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High-dose chemotherapy with autologous hematopoietic cell transplantation (AutoHCT) has long been an integral treatment modality for multiple myeloma and non-Hodgkin lymphoma. Over the past 25 years, numerous institutions have shifted this practice from requiring hospitalization to one that can be performed in an ambulatory setting, resulting in cost savings and improved quality of life for patients. The recent advent immune-effector cell (IEC) therapies and expansion of their indications is changing the treatment landscape for hematologic and non-hematologic malignancies. However, current financial models and reimbursement structures threaten the viability and sustainability of this treatment modality should it continue to require inpatient administration and management. This threat is leading institutions to develop outpatient IEC programs based off the outpatient AutoHCT templates. Integral to the success of both is a cohesive program with outpatient-specific standard operating protocols, highly-trained providers and staff with expertise specific in these treatment modalities, evidenced-based supportive care and prophylaxis plans, extensive caregiver vetting and education, and the infrastructure to support all individuals involved. In this policy and practice review we provide an overview of the guidelines and published academic experiences, give a perspective-based description of the roles and responsibilities of the individuals involved in this process at our institution, and highlight actionable recommendations that could allow for the dissemination and implementation of outpatient AutoHCT and IEC programs more broadly.

The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

This research introduces the design, implementation, and rigorous evaluation of a novel 2-channel, multi-functional therapeutic electrical stimulator, meticulously engineered to meet the stringent demands of contemporary clinical applications. The device integrates a high-speed R-2R ladder DAC and a sophisticated pulse generator unit, capable of producing twelve essential current waveforms with fully adjustable parameters, including pulse amplitude, pulse duration, and pulse repetitive frequency. The proposed driving stage unit ensures precise voltage-to-current conversion, delivering stable and accurate output currents even under varying load conditions, which effectively simulate the diverse impedance characteristics of human tissue. Extensive testing confirmed the compliance with international medical standards, notably IEC 60601-1, IEC 60601-1-2, and IEC 60601-2-10. The experimental results underscore the device’s consistent operation within prescribed safety and performance thresholds, with all deviations in pulse parameters remaining well below the permissible limits. Furthermore, the proposed electrical stimulator demonstrated exceptional stability across variable load conditions, as evidenced by minimal amplitude errors and high correlation between waveform characteristics. These findings highlight the proposed device’s robustness and its potential as a versatile tool for a wide range of therapeutic applications, including pain management, muscle stimulation, and nerve rehabilitation, thus marking a significant advancement in the field of therapeutic electrical stimulation.

Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases. We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, high-dose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.

Background: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a rare, life-threatening complication following CAR T-cell therapy. Diagnosis is challenging due to overlap with severe CRS, sepsis and lack of standardized criteria. Clinical data remain limited. Methods: We retrospectively analyzed 301 patients treated with CD19- or BCMA-directed CAR T-cells for hematologic malignancies at a single center from January 2019 to January 2026. IEC-HS was defined according to American Society for Transplantation and Cellular Therapy criteria. Results: Median follow-up was 31 months. IEC-HS was diagnosed in 14 patients (4.7%), median age 67 years. Underlying diseases included diffuse large B-cell lymphoma (n = 4), multiple myeloma (n = 7), mantle cell lymphoma, Burkitt lymphoma and B-lymphoblastic leukemia (n = 1 each). All patients had hyperferritinemia and cytopenias at baseline; most had high tumor burden (9/14) and elevated LDH (10/14). CRS occurred in all patients and ICANS in 6/14. IEC-HS occurred at median 10 days and was characterized by hyperferritinemia (median 15,321 µg/L), neutropenia, thrombocytopenia, hepatic dysfunction and high CAR-T-cell expansion in peripheral blood. Treatment included corticosteroids and anakinra (12/14). Refractory patients received IVIG (5/14), tocilizumab (3/14), siltuximab, ruxolitinib, emapalumab or etoposide (each n = 1). Infections occurred in 11/14; 4/14 had mixed infections. IEC-HS resolved in 7/14 (median 7 days). Mortality was 79% (11/14), mainly due to IEC-HS (7/14). Three patients were alive at last follow-up. One-year OS was lower vs. the whole cohort (31% vs. 69%, p < 0.0001). Conclusions: IEC-HS was associated with severe cytopenias, hyperferritinemia, hepatic dysfunction and high infection risk. Despite intensive immunosuppressive therapy, outcomes remain poor. Early biomarker-driven identification and multicenter studies are needed.

Diet–microbiota interactions are emerging as important contributors in the pathogenesis of inflammatory bowel diseases (IBD), characterized by chronic inflammation of the GI tract. The aryl hydrocarbon receptor (AhR) transcription factor regulates xenobiotic metabolism and is activated by exogenous ligands, including indole-3-carbinole (I3C), which is found in cruciferous vegetables. However, studies investigating the impact of dietary I3C and AhR in preclinical models resembling human IBD are lacking. Mice (WT or AhR KO in IECs, 6–8 weeks) or SAMP/YitFC and AKR/J control (4 weeks, m/f) were fed an AhR ligand-depleted or I3C (200 ppm)-supplemented diet. There were increased levels of LPS and exacerbated inflammation, resulting in increased mortality in AhRΔIEC mice fed the AhR ligand-depleted diet in response to chronic DSS. The mechanisms underlying the protective effects of I3C supplementation during colonic colitis involved amelioration of intestinal inflammation and restoration of the altered gut microbiota, particularly the families of clostridicae and lachnospriaceae. Furthermore, the AhR-depleted diet led to the emergence of pathobiont Parvibacter caecicola in WT mice. SAMP/YitFc mice with spontaneous ileitis showed significant recovery in epithelial abnormalities when fed dietary I3C. These data demonstrate the critical role of AhR and the mechanisms of dietary I3C in maintaining epithelial homeostasis and ameliorating inflammation.

Chimeric antigen receptor (CAR) T-cell infusion has led to improved outcomes in patients with B-lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. The spectrum of post-CAR T-cell hematolymphoid abnormalities is expanding, although they remain under-recognized. Pathologists play a key role in characterizing hematolymphoid proliferation after CAR T-cell therapy. This review presents clinical and pathologic findings of common hematolymphoid proliferation after CAR T-cell therapy, illustrated by selected cases. A review of the literature is presented in the context of individual cases, and our current understanding of the pathomechanism is discussed. Infused CAR T-cells undergo a series of four phases: distribution, expansion, contraction, and persistence. In the expansion phase, transient peripheral blood lymphocytosis occurs, reaching a peak two weeks post-infusion. Delayed contraction of CAR T-cells may give rise to hemophagocytic lymphohistiocytosis-like syndrome. Immune effector cell-associated enterocolitis presents in the persistence phase, about 3–6 months after infusion. Pathologic findings include a T-cell infiltrate in the intestinal mucosa and changes resembling graft versus host disease (GVHD). This entity requires differentiation from infections and from T-cell neoplasms, including those derived from CAR T-cells. Secondary myeloid malignancies follow the same pathways as therapy-related myeloid neoplasm but present with a shorter median latency. It is essential for pathologists to recognize post-CAR T-cell hematolymphoid proliferation to support clinical decision making in a high-risk patient population.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies. While its clinical efficacy is well established, CAR T-cell therapy is frequently associated with severe immune-mediated toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), coagulopathy, and hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Increasing evidence suggests that endothelial dysfunction, hemostatic imbalance, and complement activation are key contributors to the pathogenesis of these complications. Substantial research efforts have focused on identifying circulating biomarkers capable of predicting toxicity onset and severity, as well as stratifying patients at risk for early non-relapse mortality. In this review, we summarize the current understanding of the pathophysiological mechanisms underlying early CAR T cell–related toxicities, with particular emphasis on biomarkers of endotheliopathy and related pathways involved in their development. We focus on highlighting translational biomarkers with potential diagnostic, prognostic, and monitoring value that could be implemented in clinical practice to improve patient risk stratification, differential diagnosis, and therapeutic follow-up.

The mechanism underlying intestinal fibrosis, the main complication of inflammatory bowel disease (IBD), is not yet fully understood, and there is no therapy to prevent or reverse fibrosis. We evaluated, in in vitro cellular models, the ability of different classes of drugs currently used in IBD to counteract two pivotal processes of intestinal fibrosis, the differentiation of intestinal fibroblasts to activated myofibroblasts using CCD-18Co cells, and the epithelial-to-mesenchymal transition (EMT) of intestinal epithelial cells using Caco-2 cells (IEC), both being processes induced by transforming growth factor-β1 (TGF-β1). The drugs tested included mesalamine, azathioprine, methotrexate, prednisone, methylprednisolone, budesonide, infliximab, and adalimumab. The expression of fibrosis and EMT markers (collagen-I, α-SMA, pSmad2/3, occludin) was assessed by Western blot analysis and by immunofluorescence. Of the drugs used, only prednisone, methylprednisolone, budesonide, and adalimumab were able to antagonize the pro-fibrotic effects induced by TGF-β1 on CCD-18Co cells, reducing the fibrosis marker expression. Methylprednisolone, budesonide, and adalimumab were also able to significantly counteract the TGF-β1-induced EMT process on Caco-2 IEC by increasing occludin and decreasing α-SMA expression. This is the first study that evaluates, using in vitro cellular models, the direct antifibrotic effects of drugs currently used in IBD, highlighting which drugs have potential antifibrotic effects.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has revolutionized multiple myeloma treatment (MM). However, managing its immune-mediated adverse events, particularly macrophage activation syndrome- (MAS- ), remains challenging due to underreporting. This multicentre, retrospective, analytical study evaluated MM patients treated with the anti-BCMA academic product ARI0002h. MAS- was defined using the University of California San Francisco (UCSF) consensus criteria. Primary endpoints included baseline characteristics, predictive factors, and survival outcomes associated with MAS- . Of 80 patients, 12 (15%) met the UCSF criteria for MAS- . These patients presented higher ISS scores (ISS III: 54.5% vs. 15.2%; = 0.006), elevated serum monoclonal components (31.3 g/L vs. 6.8 g/L; = 0.004), and a higher prevalence of extramedullary disease (41.7% vs. 16.2%; = 0.057). MAS- typically emerged 9 days post-infusion, with elevated ferritin, followed by LDH (median 11.5 days) and hypofibrinogenemia (median 14 days). One-third of patients met all UCSF criteria, and all exhibited hypertriglyceridemia, hypertransaminasemia, and cytopenias. Histopathological examination was positive in 63% of evaluated patients. Patients who developed MAS- had poorer responses (CR: 25% vs. 68%; p = 0.008) and shorter median PFS and OS (7 months vs. 21.4 months and 18 months vs. not reached, respectively; p = 0.004). Those meeting all UCSF criteria had even inferior outcomes. MAS- is associated with poorer responses, reduced PFS and OS, especially in patients meeting all UCSF criteria. High tumour burden, including elevated monoclonal component, high ISS and extramedullary disease, seems to contribute to MAS- development.