The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

BACKGROUND: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. METHODS: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy. RESULTS: At lymphodepletion, 63 patients were HTlow (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). CONCLUSIONS: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

How to Sequence Therapies in Diffuse Large B-Cell Lymphoma Post-CAR-T Cell Failure.

OPINION STATEMENT: Post CAR-T failures represent a new unmet need in R/R LBCL. The prognosis is usually very poor and standard treatment options that can guide clinicians are, unfortunately, not available. While polatuzumab, tafasitamab, selinexor, and loncastuximab tesirine are available as SOC since they are FDA approved, data is lacking in the post CAR-T setting. However, they could be used in the absence of other treatment options (clinical trials). A selected group of patients may be treated with checkpoint inhibitors, likely low tumor burden or low proliferative lymphomas or those with PD-L1 expression. For localized relapses, radiation therapy could be considered. A main consideration should be given to clinical trials. So far, it appears that bi-specific antibodies have the best encouraging data (high response rates) with manageable toxicities and logistics; thus, we recommend clinicians to enroll patients in clinical trials utilizing these agents. Other cell therapies (such as dual CAR-T or allogeneic products) should also be considered; however, challenges with logistics and further immunosuppression (especially if patients had prolonged cytopenias from prior CAR-T therapy) may affect its applicability right after CAR-T relapse. It is unclear whether these options will lead to long-term remissions; thus, consolidation with stem cell transplantation (either auto or allogeneic SCT) could be considered in eligible patients.

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma.

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/µl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.

Pazopanib and Statin-Induced Rhabdomyolysis.

BACKGROUND: The VEGF inhibitor pazopanib is a widely used first-line therapy for the treatment of advanced renal cell carcinoma. Potential drug-drug interactions and toxicities may be underrecognized. CASE PRESENTATION: A 73-year-old woman with metastatic renal cell carcinoma on treatment with pazopanib presented with progressive inability to ambulate. The initial concern was for metastasis to the spine. However, MRI of the spine revealed diffuse muscle edema with no metastatic deposits or lytic lesions. Upon further evaluation, creatine kinase was significantly elevated and the diagnosis of rhabdomyolysis was made. With aggressive hydration and discontinuation of both pazopanib and rosuvastatin, the patient made a full recovery. CONCLUSION: This case of drug-induced rhabdomyolysis demonstrates an unexpected toxicity resulting from concomitant pazopanib and rosuvastatin therapy. This combination is predicted to be safe due to different, nonoverlapping effects on the cytochrome p450 enzymes. Discontinuation of statin therapy in patients with metastatic cancer should be considered when the risk of cancer-related death exceeds the risk of cardiovascular-related death.

Emissions from Electronic Cigarettes: Assessing Vapers' Intake of Toxic Compounds, Secondhand Exposures, and the Associated Health Impacts.

E-cigarettes likely represent a lower risk to health than traditional combustion cigarettes, but they are not innocuous. Recently reported emission rates of potentially harmful compounds were used to assess intake and predict health impacts for vapers and bystanders exposed passively. Vapers' toxicant intake was calculated for scenarios in which different e-liquids were used with various vaporizers, battery power settings and vaping regimes. For a high rate of 250 puff day-1 using a typical vaping regime and popular tank devices with battery voltages from 3.8 to 4.8 V, users were predicted to inhale formaldehyde (up to 49 mg day-1), acrolein (up to 10 mg day-1) and diacetyl (up to 0.5 mg day-1), at levels that exceeded U.S. occupational limits. Formaldehyde intake from 100 daily puffs was higher than the amount inhaled by a smoker consuming 10 conventional cigarettes per day. Secondhand exposures were predicted for two typical indoor scenarios: a home and a bar. Contributions from vaping to air pollutant concentrations in the home did not exceed the California OEHHA 8-h reference exposure levels (RELs), except when a high emitting device was used at 4.8 V. In that extreme scenario, the contributions from vaping amounted to as much as 12 µg m-3 formaldehyde and 2.6 µg m-3 acrolein. Pollutant concentrations in bars were modeled using indoor volumes, air exchange rates and the number of hourly users reported in the literature for U.S. bars in which smoking was allowed. Predicted contributions to indoor air levels were higher than those in the residential scenario. Formaldehyde (on average 135 µg m-3) and acrolein (28 µg m-3) exceeded the acute 1-h exposure REL for the highest emitting vaporizer/voltage combination. Predictions for these compounds also exceeded the 8-h REL in several bars when less intense vaping conditions were considered. Benzene concentrations in a few bars approached the 8-h REL, and diacetyl levels were close to the lower limit for occupational exposures. The integrated health damage from passive vaping was derived by computing disability-adjusted life years (DALYs) lost due to exposure to secondhand vapor. Acrolein was the dominant contributor to the aggregate harm. DALYs for the various device/voltage combinations were lower than-or comparable to-those estimated for exposures to secondhand and thirdhand tobacco smoke.

Assessing cumulative acute toxicity of chemoradiotherapy in head and neck cancer with or without induction chemotherapy.

BACKGROUND: To compare cumulative acute toxicity in head and neck cancer patients treated with concurrent chemoradiotherapy alone (CCRT) versus induction chemotherapy (IC) followed by CCRT (I/CCRT). METHODS: 77 patients underwent definitive CCRT (30 I/CCRT and 47 CCRT). Toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0. Using the TAME adverse event reporting system, short-term toxicity (T) scores were generated for IC (TIC), CCRT (TCCRT), total treatment duration (TRx), post-treatment period (TPT) and an overall score (Toverall) from treatment start to post treatment period. RESULTS: Acute toxicity other than dysphagia, odynophagia, or dermatitis was reported in 90.0% and 66.0% of I/CCRT and CCRT patients, respectively (P=0.02). Compared to CCRT group, I/CCRT patients reported greater mean TRx (TRx: 2.11 vs. 2.87, P=0.01) and Toverall (Toverall: 2.60 vs. 3.70, P=0.003). CONCLUSION: I/CCRT patients reported more cumulative acute toxicity during treatment compared to CCRT patients using the TAME reporting system.

Emissions from Electronic Cigarettes: Key Parameters Affecting the Release of Harmful Chemicals.

Use of electronic cigarettes has grown exponentially over the past few years, raising concerns about harmful emissions. This study quantified potentially toxic compounds in the vapor and identified key parameters affecting emissions. Six principal constituents in three different refill "e-liquids" were propylene glycol (PG), glycerin, nicotine, ethanol, acetol, and propylene oxide. The latter, with mass concentrations of 0.4-0.6%, is a possible carcinogen and respiratory irritant. Aerosols generated with vaporizers contained up to 31 compounds, including nicotine, nicotyrine, formaldehyde, acetaldehyde, glycidol, acrolein, acetol, and diacetyl. Glycidol is a probable carcinogen not previously identified in the vapor, and acrolein is a powerful irritant. Emission rates ranged from tens to thousands of nanograms of toxicants per milligram of e-liquid vaporized, and they were significantly higher for a single-coil vs a double-coil vaporizer (by up to an order of magnitude for aldehydes). By increasing the voltage applied to a single-coil device from 3.3 to 4.8 V, the mass of e-liquid consumed doubled from 3.7 to 7.5 mg puff(-1) and the total aldehyde emission rates tripled from 53 to 165 µg puff(-1), with acrolein rates growing by a factor of 10. Aldehyde emissions increased by more than 60% after the device was reused several times, likely due to the buildup of polymerization byproducts that degraded upon heating. These findings suggest that thermal degradation byproducts are formed during vapor generation. Glycidol and acrolein were primarily produced by glycerin degradation. Acetol and 2-propen-1-ol were produced mostly from PG, while other compounds (e.g., formaldehyde) originated from both. Because emissions originate from reaction of the most common e-liquid constituents (solvents), harmful emissions are expected to be ubiquitous when e-cigarette vapor is present.

Inhalable constituents of thirdhand tobacco smoke: chemical characterization and health impact considerations.

Tobacco smoke residues lingering in the indoor environment, also termed thirdhand smoke (THS), can be a source of long-term exposure to harmful pollutants. THS composition is affected by chemical transformations and by air-surface partitioning over time scales of minutes to months. This study identified and quantified airborne THS pollutants available for respiratory exposure, identified potential environmental tracers, and estimated health impacts to nonsmokers. In a ventilated 18 m(3) laboratory chamber, six cigarettes were machine-smoked, and levels of particulate matter (PM2.5) and 58 volatile organic compounds (VOCs) were monitored during an aging period of 18 h. Results were compared with field measurements taken in a smoker's home 8 h after the last cigarette had been smoked. Initial chamber levels of individual VOCs in freshly emitted secondhand smoke (SHS) were in the range of 1-300 µg m(-3). The commonly used SHS tracers 3-ethenylpyridine (3-EP) and nicotine were no longer present in the gas phase after 2 h, likely due mostly to sorption to surfaces. By contrast, other VOCs persisted in the gas phase for at least 18 h, particularly furans, carbonyls, and nitriles. The concentration ratio of acetonitrile to 3-EP increased substantially with aging. This ratio may provide a useful metric for differentiating freshly emitted (SHS) from aged smoke (THS). Among the 29 VOCs detected in the smoker's home at moderate to high concentrations, 18 compounds were also detected in simultaneously sampled outdoor air, but acetonitrile, 2-methyl furan, and 2,5-dimethyl furan appeared to be specific to cigarette smoke. The levels of acrolein, methacrolein, and acrylonitrile exceeded concentrations considered harmful by the State of California. An initial exposure and impact assessment was conducted for a subset of pollutants by computing disability-adjusted life years lost, using available toxicological and epidemiological information. Exposure to PM2.5 contributed to more than 90% of the predicted harm. Acrolein, furan, acrylonitrile, and 1,3-butadiene were considered to be the most harmful VOCs. Depending on which criteria are used to establish the separation between SHS and THS, 5-60% of the predicted health damage could be attributed to THS exposure. Benefits and limitations of this approach are discussed.

Pollutant exposures from natural gas cooking burners: a simulation-based assessment for Southern California.

BACKGROUND: Residential natural gas cooking burners (NGCBs) can emit substantial quantities of pollutants, and they are typically used without venting range hoods. OBJECTIVE: We quantified pollutant concentrations and occupant exposures resulting from NGCB use in California homes. METHODS: A mass-balance model was applied to estimate time-dependent pollutant concentrations throughout homes in Southern California and the exposure concentrations experienced by individual occupants. We estimated nitrogen dioxide (NO2), carbon monoxide (CO), and formaldehyde (HCHO) concentrations for 1 week each in summer and winter for a representative sample of Southern California homes. The model simulated pollutant emissions from NGCBs as well as NO2 and CO entry from outdoors, dilution throughout the home, and removal by ventilation and deposition. Residence characteristics and outdoor concentrations of NO2 and CO were obtained from available databases. We inferred ventilation rates, occupancy patterns, and burner use from household characteristics. We also explored proximity to the burner(s) and the benefits of using venting range hoods. Replicate model executions using independently generated sets of stochastic variable values yielded estimated pollutant concentration distributions with geometric means varying by <10%. RESULTS: The simulation model estimated that-in homes using NGCBs without coincident use of venting range hoods-62%, 9%, and 53% of occupants are routinely exposed to NO2, CO, and HCHO levels that exceed acute health-based standards and guidelines. NGCB use increased the sample median of the highest simulated 1-hr indoor concentrations by 100, 3,000, and 20 ppb for NO2, CO, and HCHO, respectively. CONCLUSIONS: Reducing pollutant exposures from NGCBs should be a public health priority. Simulation results suggest that regular use of even moderately effective venting range hoods would dramatically reduce the percentage of homes in which concentrations exceed health-based standards.

Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling.

The future site of skin appendage development is marked by a placode during embryogenesis. Although Wnt/ß-catenin signaling is known to be essential for skin appendage development, it is unclear which cellular processes are controlled by the signaling and how the precise level of the signaling activity is achieved during placode formation. We have investigated roles for Lrp4 and its potential ligand Wise (Sostdc1) in mammary and other skin appendage placodes. Lrp4 mutant mice displayed a delay in placode initiation and changes in distribution and number of mammary precursor cells leading to abnormal morphology, number and position of mammary placodes. These Lrp4 mammary defects, as well as limb defects, were associated with elevated Wnt/ß-catenin signaling and were rescued by reducing the dose of the Wnt co-receptor genes Lrp5 and Lrp6, or by inactivating the gene encoding ß-catenin. Wise-null mice phenocopied a subset of the Lrp4 mammary defects and Wise overexpression reduced the number of mammary precursor cells. Genetic epistasis analyses suggest that Wise requires Lrp4 to exert its function and that, together, they have a role in limiting mammary fate, but Lrp4 has an early Wise-independent role in facilitating placode formation. Lrp4 and Wise mutants also share defects in vibrissa and hair follicle development, suggesting that the roles played by Lrp4 and Wise are common to skin appendages. Our study presents genetic evidence for interplay between Lrp4 and Wise in inhibiting Wnt/ß-catenin signaling and provides an insight into how modulation of Wnt/ß-catenin signaling controls cellular processes important for skin placode formation.

A method to estimate the chronic health impact of air pollutants in U.S. residences.

BACKGROUND: Indoor air pollutants (IAPs) cause multiple health impacts. Prioritizing mitigation options that differentially affect individual pollutants and comparing IAPs with other environmental health hazards require a common metric of harm. OBJECTIVES: Our objective was to demonstrate a methodology to quantify and compare health impacts from IAPs. The methodology is needed to assess population health impacts of large-scale initiatives-including energy efficiency upgrades and ventilation standards-that affect indoor air quality (IAQ). METHODS: Available disease incidence and disease impact models for specific pollutant-disease combinations were synthesized with data on measured concentrations to estimate the chronic heath impact, in disability-adjusted life-years (DALYs) lost, due to inhalation of a subset of IAPs in U.S. residences. Model results were compared with independent estimates of DALYs lost due to disease. RESULTS: Particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5), acrolein, and formaldehyde accounted for the vast majority of DALY losses caused by IAPs considered in this analysis, with impacts on par or greater than estimates for secondhand tobacco smoke and radon. Confidence intervals of DALYs lost derived from epidemiology-based response functions are tighter than those derived from toxicology-based, interspecies extrapolations. Statistics on disease incidence in the United States indicate that the upper-bound confidence interval for aggregate IAP harm is implausibly high. CONCLUSIONS: The approach demonstrated in this study may be used to assess regional and national initiatives that affect IAQ at the population level. Cumulative health impacts from inhalation in U.S. residences of the IAPs assessed in this study are estimated at 400-1,100 DALYs lost annually per 100,000 persons.

Spatial variation in ambient air toxics concentrations and health risks between industrial-influenced, urban, and rural sites.

Concentrations of 38 gas-phase organic air toxics were measured over a 2-yr period at four different sites in and around Pittsburgh, PA, to investigate spatial variations in health risks from chronic exposure. The sites were chosen to represent different exposure regimes: a downtown site with substantial mobile source emissions; two residential sites adjacent to one of the most heavily industrialized zones in Pittsburgh; and a regional background site. Lifetime cancer risks and non-cancer hazard quotients were estimated using a traditional and interactive risk models. Although study average concentrations of specific air toxics varied by as a much as a factor of 26 between the sites, the additive cancer risks of the gas-phase organic air toxics varied by less than a factor of 2, ranging from 6.1 x 10(-5) to 9.5 x 10(-5). The modest variation in risks reflects the fact that two regionally distributed toxics, formaldehyde and carbon tetrachloride (CCl4), contributed more than half of the cancer risk at all four sites. Benzene contributed substantial cancer risks at all sites, whereas trichloroethene and 1,4-dichlorobenzene only contributed substantial cancer risks at the downtown site. Only acrolein posed a non-cancer risk. Diesel particulate matter is estimated to pose a much greater cancer risk in Pittsburgh than other classes of air toxics including gas-phase organic, metals, polycyclic aromatic hydrocarbons, and coke oven emissions. Health risks of air toxics in Pittsburgh are comparable with those in other urban areas in the United States.

Identifying priority pollutant sources: apportioning air toxics risks using positive matrix factorization.

Hazardous air pollutants or air toxics are pollutants that are known or suspected to cause serious health effects. This paper presents a methodology to quantify source contributions to air toxics health risks. First, a linear, no-threshold risk model was used to identify gas-phase organic air toxics that contribute significantly to cancer risks. Next, Positive Matrix Factorization (PMF) was performed on high time-resolved measurements of these air toxics, and the additive cancer risks associated with each factor was determined. Finally, the PMF factors were linked to sources and source classes (mobile, nonmobile, secondary/background) using a combination of meteorological data and comparisons with published source profiles. The analysis was performed using data from three sites in Pittsburgh, Pennsylvania: a downtown site near a heavily traveled bus route, a residential site adjacent to a heavily industrialized area, and an urban background site. At all three sites emissions from nonmobile sources were the dominant contributors to the cancer risks from air toxics included in the PMF model, including benzene and other air toxics often associated with mobile source emissions. Emissions from both large industrial sources, such as coke works and chemical facilities, and smaller point sources, such as dry cleaners, contributed significantly to the cancer risks at all sites. This method can provide insight for decision makers to prioritize sources for risk reduction.