Fludarabine, cytarabine, and idarubicin with or without venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) without or with venetoclax (FLAVIDA) in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLAIDA- treated patients (78% vs. 47%; P=0.001), while measurable residual disease was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eighty-one percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation or donor lymphocyte infusion after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA- and FLA-IDA-treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing measurable residual disease-negative remission in a high proportion of R/R AML patients.

Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease.

BACKGROUND: Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. METHODS: We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1-2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1-10) in adults and 7 (2-11) in children. RESULTS: The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36-55%) in adults and 64% (45-80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38-56%), 35% (27-44%) and 30% (22-39%) for adults, and 59% (40-74%), 42% (24-58%) and 35% (19-53%) for children, respectively (whole cohort: median OS 5.8 months). CONCLUSION: A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.

The graft-versus-leukemia effect of prophylactic donor lymphocyte infusions after allogeneic stem cell transplantation is equally effective in relapse prevention but safer compared to spontaneous graft-versus-host disease.

Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS.

Antiviral T-Cell Frequencies in a Healthy Population: Reference Values for Evaluating Antiviral Immune Cell Profiles in Immunocompromised Patients.

Viral infections and reactivations are major causes of morbidity and mortality after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) as well as in patients with immunodeficiencies. Latent herpesviruses (e.g., cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6), lytic viruses (e.g., adenovirus), and polyomaviruses (e.g., BK virus, JC virus) can cause severe complications. Antiviral drugs form the mainstay of treatment for viral infections and reactivations after transplantation, but they have side effects and cannot achieve complete viral clearance without prior reconstitution of functional antiviral T-cell immunity. The aim of this study was to establish normal ranges for virus-specific T-cell (VST) frequencies in healthy donors. Such data are needed for better interpretation of VST frequencies observed in immunocompromised patients. Therefore, we measured the frequencies of VSTs against 23 viral protein-derived peptide pools from 11 clinically relevant human viruses in blood from healthy donors (n = 151). Specifically, we determined the VST frequencies by interferon-gamma enzyme-linked immunospot assay and classified their distribution according to age and gender to allow for a more specific evaluation and prediction of antiviral immune responses. The reference values established here provide an invaluable tool for immune response evaluation, intensity of therapeutic drugs and treatment decision-making in immunosuppressed patients. This data should make an important contribution to improving the assessment of immune responses in immunocompromised patients.

Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

OBJECTIVE: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Endothelial damage and dysfunction in acute graft-versus-host disease.

Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options.

Treatment and Mortality of Hemophagocytic Lymphohistiocytosis in Adult Critically Ill Patients: A Systematic Review With Pooled Analysis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis is a cytokine release syndrome caused by uncontrolled immune activation resulting in multiple organ failure and death. In this systematic review, we aimed to analyze triggers, various treatment modalities, and mortality in critically ill adult hemophagocytic lymphohistiocytosis patients. DATA SOURCES: MEDLINE database (PubMed) at October 20, 2019. STUDY SELECTION: Studies and case series of patients greater than or equal to 18 years old, of whom at least one had to be diagnosed with hemophagocytic lymphohistiocytosis and admitted to an ICU. DATA EXTRACTION: Source data of studies and case series were summarized and analyzed on an individual basis. Multivariable logistic regression analysis was performed adjusting for age, sex, and trigger groups. Each single treatment agent was entered as a dichotomous variable to determine treatments associated with survival, regardless if given alone or in combination. DATA SYNTHESIS: In total, 661 patients from 65 studies and case series were included. Overall mortality was 57.8%. Infections were the most frequent trigger (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%), unknown triggers (9.4%), and drugs (0.6%). Treatment with IV immunoglobulins was associated with improved survival (odds ratio, 0.548; 95% CI, 0.337-0.891; p = 0.015), while treatment with cyclosporine was associated with increased risk of death (odds ratio, 7.571; 95% CI, 3.702-15.483; p < 0.001). Considering different trigger groups separately, same results occurred only for infection-triggered hemophagocytic lymphohistiocytosis. No information was available on disease severity and other confounding factors. CONCLUSIONS: Mortality of hemophagocytic lymphohistiocytosis in the ICU is high. Most common triggers were infections. Results of survival analyses may be biased by treatment indication and disease severity. Future studies prospectively investigating treatment tailored to critically ill hemophagocytic lymphohistiocytosis patients are highly warranted.

Echocardiography and biomarkers for the diagnosis of cardiotoxicity.

As a result of better treatment options for malignant cancer, the cardiovascular side effects of such therapies have increasingly come into focus in recent years. The new cardiological subspecialty of oncocardiology is developing strategies to prevent and/or detect those effects early in order to treat them in a timely and adequate manner. The diagnosis of cardiotoxic effects is based mainly on imaging and specific biomarkers. Echocardiography has become the main imaging technique due to its wide availability. In addition to quantitative determination of left ventricular function using two-dimensional methods, three-dimensional methods offer better precision and less variability in the detection of cardiac dysfunction. Furthermore, the analysis of the global longitudinal strain (GLS) reveals even subtle changes in left ventricular function and thus detects very early damage before left ventricular ejection fraction drops. Various biomarkers have been tested recently for their potential to detect cardiotoxicity. Cardiac troponins are currently the best investigated biomarkers and certainly have the highest impact. Due to contradicting results, the importance of natriuretic peptides has not yet been conclusively clarified. Results for myeloperoxidase are promising, as are the results for circulating microRNAs, which still mainly derive from experimental data. In this context, further studies still need to show the value of these in everyday clinical practice.

Characteristics and Outcome of Patients After Allogeneic Hematopoietic Stem Cell Transplantation Treated With Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

OBJECTIVES: The acute respiratory distress syndrome is a frequent condition following allogeneic hematopoietic stem cell transplantation. Extracorporeal membrane oxygenation may serve as rescue therapy in refractory acute respiratory distress syndrome but has not been assessed in allogeneic hematopoietic stem cell transplantation recipients. DESIGN: Multicenter, retrospective, observational study. SETTING: ICUs in 12 European tertiary care centers (Austria, Germany, France, and Belgium). PATIENTS: All allogeneic hematopoietic stem cell transplantation recipients treated with venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome between 2010 and 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-seven patients, nine of whom underwent noninvasive ventilation at the time of extracorporeal membrane oxygenation initiation, were analyzed. ICU admission occurred at a median of 146 (interquartile range, 27-321) days after allogeneic hematopoietic stem cell transplantation. The main reason for acute respiratory distress syndrome was pneumonia in 81% of patients. All but one patient undergoing noninvasive ventilation at extracorporeal membrane oxygenation initiation had to be intubated thereafter. Overall, seven patients (19%) survived to hospital discharge and were alive and in remission of their hematologic disease after a follow-up of 18 (range, 5-30) months. Only one of 24 patients (4%) initiated on extracorporeal membrane oxygenation within 240 days after allogeneic hematopoietic stem cell transplantation survived compared to six of 13 (46%) of those treated thereafter (p < 0.01). Fourteen patients (38%) experienced bleeding events, of which six (16%) were associated with fatal outcomes. CONCLUSIONS: Discouraging survival rates in patients treated early after allogeneic hematopoietic stem cell transplantation do not support the use of extracorporeal membrane oxygenation for acute respiratory distress syndrome in this group. On the contrary, long-term allogeneic hematopoietic stem cell transplantation recipients otherwise eligible for full-code ICU management may be potential candidates for extracorporeal membrane oxygenation therapy in case of severe acute respiratory distress syndrome failing conventional measures.

New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

Long-term outcome of liver transplant patients with Budd-Chiari syndrome secondary to myeloproliferative neoplasms.

BACKGROUND: A considerable proportion of patients receiving liver transplants for Budd-Chiari syndrome (BCS) suffer from myeloproliferative neoplasms (MPN). This study evaluated the long-term prognosis of liver-transplanted patients with BCS secondary to MPN and the effect of immunosuppression on MPN progression. METHODS: A total of 78 patients with BCS were evaluated between 1982 and 2013. Of those, 40 patients suffered from polycythaemia vera (PV) and essential thrombocythaemia (ET). One patient had primary myelofibrosis (PMF). All patients received the standard immunosuppressive regimen. We retrospectively evaluated the long-term survival, clinical course and laboratory parameters of patients with MPN. RESULTS: Exactly 29/41 patients (71%) with MPN survived ≥ 3 years [mean age 36 ± 11 years; females n = 27 (93%)]. Mean follow-up after orthotopic liver transplantation (OLT) was 12.4 ± 7.3 years (range 3-28 years). Five- and 10-year survival rates were not significantly different in patients with and without MPN (P = 0.81 and P = 0.66 respectively) or in patients with PV and ET (P = 0.29 and P = 0.55 respectively). Thrombosis and bleeding developed in 7/29 (24%) long-term MPN survivors with no significant difference between ET and PV (P = 0.18). In the long-term follow-up, there was no evidence of progression to overt myelofibrosis or acute myeloid leukaemia (AML). In the uni- and multivariate Cox-regression analyses, MPN did not influence survival after OLT. CONCLUSIONS: Budd-Chiari syndrome patients with and without underlying MPN had similar long-term survival rates after OLT. There was no evidence of enhanced progression of MPN after OLT secondary to immunosuppressive therapy. However, major haemorrhage and recurrent thrombosis contributed to morbidity and mortality after OLT in those patients.

Cardiac awake extracorporeal life support-bridge to decision?

Severe acute heart failure requires immediate intensive care unit (ICU) treatment, but prognosis and outcome of further treatment regimens largely depends on the preprocedural status of the patient. Especially, multiorgan failure including mechanical ventilation are unfavorable predictors of clinical outcome. Here, we report a strategy of immediate initiation of extracorporeal life support (ECLS) in awake and spontaneously breathing patients with acute heart failure to achieve early multiorgan recovery and gain sufficient time for further treatment planning. Twenty-three patients with severe cardiac failure refractory to standard medical management underwent ECLS treatment, after first clinical signs of cardiac failure appeared to avoid mechanical ventilation. Hemodynamic parameters and renal and liver functions were monitored. Outcome at 1 and 6 months was determined. Patients 46.1 ± 15.5 years of age were placed on ECLS due to various underlying diagnosis: ischemic heart disease (n = 6), dilatative cardiomyopathy (n = 4), myocarditis (n = 2), graft failure following heart transplantation (n = 6), or other diseases (n = 5). ECLS lasted 11.9 ± 12.9 days. Hemodynamic stabilization was achieved immediately after ECLS initiation. Vasopressors were reduced subsequently and the cardiac situation improved indicated by central venous saturation, which increased from 38.5 ± 11.3% before to 74.26 ± 8.4% (P < 0.0001) 24 h after ECLS initiation. Similarly, serum lactate levels decreased from 4.7 ± 4.6 to 1.7 ± 1.51 mmol/L (P = 0.003). Cumulative 30-day survival was 87.5%, and 6-month survival was 70.8%. In acute cardiac failure, early ECLS treatment is a safe, feasible treatment in awake patients allowing a gain of time for final decision. Moreover, this strategy avoids complications associated with sedation and mechanical ventilation and leads to recovery of secondary organ function, enabling destination therapy.

Therapeutic plasma exchange as rescue therapy in severe sepsis and septic shock: retrospective observational single-centre study of 23 patients.

BACKGROUND: Several case series and small randomized controlled trials suggest that therapeutic plasma exchange (TPE) improves coagulation, hemodynamics and possibly survival in severe sepsis. However, the exact role of TPE in modern sepsis therapy remains unclear. METHODS: We performed a retrospective observational single-centre study on the use of TPE as rescue therapy in 23 consecutive patients with severe sepsis or septic shock from 2005 to 2012. Main surrogate markers of multiple organ failure (MOF) before, during and after TPE as well as survival rates are reported. RESULTS: At baseline, mean SOFA score was 13 (standard deviation [SD] 4) and median number of failed organ-systems was 5 (interquartile range [IQR] 4-5). TPEs were performed 3 days (IQR 2-10) after symptom onset and 1 day (IQR 0-8) after ICU admission. The median total exchange volume was 3750 ml (IQR 2500-6000), which corresponded to a mean of 1.5 times (SD 0.9) the individual plasma volume. Fresh frozen plasma was used in all but one treatments as replacement fluid. Net fluid balance decreased significantly within 12 hrs following the first TPE procedure by a median of 720 mL (p = 0.002), irrespective of outcome. Reductions of norepinephrine dose and improvement in cardiac index were observed in individual survivors, but this was not significant for the overall cohort (p = 0.574). Platelet counts decreased irrespective of outcome between days 0 and 2 (p < 0.003), and increased thereafter in many survivors. There was a non-significant trend towards younger age and higher procalcitonin levels among survivors. Nine out of 23 TPE treated patients (39%) survived until ICU discharge (among them 3 patients with baseline SOFA scores of 15, 17, and 20). CONCLUSIONS: Our data suggest that some patients with severe sepsis and septic shock may experience hemodynamic stabilisation by early TPE therapy.

COVID-19 in Patients with Active Cancer: Higher Inflammatory Activity Predicts Poor Outcome.

INTRODUCTION: Active malignancies have been identified as an independent risk factor for severity and mortality in COVID-19. However, direct comparisons between SARS-CoV-2-infected patients with active (acP) and non-active cancers (n-acP) remain scarce. PATIENTS AND METHODS: We retrospectively analyzed a cohort of cancer patients with PCR-confirmed SARS-CoV-2 infection, enrolled from March 16, 2020, to July 31, 2021. Data on demographics, cancer, and laboratory findings were collected. Descriptive and subsequent regression analyses were performed. Endpoints were "deterioration to severe COVID-19" and "infection-associated mortality." RESULTS: In total, 987 cancer patients (510 acP vs. 477 n-acP) were included in our analysis. The majority was >55 years old, more men than women were included. At detection of SARS-CoV-2, 65.5% of patients had mild/moderate symptoms, while deterioration to severe COVID-19 was slightly more common in acP (19 vs. 16%; p = 0.284). COVID-19-associated mortality was significantly higher in acP (24 vs. 17.5%, p < 0.001). In terms of laboratory tests, severe cytopenia and elevated levels of inflammatory markers were common findings in acP at baseline, particularly in those who developed a severe infection or died. Multivariate analysis revealed that ferritin (HR 14.24 [2.1-96], p = 0.006) and CRP (HR 2.85 [1.02-8.02], p = 0.046) were associated with severity and mortality. In n-acP, association was seen for ferritin only (HR 4.1 [1.51-11.17], p = 0.006). CONCLUSION: Comparing patients with active and non-active cancer, the former showed higher mortality rates. Also, inflammatory markers were significantly increased, assuming higher levels of inflammation may play a role in the adverse outcome of COVID-19 in aCP.

Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time.

Variability or stability might have an impact on treatment success and toxicity of CD19 CAR T-cells. We conducted a prospective observational study of 12 patients treated with Tisagenlecleucel for CD19+ B-cell malignancies. Using a 31-color spectral flow cytometry panel, we analyzed differentiation stages and exhaustion markers of CAR T-cell subsets prior to CAR T-cell infusion and longitudinally during 6 months of follow-up. The majority of activation markers on CAR T-cells showed stable expression patterns over time and were not associated with response to therapy or toxicity. Unsupervised cluster analysis revealed an immune signature of CAR T-cell products associated with the development of immune cell-associated neurotoxicity syndrome. Warranting validation in an independent patient cohort, in-depth phenotyping of CAR T-cell products as well as longitudinal monitoring post cell transfer might become a valuable tool to increase efficacy and safety of CAR T-cell therapy.