Cellular therapies in older adults with hematological malignancies: A case-based, state-of-the-art review.

Cellular therapies, including autologous stem cell transplant (ASCT), allogeneic hematopoietic cell transplantation (alloHCT), and chimeric antigen receptor- (CAR-) T cell therapies are essential treatment modalities for many hematological malignancies. Although their use in older adults has substantially increased within the past decades, cellular therapies represent intensive treatment approaches that exclude a large percentage of older adults due to comorbidities and frailty. Under- and overtreatment in older adults with hematologic malignancy is a challenge and many treatment decisions are influenced by chronologic age. The advent of efficient and well-tolerated newer treatment approaches for multiple myeloma has challenged the role of ASCT. In the modern era, there are no randomized clinical trials of transplant versus non-transplant strategies for patients ≥65 years. Nonetheless, ASCT is feasible for selected older patients and does not result in long-term compromise in quality of life. AlloHCT is the only curative approach for acute myeloid leukemia of intermediate and unfavourable risk but carries a significant risk for non-relapse mortality depending on comorbidities, general fitness, and transplant-specific characteristics, such as intensity of conditioning and donor choice. However, alloHCT is feasible in appropriately-selected older adults. Early referral for evaluation is strongly encouraged as this is the most obvious barrier. CAR-T cell therapies have shown unprecedented clinical efficacy and durability in relapsed and refractory diffuse large B cell lymphoma. Its use is well tolerated in older adults, although evidence comes from limited case numbers. Whether patients who are deemed unfit for ASCT qualify for CAR-T cell therapy remains elusive, but the tolerability and efficacy of CAR-T cell therapy appears promising, especially for older patients. The evidence from randomized trials is strong in favor of using a comprehensive geriatric assessment (CGA) to reduce treatment-related toxicities and guide treatment intensity in the care for solid tumors; its use for evaluation of cellular therapies is less evidence-based. However, CGA can provide useful information on patients' fitness, resilient mechanisms, and reveal potential optimization strategies for compensating for vulnerabilities. In this narrative review, we will discuss key questions on cellular therapies in older adults based on illustrative patient cases.

Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release.

Myotonic dystrophy type 2 (DM2) is a tetranucleotide CCTG repeat expansion disease associated with an increased prevalence of autoimmunity. Here, we identified an elevated type I interferon (IFN) signature in peripheral blood mononuclear cells and primary fibroblasts of DM2 patients as a trigger of chronic immune stimulation. Although RNA-repeat accumulation was prevalent in the cytosol of DM2-patient fibroblasts, type-I IFN release did not depend on innate RNA immune sensors but rather the DNA sensor cGAS and the prevalence of mitochondrial DNA (mtDNA) in the cytoplasm. Sublethal mtDNA release was promoted by a chronic activation of the ATF6 branch of the unfolded protein response (UPR) in reaction to RNA-repeat accumulation and non-AUG translated tetrapeptide expansion proteins. ATF6-dependent mtDNA release and resulting cGAS/STING activation could also be recapitulated in human THP-1 monocytes exposed to chronic endoplasmic reticulum (ER) stress. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic endoplasmic reticulum stress and associated mtDNA leakage. This mtDNA is, in turn, sensed by the cGAS/STING pathway and induces a type-I IFN response predisposing to autoimmunity. Elucidating this pathway reveals new potential therapeutic targets for autoimmune disorders associated with repeat expansion diseases.

An inducible Cd79b mutation confers ibrutinib sensitivity in mouse models of Myd88-driven diffuse large B-cell lymphoma.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.

Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA.

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.

E-64c-Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1'-S2' Area.

The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro-inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E-64c-hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n-butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1'-S2' area was now investigated by a combinatorial approach, showing that Nle-tryptamide is a ligand superior to the initially used Leu-isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.

Spontaneous abortion as differential diagnosis of intermittent glomerular proteinuria in inactive systemic lupus erythematosus.

In women of childbearing age, severe proteinuria in systemic lupus erythematosus raises concern for renal involvement and pregnancy complications. While persisting renal loss of protein is known to culminate in extensive interventions, intermittent proteinuria in inactive disease requires an adjusted approach. Contextual awareness of this urinary finding is thus essential.

Early report on the severity of COVID-19 in hematologic patients infected with the SARS-CoV2 omicron variant.

INTRODUCTION: Patients with hematologic disease are at high risk of morbidity and mortality from COVID-19 due to disease-inherent and therapy-related immunodeficiency. Whether infection with the SARS-CoV2 omicron variant leads to attenuated disease severity in these patients is currently unknown. METHODS: We assessed clinical and laboratory parameters in 61 patients with underlying hematologic conditions with a SARS-CoV2 omicron variant infection confirmed by nucleic acid amplification testing. RESULTS: Fifty patients reported symptoms of COVID-19, most commonly fatigue (37 patients, 60.66%) and cough (32 patients, 52.46%). 39.34% of patients reported fever. Dyspnea was reported by 10 patients and 7 patients (11.48%) required oxygen therapy. Anosmia and ageusia were relatively rare, occurring in less than 10% of patients. Severity of SARS-CoV2 infection could be assessed in 60 patients. Five cases of critical illness leading to ICU admission occurred during the observation period. Overall mortality was 9.84% in this patient cohort, with heterogeneous causes of death. The majority of omicron-infected hematologic patients experienced mild symptoms or remained asymptomatic. DISCUSSION: In this study, symptoms of COVID-19 tended to be milder than described for previous SARS-CoV2 variants. However, the extent to which attenuated severity of omicron-variant SARS-CoV2 infection is caused by altered viral pathogenicity or pre-existing host immunity cannot be inferred from our data and should be investigated in larger prospective studies.