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Provides information on a study investigating arterial vasomotion. Methodology used to conduct the study; Information on regular and irregular vasomotion; Details on the sensitivity to external perturbations; Findings of the study.

Background and Objectives : In clinical practice, neutropenia is frequently accompanied by other cytopenia; isolated non-chemotherapy-induced severe neutropenia is less frequent and its differential diagnosis can be challenging. In this real-world study with data collected over a 5-year period in a tertiary referral hospital, we primarily sought to identify underlying causes of isolated severe neutropenia (<0.5 × 10 9 /L). Secondly, we aimed to analyze its management and outcomes. Materials and Methods : From 444,926 screened patients, after exclusion of patients with chemotherapy, radiotherapy, hematological neoplasms, additional cytopenia, and benign ethnic neutropenia, we identified and analyzed data from 70 patients (0.015%) with isolated severe neutropenia. We thus confirmed that the occurrence of isolated severe neutropenia is a rare event, even in a tertiary hospital. Results : The median age at diagnosis was 34 years (range 1-81) and 65% were female. Acute neutropenia was more frequently observed (n = 46/70, 65.7%); the main underlying causes in this group were drugs (n = 36/46, 78%) followed by infections (n = 10/46, 21.7%). We identified 24 (34.3%) patients with chronic neutropenia. The majority of them (n = 12/24, 50%) had an idiopathic form (CIN), 8/24 (33%) were autoimmune (AIN), and 4/24 (17%) were congenital. Conclusions : This study demonstrates the rarity and heterogeneity of isolated severe neutropenia and the steps to consider in its diagnostic work-up and management. Epidemiological characteristics, diagnostic work-up, and management including hospitalizations are described. Due to the high frequency of metamizole-induced neutropenia observed in this study, we want to raise awareness about its use, since this complication generates frequent hospitalizations even in young, otherwise healthy patients. Furthermore, recurrent infections in chronic forms of idiopathic neutropenia were quite common, suggesting a difference in phenotypes and need for therapy consideration depending on the clinical course.

Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are significant complications in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy. However, it remains unclear whether CAR-T cell expression itself is clinically relevant. We assessed CAR-T cell mRNA expression and DNA concentration by digital droplet PCR in peripheral blood from 14 sequential CAR-T cell recipients. Patients were grouped according to CAR-T cell peak expression. Patients with high CAR-T cell peak expression (8 patients; 57%) had higher rates of ICANS (p=0.0308) and intensive care unit admission (p=0.0404), longer durations of hospitalization (p=0.0077), and, although not statistically significant, a higher rate of CRS (p=0.0778). There was a correlation of CAR-T cell mRNA expression with DNA concentration, but CAR-T cell expression levels failed to correlate to response or survival. Our data suggest that higher CAR-T cell peak mRNA expression is associated with increased risk for ICANS and possibly CRS, requiring further investigation in larger studies., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2023 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House.)

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM), leading to unprecedented responses in this patient population. Idecabtagene vicleucel (ide-cel) has been recently approved for treatment of triple-class exposed RRMM. We report real-life experiences with the commercial use of ide-cel in RRMM patients., Methods: We performed a retrospective analysis of the first 16 triple-class exposed RRMM patients treated with ide-cel at a single academic center. We assessed toxicities, response to treatment, CAR T expansion and soluble BCMA (sBCMA) levels., Results: We identified 16 consecutive RRMM patients treated with ide-cel between 06-10/2022. Median age was 69 years, 6 (38%) patients had high-risk cytogenetics, 3 (19%) R-ISS stage III, and 5 (31%) extramedullary disease. Median number of previous treatment lines was 6 (3-12). Manufacturing success rate was 88% (6% required second lymphapheresis, 6% received an out-of-specification product). At 3 months, the overall response rate (ORR) was 69% (44% sCR, 6% CR, 19% VGPR). Cytokine release syndrome (CRS) occurred in 15 (94%) patients (88% G1, 6% G2), immune effector-cell associated neurotoxicity syndrome (ICANS) in 1 (6% G1), febrile neutropenia in 11 (69%), and infections in 5 (31%). Prolonged hematologic toxicity occurred in 4/16 (25%) patients. Other non-hematological toxicities were elevated hepatic enzymes (38%), colitis (6%, G3) and DIC (6%, G2). Responses were more frequent in patients with higher CAR T expansion (100% vs 38%), and lack of decrease or plateau of sBCMA levels was typically observed in non-responders., Conclusions: We report one of the first cohorts of RRMM treated with commercial ide-cel. The ORR was 69% and safety profile was manageable, but prolonged hematologic toxicity still represents a major challenge. Responses correlated with in vivo CAR T cell expansion, underlining the need of further research to optimize CAR T expansion., (© 2023. The Author(s).)

Chimeric antigen receptor (CAR) T-cell therapy has led to profound and durable tumor responses in a relevant subset of patients with relapsed/refractory (r/r) B-cell lymphomas. Still, some patients show insufficient benefit or relapse after CAR T-cell therapy. We performed a retrospective study to investigate the correlation between CAR T-cell persistence in the peripheral blood (PB) at 6 months, assessed by droplet digital PCR (ddPCR), with CAR T-cell treatment outcome. 92 patients with r/r B-cell lymphomas were treated with CD19-targeting CAR T-cell therapies at our institution between 01/2019-08/2022. Six months post-treatment, 15 (16%) patients had no detectable circulating CAR-T constructs by ddPCR. Patients with CAR T-cell persistence had a significantly higher CAR T-cell peak (5432 vs. 620 copies/ug cfDNA, p = 0.0096), as well as higher incidence of immune effector cell-associated neurotoxicity syndrome (37% vs. 7%, p = 0.0182). After a median follow-up of 8.5 months, 31 (34%) patients relapsed. Lymphoma relapses were less frequent among patients with CAR T-cell persistence (29% vs. 60%, p = 0.0336), and CAR T-cell persistence in the PB at 6 months was associated with longer progression-free survival (PFS) (HR 2.79, 95% CI: 1.09-7.11, p = 0.0319). Moreover, we observed a trend towards improved overall survival (OS) (HR 1.99, 95% CI: 0.68-5.82, p = 0.2092) for these patients. In our cohort of 92 B-cell lymphomas, CAR T-cell persistence at 6 months was associated with lower relapse rates and longer PFS. Moreover, our data confirm that 4-1BB-CAR T-cells have a longer persistence as compared to CD-28-based CAR T-cells.

Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton's tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy.

Chimeric antigen receptor T-cells (CAR T) treatment has become a standard option for patients with diffuse large B-cell lymphomas (DLBCL), which are refractory or relapse after two prior lines of therapy. However, little evidence exists for treatment recommendations in patients who relapse after CAR T-cell treatment and the outcome for such patients is poor. In this study, we evaluated the safety and efficacy of a monotherapy with the bispecific CD20xCD3 antibody glofitamab in patients who progressed after CAR T treatment. We report nine consecutive patients with progressive DLBCL after preceding CAR T-cell therapy. The patients received a maximum of 12 cycles of glofitamab after a single obinutuzumab pre-treatment at an academic institution. CRS was observed in two patients (grade 2 in both patients). We observed an overall response rate of 67%, with four patients achieving a complete response and a partial remission in two patients. Interestingly, we identified increased persistence of circulating CAR T-cells in peripheral blood in three of the five patients with measurable CAR T-cells. Our data suggest that glofitamab treatment is well tolerated and effective in patients with DLBCL relapsing after CAR T-cell therapy and can enhance residual CAR T-cell activity.

Background: Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine., Methods: Plasma levels of soluble BCMA (sBCMA) and anti-BCMA CAR-T cell copy numbers were monitored in the blood, following CAR-T cell infusion in patients with relapsed multiple myeloma. sBCMA peptide concentration was determined in the plasma, applying a human BCMA/TNFRS17 ELISA. ddPCR was performed using probes targeting the intracellular signaling domains 4-1BB und CD3zeta of the anti-BCMA CAR-T construct., Results: We report responses in the first five patients who received anti-BCMA CAR- T cell therapy at our center. Four patients achieved a complete remission (CR) in the bone marrow one month after CAR-T infusion, with three patients achieving stringent CR, determined by flow cytometry techniques. Anti-BCMA CAR-T cells were detectable in the peripheral blood for up to 300 days, with copy numbers peaking 7 to 14 days post-infusion. sBCMA plasma levels started declining one to ten days post infusion, reaching minimal levels 30 to 60 days post infusion, before rebounding to normal levels., Conclusions: Our data confirm a favorable response to treatment in four of the first five patients receiving anti-BCMA CAR-T at our hospital. Anti-BCMA CAR-T cell expansion seems to peak in the peripheral blood in a similar pattern compared to the CAR-T cell products already approved for lymphoma treatment. sBCMA plasma level may be a valid biomarker in assessing response to BCMA-targeting therapies in myeloma patients.

Background: Intraocular lymphoma (IOL) presents a real challenge in daily diagnostics. Cyto- and/or histopathology of vitreous body represent the diagnostic cornerstones. Yet, false negative results remain common. Therefore, we analyzed the diagnostic significance of flow cytometry (FC) within the workup algorithm of IOL and compared its sensitivity with the results obtained from routine cytopathology and molecular genetics; Methods: Seven patients undergoing vitrectomy due to suspected IOL were investigated by FC and parallel cytopathology and, if available, digital droplet PCR (ddPCR) for MYD88 L265P; Results: Four out of seven patients were finally diagnosed with IOL. Among the IOL patients, cytopathology confirmed the presence of lymphoma cells in only two cases. In contrast, FC was positive for IOL in all four cases, and FC additionally confirmed the lack of IOL in the remaining patients. In IOL patients diagnosed by FC and with available ddPCR, the diagnosis of IOL was confirmed by the presence of the MYD88 L265P mutation in all three patients; Conclusions: The combination with FC was superior to cytopathology alone in the diagnostic work-up of IOL, and it showed an excellent correlation with ddPCR results. A comprehensive diagnostic panel consisting of cytopathology, FC and molecular genetics should be considered for the work-up of suspected IOL.

Introduction: Despite a 50% cure rate, relapse remains the main cause of death in patients with acute myeloid leukemia (AML) consolidated with autologous stem cell transplantation (ASCT) in first remission (CR1). Clonal hematopoiesis of indeterminate potential (CH) increases the risk for hematological and cardiovascular disorders and death. The impact of CH persisting after ASCT in AML patients is unclear., Materials and Methods: We retrospectively investigated the prognostic value of persisting DNMT3A , TET2 , or ASXL1 (DTA) mutations after ASCT. Patients underwent stratification depending on the presence of DTA mutations., Results: We investigated 110 consecutive AML patients receiving ASCT in CR1 after two induction cycles at our center between 2007 and 2020. CH-related mutations were present in 31 patients (28.2%) after ASCT. The baseline characteristics were similar between patients with or without persisting DTA mutations after ASCT. The median progression free survival was 26.9 months in patients without DTA mutations and 16.7 months in patients with DTA mutations (HR 0.75 (0.42-1.33), p = 0.287), and the median overall survival was 80.9 and 54.4 months (HR 0.79 (0.41-1.51), p = 0.440), respectively., Conclusion: We suggest that DTA-CH after ASCT is not associated with an increased risk of relapse or death. The persistence of DTA mutations after induction should not prevent AML patients in CR1 from ASCT consolidation. Independent studies should confirm these data.

Thrombocytopenia can arise from various conditions, including myelodysplastic syndromes (MDS) and bone marrow failure (BMF) syndromes. Meticulous assessment of the peripheral blood smear, identification of accompanying clinical conditions, and characterization of the clinical course are important for initial assessment of unexplained thrombocytopenia. Increased awareness is required to identify patients with suspected MDS or BMF, who are in need of further investigations by a step-wise approach. Bone marrow cytomorphology, histopathology, and cytogenetics are complemented by myeloid next-generation sequencing (NGS) panels. Such panels are helpful to distinguish reactive cytopenia from clonal conditions. MDS are caused by mutations in the hematopoietic stem/progenitor cells, characterized by cytopenia and dysplasia, and an inherent risk of leukemic progression. Aplastic anemia (AA), the most frequent acquired BMF, is immunologically driven and characterized by an empty bone marrow. Diagnosis remains challenging due to overlaps with other hematological disorders. Congenital BMF, certainly rare in adulthood, can present atypically with thrombocytopenia and can be misdiagnosed. Analyses for chromosome fragility, telomere length, and germline gene sequencing are needed. Interdisciplinary expert teams contribute to diagnosis, prognostication, and choice of therapy for patients with suspected MDS and BMF. With this review we aim to increase the awareness and provide practical approaches for diagnosis of these conditions in suspicious cases presenting with thrombocytopenia.

Relapse of acute myeloid leukemia (AML) remains a major determinant of outcome. A number of molecularly directed treatment options have recently emerged making comprehensive diagnostics an important pillar of clinical decision making at relapse. Acknowledging the high degree of individual genetic variability at AML relapse, next-generation sequencing (NGS) has opened the opportunity for assessing the unique clonal hierarchy of individual AML patients. Knowledge on the genetic makeup of AML is reflected in patient customized treatment strategies thereby providing improved outcomes. For example, the emergence of druggable mutations at relapse enable the use of novel targeted therapies, including FLT3 inhibitors or the recently approved IDH1/2 inhibitors ivosidenib and enasidenib, respectively. Consequently, some patients may undergo novel bridging approaches for reinduction before allogeneic stem cell transplantation, or the identification of an adverse prognostic marker may initiate early donor search. In this review, we summarize the current knowledge of NGS in identifying clonal stability, clonal evolution, and clonal devolution in the context of AML relapse. In light of recent improvements in AML treatment options, NGS-based molecular diagnostics emerges as the basis for molecularly directed treatment decisions in patients at relapse., (© 2020 John Wiley & Sons Ltd.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used to treat relapsed B-cell lymphomas and acute lymphoblastic leukemia. Considering the frequency of cytokine release syndrome and CAR-T-related encephalopathy syndrome (CRS/CRES) after CAR-T administration, strategies enabling timely prediction of impending CRS/CRES are a clinical need., Methods: We evaluated the dynamics of serum interleukin (IL)-6 levels and CAR-T transgene copy numbers by digital droplet polymerase chain reaction in the peripheral blood of 11 consecutive patients with aggressive B-cell malignancies., Results: Four of 11 patients developed CRS, and 3 patients had CRES (33%), 2 of them had previous CRS. IL-6 levels increased on the day of clinical manifestation of CRS. All CRS patients had increased IL-6 peak levels (median IL-6 peak 606 pg/mL in CRS patients vs. 22 pg/mL in non-CRS patients, p = 0.0061). Different patterns emerged from the dynamics of CAR-T/µg genomic DNA: "rapid increase and rapid decrease with complete disappearance," "rapid increase and slow decrease with higher persistence," "rapid increase and rapid decrease with lower persistence," and "slow increase and rapid decrease with almost disappearance." Patients with the pattern "rapid increase and slow decrease with higher persistence" of CAR-T/µg genomic DNA concentration seemed to be at higher risk of developing CRS/CRES., Conclusion: Thus, the dynamics of CAR-T transgene copy numbers merits further evaluation for a possible association with manifestation of CRS. Increased IL-6 serum levels at CRS manifestation may contribute to the interpretation of symptoms., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

At present, hemato-oncologic diagnostics is facing dynamic changes. This applies to the exploration and introduction of novel technologies such as next-generation sequencing or digital droplet PCR for myeloid and lymphatic malignancies in laboratory routine, or liquid biopsy for patients with lymphoid malignancies. Targeted therapies such as FLT3 or IDH1/IDH2 inhibitors for acute myeloid leukemia are entering clinical practice. Thus, the demand for hematologic precision diagnostics both at initial diagnosis and during the course of the disease are equally increasing, and a short turn-around time becomes crucial. NGS expands the armamentarium for minimal residual disease diagnostics, but novel questions arise relating to sensitivity, the appropriate time points of this analysis, or the thresholds triggering therapeutic interventions. In this review article, we summarize some of the most relevant current changes and subsequent challenges for diagnostics in various myeloid and lymphatic malignancies. Future directions of hemato-oncologic diagnostics in the next 5-10 years are highlighted., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: The authors have declared no conflict of interest.

Reciprocal RUNX1 fusions are traditionally found in up to 10% of acute myeloid leukemia (AML) patients, usually associated with a translocation (8;21)(q22;q22) corresponding to the RUNX1-RUNX1T1 fusion gene. So far, alternative RUNX1 rearrangements have been reported only rarely in AML, and the few reports so far have focused on results based on cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction. Acknowledging the inherent limitations of these diagnostic techniques, the true incidence of rare RUNX1 rearrangements may be underestimated. In this report, we present two cases of adult AML, in which we detected rare RUNX1 rearrangements not by conventional cytogenetics but rather by next-generation panel sequencing. These include t(16;21)(q24;q22)/RUNX1-CBFA2T3 and t(7;21)(p22;q22)/RUNX1-USP42, respectively. In both patients the AML was therapy-related and associated with additional structural and numerical alterations thereby conferring bad prognosis. This is in line with previous reports on rare RUNX1 fusions in AML and emphasizes the clinical importance of their detection. In summary, our report not only confirms the clinical utility of NGS for diagnostics of rare reciprocal rearrangements in AML in a real-life scenario but also sheds light on the variety and complexity within AML. It further emphasizes the need for collection of additional cases for deepening insights on their clinical meaning as well as their frequency., (© 2019 Wiley Periodicals, Inc.)

Given the vast phenotypic and genetic heterogeneity of acute and chronic myeloid malignancies, hematologists have eagerly awaited the introduction of next-generation sequencing (NGS) into the routine diagnostic armamentarium to enable a more differentiated disease classification, risk stratification, and improved therapeutic decisions. At present, an increasing number of hematologic laboratories are in the process of integrating NGS procedures into the diagnostic algorithms of patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs). Inevitably accompanying such developments, physicians and molecular biologists are facing unexpected challenges regarding the interpretation and implementation of molecular genetic results derived from NGS in myeloid malignancies. This article summarizes typical challenges that may arise in the context of NGS-based analyses at diagnosis and during follow-up of myeloid malignancies.

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Acute fibrinous and organizing pneumonia (AFOP) is a recently described histologic pattern of diffuse pulmonary disease. In children, all cases reported to date have been fatal. In this study, we describe the first nonfatal AFOP in a child and review the literature., Description: A 10-year-old boy developed very severe aplastic anemia (VSAA) after being admitted to our hospital with a fulminant hepatic failure of unknown origin. A chest computed tomography scan revealed multiple lung nodules and a biopsy of a pulmonary lesion showed all the signs of AFOP. Infectious workup remained negative. We started immunosuppressive therapy with antithymocyte globulin and cyclosporine to treat VSAA. Subsequent chest computed tomography scans showed a considerable diminution of the lung lesions but the VSAA did not improve until we performed hematopoietic stem cell transplantation 5 months later., Conclusions: Aplastic anemia is associated with a variety of autoimmune syndromes. The sequence of events in our patient suggests that the hepatic failure, AFOP, and the VSAA may all have been part of an autoimmune syndrome. AFOP could be the result of immune dysregulation in this pediatric case with favorable outcome after immunosuppressive therapy and hematopoietic stem cell transplantation.