Safety and Feasibility of Immunoadsorption with Heparin Anticoagulation in Preparation of ABO-Incompatible Kidney Transplantation: A Retrospective Single-Center Study.

Introduction: Immunoadsorption (IA) of isohemagglutinins is an often-crucial procedure in preparation of major ABO blood group-incompatible living donor kidney transplantation (ABOi LDKT). Standard citrate-based anticoagulation during the procedure has potential disadvantages for distinct patient groups. In this study, we report our experience with an alternative anticoagulation scheme using heparin during IA for selected patients. Methods: We conducted a retrospective analysis of all patients who underwent IA with heparin anticoagulation between February 2013 and December 2019 at our institution with focus on the safety and efficacy of the adapted procedure. For further validation, we compared graft function, graft survival, and overall survival with those of all recipients of living donor kidney transplants with or without pretransplant desensitizing apheresis for ABO antibodies at our institution during the same period. Results: In thirteen consecutive patients prepared for ABOi LDKT with IA with heparin anticoagulation, no major bleeding or other significant complications were observed. All patients achieved sufficient isohemagglutinin titer reduction to proceed to transplant surgery. Graft function, graft survival, and overall survival did not significantly differ from patients treated with standard anticoagulation for IA or ABO compatible recipients of living donor kidneys. Conclusion: IA with heparin in preparation of ABOi LDKT is safe and feasible for selected patients after internal validation.

Characterization of pathogen-inactivated COVID-19 convalescent plasma and responses in transfused patients.

BACKGROUND: Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics. STUDY DESIGN AND METHODS: In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients. RESULTS: Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients. DISCUSSION: PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays.

[Future perspectives in Myelodysplastic Syndrome]. / Was erwartet uns in naher Zukunft beim myelodysplastischen Syndrom?

Future perspectives in Myelodysplastic Syndrome Abstract. In the next years the role of molecular genetics will increase in diagnosis, prognosis and therapy of MDS. In the treatment of low risk MDS anemia remains the biggest challgenge. In the treatment of high risk MDS new promising drugs are entering the field and open the possibility of combination therapies. Inclusion into interventional and observational studies is of great importance.

Daratumumab for immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. It is caused by a severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, 13) deficiency due to circulating autoantibodies, and is associated with significant morbidity and mortality. Current treatment options include plasma exchange, immunosuppression, and caplacizumab. When remission is achieved, the risk of relapse is high, especially in patients with persistent ADAMTS13 deficiency. We report the eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity using the anti-CD38 antibody daratumumab in two patients with iTTP. One patient had a frequently relapsing course, and the other a treatment-refractory first episode. There were no relevant adverse drug reactions.

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

Case Report: Opposite Effects of BRAF Inhibition on Closely Related Clonal Myeloid Disorders.

Langerhans cell histiocytosis (LCH) commonly co-occurs with additional myeloid malignancies. The introduction of targeted therapies, blocking "driver" mutations (e.g., BRAF V600E), enabled long-term remission in patients with LCH. The effect of BRAF inhibition on the course and the prognosis of co-existing clonal hematopoiesis is poorly understood. We report on a 61-year-old patient with systemic BRAF V600E positive LCH and concomitant BRAF wild-type (wt) clonal cytopenia of unknown significance (CCUS) with unfavorable somatic mutations including loss of function (LOF) of NF1. While manifestations of LCH improved after blocking BRAF by dabrafenib treatment, the BRAF wt CCUS progressed to acute myeloid leukemia (AML). The patient eventually underwent successful allogeneic hematopoietic stem cell transplantation (HSCT). We performed an in-depth analyzes of the clonal relationship of CCUS and the tissue affected by LCH by using next-generation sequencing (NGS). The findings suggest activation of the mitogen-activated protein (MAP) kinase pathway in the CCUS clone due to the presence of the RAS deregulating NF1 mutations and wt BRAF, which is reportedly associated with paradoxical activation of CRAF and hence MEK. Patients with LCH should be carefully screened for potential additional clonal hematological diseases. NGS can help predict outcome of the latter in case of BRAF inhibition. Blocking the MAP kinase pathway further downstream (e.g., by using MEK inhibitors) or allogeneic HSCT may be options for patients at risk.

Extracorporeal Photopheresis in Graft-versus-Host Disease.

BACKGROUND AND SUMMARY: Extracorporeal photopheresis (ECP) is a leukapheresis-based procedure used in the therapy of acute and chronic graft-versus-host disease (aGvHD, cGvHD) and other diseases. Based on the substantial efficacy and the excellent safety profile in the absence of immunosuppression ECP has established itself as a major treatment form for steroid-refractory GvHD. Here we review the current literature on ECP as a treatment option for patients with aGvHD as well as cGvHD. KEY MESSAGES: ECP is a well-established second-line therapy for cGvHD. Its role in the treatment of aGvHD is less clear but also points towards an effective second-line therapy option. In the future ECP could play a role in the prevention of GvHD. More experimental and randomized controlled trials are needed to define the best patient selection criteria, settings, and therapy regimens for GvHD.

[Myelodysplastic Syndromes]. / Myelodysplastische Syndrome.

Myelodysplastic Syndromes Abstract. Myelodysplastic Syndromes are a heterogenous group of myeloid neoplasias with differing prognosis. Diagnostics include morphology of blood and marrow and cytogenetic analysis. Risk scores, such as the IPSS or IPSS-R allow for prognostication of survival and the probability of transforming to acute myeloid leukemia. Most patients are elderly and may present with co-morbidities that need to be taken into account. Treatment measures include supportive care as well as low dose chemotherapy and up to hematopoetic cell transplantation and are therefore equally heterogenous in intensity. Supportive measures consist of transfusion of red cells but also platelets, erythropoiesis stimulating agents (ESA) and if transfused, iron chelation. In older patients with advanced MDS, who are not candidates for hematopoetic cell transplantation, low-dose chemotherapy such as with hypomethylating agents, e. g. azacyitinde is reasonably effective and well tolerated.

Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study.

BACKGROUND: Results of preclinical studies have shown that EGFR immunoliposomes have substantial antitumour effects. We aimed to assess the tolerability, safety, pharmokinetics, and efficacy of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in patients with solid tumours. METHODS: In this first-in-man, open-label, phase 1 clinical study, we enrolled patients at University Hospital of Basel, Switzerland, who had EGFR-overexpressing advanced solid tumours no longer amenable to standard treatment. Anti-EGFR ILs-dox nanoparticles were constructed by covalently linking pegylated liposomes containing doxorubicin to antigen-binding fragments (Fab') of cetuximab. We intravenously infused the nanoparticle at escalating doses (doxorubicin 5 mg/m(2), 10 mg/m(2), 20 mg/m(2), 30 mg/m(2), 40 mg/m(2), 50 mg/m(2), and 60 mg/m(2)) once every 4 weeks for a maximum of six cycles. The primary endpoint was to establish the maximum tolerated dose. We analysed patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01702129. FINDINGS: Between Jan 30, 2007, and March 4, 2010, we gave the drug to 29 patients, three of whom were withdrawn from the study because we could not complete a safety assessment. Of the 26 patients assessed for the primary endpoint, two who received a dose of 60 mg/m(2) had dose-limiting toxicities (one had neutropenia and the other had anaemia); therefore, the maximum tolerated dose was defined as 50 mg/m(2). At all lower doses, anti-EGFR ILs-dox was well tolerated; grade 1 skin toxicity occurred in two patients only. We recorded 22 serious adverse events (SAEs) in 17 patients, mostly due to tumour progression. Three SAEs were fatal. Only three SAEs (febrile neutropenia, septicaemia, and a fatal massive oral bleed) were probably or possibly related to study drug. No patients had palmar-plantar erythrodysaesthesia, alopecia, cardiotoxicity, or cumulative toxicity. Best response to treatment included one complete response, one partial response, and ten stable disease lasting 2-12 months (median 5·75 months). INTERPRETATION: Because anti-EGFR ILs-dox was well tolerated up to 50 mg doxorubicin per m(2), and we recorded clinical activity, further assessment of this nanoparticle at this dose in phase 2 trials is warranted. FUNDING: Cancer League Basel, Swiss Cancer League, Schoenmakers-Müller Foundation, and Werner Geissberger Foundation.