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CD19-directed chimeric antigen receptor T cells (CAR-T) have emerged as a highly efficacious treatment for patients with relapsed/refractory (r/r) B cell lymphoma (BCL). The value of CAR-T for these patients is indisputable, but one-off production costs are high, and little is known about the ancillary resource consumption associated with CAR-T treatment. Here, we compared the resource use and costs of CAR-T treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for patients with r/r BCL. Standard operating procedures were used to develop a process model in ClipMedPPM, which comprises all activities and processes to sustain or generate treatment components that together constitute a treatment path. The software allows a graphic representation and the use of standardized linguistic elements for comparison of different treatment paths. Detailed processes involved in CAR-T treatments (n = 1041 processes) and in ASCT (n = 1535) were analyzed for time consumption of treatment phases and personnel. Process costs were calculated using financial controlling data. CAR-T treatment required ~ 30% less staff time than ASCT (primarily nursing staff) due to fewer chemotherapy cycles, less outpatient visits, and shorter hospital stays. For CAR-T, production costs were ~ 8 × higher, but overall treatment time was shorter compared with ASCT (30 vs 48 days), and direct labor and overhead costs were 40% and 10% lower, respectively. Excluding high product costs, CAR-T uses fewer hospital resources than ASCT for r/r BCL. Fewer hospital days for CAR-T compared to ASCT treatment and the conservation of hospital resources are beneficial to patients and the healthcare system.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which autoreactive T and B cells play important roles. Other lymphocytes such as NK cells and innate-like T cells appear to be involved as well. To name a few examples, CD56 bright NK cells were described as an immunoregulatory NK cell subset in MS while innate-like T cells in MS were described in brain lesions and with proinflammatory signatures. Autologous hematopoietic stem cell transplantation (aHSCT) is a procedure used to treat MS. This procedure includes hematopoietic stem/progenitor cell (HSPC) mobilization, then high-dose chemotherapy combined with anti-thymocyte globulin (ATG) and subsequent infusion of the patients own HSPCs to reconstitute a functional immune system. aHSCT inhibits MS disease activity very effectively and for long time, presumably due to elimination of autoreactive T cells. Here, we performed multidimensional flow cytometry experiments in peripheral blood lymphocytes of 27 MS patients before and after aHSCT to address its potential influence on NK and innate-like T cells. After aHSCT, the relative frequency and absolute numbers of CD56 bright NK cells rise above pre-aHSCT levels while all studied innate-like T cell populations decrease. Hence, our data support an enhanced immune regulation by CD56 bright NK cells and the efficient reduction of proinflammatory innate-like T cells by aHSCT in MS. These observations contribute to our current understanding of the immunological effects of aHSCT in MS.

The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65–77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70−180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264–2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.

Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8+ memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

BackgroundImmune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited.Main bodyWe here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months.ConclusionsThis case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment.

Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.

While for most cancers incidence and mortality are decreasing, those of non-Hodgkin's lymphoma (NHL) are steadily increasing. Research to define reasons for this increase is extensive, but has not yet resolved them. We have conducted a literature analysis on trends regarding changes in the incidence, geographic distribution, and etiologic factors of NHL. From our own and previous analyses, an increasing NHL incidence at a rate of 3-4% per year was observed for the 1970s and 1980s. This stabilized in the 1990s, nevertheless still with an annual rise of 1-2%, resulting in almost a doubling of the NHL incidence. This rise has been noted worldwide, particularly in elderly persons >55 years. Concerning gender subgroups, a male predominance throughout all age groups is apparent. Although the NHL incidence has historically been higher in whites than blacks, disproportional increases have recently been observed in the latter group. Increases in high-grade NHL and extranodal disease are predominant. Differences in geographic distribution are striking for follicular lymphoma, which is more common in Western countries than elsewhere. Asians have higher rates of aggressive NHL, T-cell lymphomas, and extranodal disease. In the Middle East, high rates of intestinal extranodal disease are observed, whereas in Africa, endemic Burkitt's lymphoma accounts for a substantial proportion. Risks for developing NHL include immunosuppression and a causal link between infectious agents, and lymphomagenesis has also been determined, particularly for human T-cell leukemia/lymphoma virus type 1 (HTLV-1), Epstein-Barr virus (EBV), and Helicobacter pylori infections. Exposure to environmental agents and occupational risks have been studied; however, their significance is as yet uncertain.

Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.

Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders characterized by sustained and otherwise unexplained overproduction of eosinophils with organ involvement and consecutive dysfunction. Recent reports document the efficacy of imatinib mesylate in a large proportion of HES patients (65%). Rearrangements involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), both tyrosine kinase receptors, have been demonstrated to be pathogenetically linked to the dysregulated clonal overproduction of eosinophils. This refined hypothesis has been confirmed by the discovery of the novel FIP1L1-PDGFRA fusion gene, which is a gain-of-function gene on chromosome 4q12. Its product is an imatinib-sensitive tyrosine kinase, which can be found in a subset of patients with HES, particularly in those responding to treatment with imatinib mesylate. Here, we sum up recent knowledge of clinical features, pathophysiology and novel treatment aspects of HES by performing a comprehensive search of the available literature and report on 94 patients. We particularly address the issue of organ involvement and specific characteristics of the variable clinical pictures. In addition, two cases will be presented, which illustrate typical clinical scenarios and treatment outcome.

Abstract Background Severe coronavirus disease 2019 (COVID-19) has been increasingly recognized as a multisystem disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect literally any cell type that expresses its target receptor angiotensin-converting enzyme 2. However, COVID-19-associated organ dysfunction is not only mediated by direct viral effects but also by the interaction between the host’s immune response, endotheliopathy, and microvascular coagulopathy. It has been proposed that the activation of the complement system plays a central role in the pathophysiology of severe COVID-19 and the associated endotheliopathy. Case summary A 76-year-old male patient with indeterminate cardiogenic shock in the setting of confirmed SARS-CoV-2 infection was admitted to our intensive care unit. Coronary angiography did not reveal a plausible explanation for his symptoms. The patient developed renal failure, neurological symptoms, severe thrombocytopenia, and a Coombs-negative haemolytic anaemia with schistocytes. All together the clinical picture was highly suggestive of a thrombotic microangiopathy (TMA) with microvascular cardiac involvement. Conventional therapeutic strategies including high-dose steroids and seven sessions of therapeutic plasma exchange were all unsuccessful. Interestingly, complement inhibition with Eculizumab as rescue approach led to a rapid clinical and laboratory improvement and the patients were discharged with normalized organ functions at Day 36. Conclusion The aetiology of cardiogenic shock observed in this patient cannot simply be explained by his focal and chronic coronary findings. Although viral myocarditis was not formally excluded, both the clinical features of TMA and the rapid resolution of all clinical signs and symptoms after pharmacological complement inhibition suggest a SARS-CoV-2-driven microangiopathic origin of heart failure.