agents have been incorporated into treatment algorithms, while others are currently under investigation demonstrating promising results. This review focuses on highlighting the underlying tumor biology forming the basis of therapeutics in HL, and reviews some of the emerging and established novel therapies.

Symptoms and disease severity in lung transplant candidates co-managed with palliative care.

BACKGROUND: Lung transplant (LTx) candidates experience significant respiratory symptoms often necessitating palliative care (PC) support. We aimed to describe symptoms experienced by interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) LTx candidates referred for PC using the Edmonton Symptom Assessment System (ESAS) and to assess the change in ESAS in relation to pre-LTx exercise capacity, oxygen requirements, and respiratory exacerbations. Understanding symptom trajectory of these two patient groups will help inform PC management. METHODS: Single centre, retrospective cohort of 102 ILD and 24 COPD LTx candidates who were assessed in the Toronto Transplant PC Clinic (TPCC) from 2014-2017. Chi-square and t-tests were used to compare clinical characteristics, physiological parameters, and ESAS scores. RESULTS: The most common symptom in ILD and COPD patients was dyspnea (median score of 8, cough 7, fatigue 6). ILD patients reported higher cough scores (7 vs. 4, P<0.001). There was no association between the change in ESAS domains and six-minute walk distance (6MWD), oxygen requirements, or respiratory exacerbations, despite increased oxygen requirements and a greater decline in 6MWD in ILD compared to COPD pre-LTx (-47 vs. -8 meters, P=0.01). ILD candidates who were delisted/died compared to those transplanted, experienced worse depression (median ESAS; 4.5 vs. 1), anxiety (5.5 vs. 2) and dyspnea (9.5 vs. 8); P<0.05. CONCLUSIONS: ILD patients had similar symptoms as COPD patients, despite increased oxygen requirements and decreasing 6MWD pre-LTx. This study highlights the importance of symptom management of LTx candidates co-managed with PC, independent of traditional measures of disease severity.

CAR-T Cell Therapy: the Efficacy and Toxicity Balance.

PURPOSE OF REVIEW: Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy. RECENT FINDINGS: Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Computed tomography-based body composition measures in COPD and their association with clinical outcomes: A systematic review.

BACKGROUND: Computed tomography (CT) is commonly utilized in chronic obstructive pulmonary disease (COPD) for lung cancer screening and emphysema characterization. Computed tomography-morphometric analysis of body composition (muscle mass and adiposity) has gained increased recognition as a marker of disease severity and prognosis. This systematic review aimed to describe the CT-methodology used to assess body composition and identify the association of body composition measures and disease severity, health-related quality of life (HRQL), cardiometabolic risk factors, respiratory exacerbations, and survival in patients with COPD. METHODS: Six databases were searched (inception-September 2021) for studies evaluating adult COPD patients using thoracic or abdominal CT-muscle or adiposity body composition measures. The systematic review was conducted in accordance with the PRISMA guidelines. RESULTS: Twenty eight articles were included with 15,431 COPD patients, across all GOLD stages with 77% males, age range (mean/median 59-78 years), and BMI range 19.8-29.3 kg/m2. There was heterogeneity in assessment of muscle mass and adiposity using thoracic (n = 22) and abdominal (n = 8) CT-scans, capturing different muscle groups, anatomic locations, and adiposity compartments (visceral, subcutaneous, and epicardial). Low muscle mass and increased adiposity were associated with increased COPD severity measures (lung function, exercise capacity, dyspnea) and lower HRQL, but were not consistent across studies. Increased visceral adiposity (n = 6) was associated with cardiovascular disease or risk factors (hypertension, hyperlipidemia, and diabetes). Low muscle CSA was prognostic of respiratory exacerbations or mortality in three of six studies, whereas the relationship with increased intermuscular adiposity and greater mortality was only observed in one of three studies. CONCLUSION: There was significant variability in CT-body composition measures. In several studies, low muscle mass was associated with increased disease severity and lower HRQL, whereas adiposity with cardiovascular disease/risk factors. Given the heterogeneity in body composition measures and clinical outcomes, the prognostic utility of CT-body composition in COPD requires further study.

Insurance-based disparities impact survival outcomes in Waldenström macroglobulinemia within the United States.

Considerable healthcare resource utilization and financial burden have been associated with the treatment of WM; however, the impact of health insurance status on outcomes has not been previously reported. We conducted a National Cancer Database analysis of newly diagnosed cases of active WM between 2004 and 2017 to evaluate the impact of insurance status on outcomes. For patients <65 years old (n = 1249, male sex: 62.4%, median age: 58 years), significant insurance-based survival differences were observed on multivariable analysis; patients who were uninsured [n = 63; HR 3.11 (95%CI, 1.77-5.45), p < 0.001], on Medicaid [n = 87; HR 1.88 (95% CI, 1.01-3.48), p = 0.045], or on Medicare [n = 122; HR 2.78 (95%CI, 1.76-4.38), p < 0.001], had inferior survival compared to patients with private insurance (n = 977; reference). In patients ≥65 years, no insurance-based survival differences were found (p = 0.10). Overall, significant insurance-based outcome disparities exist in WM. Further work is desperately needed to systematically uncover and address these disparities.

A real-world study of combined modality therapy for early-stage Hodgkin lymphoma: too little treatment impacts outcome.

Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P < .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded.

Current salvage therapies in Hodgkin lymphoma.

Hodgkin lymphoma is a B-cell malignancy with approximately 85-95% complete remission rate following frontline therapy; however, relapsed/refractory disease occurs in roughly 10-30% of patients after treatment. Salvage therapy conventionally relies upon cytotoxic chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation. A considerable number of patients experience relapse after transplantation, and further salvage management has included the use of allogeneic transplantation and radiotherapy. In the past decade, novel therapies including, brentuximab vedotin, PD-1 inhibitors, and the incorporation of PET-imaging into management have changed the paradigm of relapsed/refractory disease care. Novel therapies have been investigated in both single and combination regimens with other novel therapies and traditional chemotherapies. There is promising early work into the utility of CD30.CAR-T cell therapy, AFM13, camidanlumab tesirine, novel PD-1 inhibitors, and JAK1/JAK2 inhibition in management. Herein, we will review current salvage therapies in Hodgkin lymphoma and future directions in relapsed/refractory disease management.

Feasibility and Outcomes of a Standardized Management Protocol for Acute Exacerbation of Interstitial Lung Disease.

BACKGROUND AND OBJECTIVE: Despite the high mortality of acute exacerbations of interstitial lung disease (AE-ILD), there is minimal evidence to guide management decisions. We aimed to assess the feasibility and outcomes of a standardized management protocol for AE-ILD. METHODS: We performed a retrospective cohort study of patients with AE-ILD admitted to hospital between January 2015 and August 2019. Patients were managed with a standardized protocol including chest computed tomography (CT) at diagnosis, pulse corticosteroid treatment, and a follow-up CT 7 days after corticosteroid pulse. The association between idiopathic pulmonary fibrosis (IPF) versus non-IPF diagnosis and transplant-free survival within 1-year of AE-ILD was assessed using adjusted Cox proportional hazards regression survival analysis. Associations with CT chest improvement 7 days after corticosteroid pulse were secondarily assessed. RESULTS: 89 patients with AE-ILD were identified. 1-year transplant-free and overall survival were 20.2 and 51.7%, respectively. Protocol adherence to pulse corticosteroids was high (95.5%). A diagnosis of IPF was associated with higher risk of death or transplant at 1-year versus a non-IPF diagnosis [hazard ratio (HR) 2.23, 95% CI 1.19-4.17, p = 0.012]. There were no significant associations with 7-day CT improvement; however, CT improvement was associated with higher transplant-free survival (p = 0.02) and a lower risk of in-hospital mortality (χ2 = 7.06, p = 0.01) on unadjusted analysis. CONCLUSIONS: IPF is associated with a higher risk of death or transplant at 1-year as compared to a non-IPF diagnosis in patients with AE-ILD managed using a standardized protocol. Improvement on CT chest 7 days after corticosteroid pulse is associated with better survival.

A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

BACKGROUND: Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD. METHODS: A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English. RESULTS: Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training. CONCLUSION: Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.