Successful treatment with T depleted autologous peripheral blood stem cell transplantation of refractory chronic autoimmune thrombocytopenic purpura

Autoimmune thrombocytopenia (AITP) is a disorder due to specific platelet auto-antibodies directed against platelet surface glycoproteins. AITP in adults is usually chronic, idiopathic and frequently refractory to conventional treatments. Myelo- and immuno- suppressive chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation is an experimental approach for severe chronic refractory AITP. We report a case of a woman with AITP, refractory to the conventional therapy, submitted to T-cell-depleted autologous PBSC transplantation, which obtained long term stable response on platelet count. We deem that the positive outcome of our patient depends on T-cells depletion of the graft, which reduces autoreactive T clones

Platelet-Lysate-Expanded Mesenchymal Stromal Cells for the Treatment of Resistant GVHD

n/

Mesenchymal Stromal Cells Do Not Increase the Risk of Viral Reactivation Nor the Severity of Viral Events in Recipients of Allogeneic Stem Cell Transplantation

Mesenchymal stromal cells (MSC) are tested in clinical trials to treat graft versus host disease (GvHD) after stem cell transplantation (SCT). In vitro studies demonstrated MSC's broad immunosuppressive activity. As infections represent a major risk after SCT, it is important to understand the role of MSC in this context. We analyzed 24 patients (pts) receiving MSC for GvHD in our Unit between 2009 and 2011. We recorded viral reactivations as measured in whole blood with polymerase chain reaction for 100 days following MSC administration. In patients with a documented viral reactivation in the first 3 days following MSCs infusion the frequency of virus-specific IFNgamma-producing cells was determined through enzyme-linked immunospot assay. In our cohort of patients viral reactivation after MSC infusion occurred in 45% of the cases, which did not significantly differ from the incidence in a historical cohort of patients affected by steroid resistant GvHD and treated with conventional immunosuppression. No patient presented severe form of infection. Two cases could be checked for immunological response to viral stimulus and demonstrated virus specific T-cytotoxic lymphocyte activity. In our experience MSC infusion did not prove to trigger more frequent or severer viral reactivations in the post transplantation setting

Treatment of Graft versus Host Disease with Mesenchymal Stromal Cells: A Phase I Study on 40 Adult and Pediatric Patients

Abstract This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow–derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 10 6 /kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100

Paradoxical Increase in TAG and DAG Content Parallel the Insulin Sensitizing Effect of Unilateral DGAT1 Overexpression in Rat Skeletal Muscle

BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle. CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling

Central venous catheter insertion in peripheral blood hematopoietic stem cell sibling donors: The SIdEM (Italian Society of Hemapheresis and Cell Manipulation) point of view

Collection of peripheral blood hematopoietic stem cells (PBSC) is the practice of choice for graft procurement in both autologous and allogeneic setting. The success of this procedure depends on the use of adequate vascular accesses. Well-sized peripheral veins are the first option in autologous and allogeneic donations. In autologous setting, in case of lack of adequate veins, central venous catheters (CVC) may be used for collection. In the allogeneic setting, although available data have shown the safety of the use of CVC, there are still some controversies about the possible insertion of a CVC in donors. A specific policy from competent registries is usually applied in the different countries to regulate the use of CVC in unrelated donors. In siblings, the question is still undefined due both to the lack of shared guidelines and to the specific characteristics of this donation. In fact, in not so rare cases, larger stem cell doses for specific cell manipulations (e.g., T/B cell depletion in the haploidentical setting) are needed. The lack of international rules or standard that forbid the use of a CVC in siblings and published data that document the safety of this procedure, allowed the Societa Italiana di Emaferesi e Manipolazione Cellulare (SIdEM) national Board to identify a possible, shared, operational approach to address this issue by a case-specific risk-benefit assessment. (C) 2014 Elsevier Ltd. All rights reserved

Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Tra

Background Extracorporeal photopheresis (ECP) is an effective treatment for both acute and chronic graft-versus-host disease (GVHD) in children and adults. Despite the large use of this treatment, a large heterogeneity in current application of ECP has been reported so far and recent evidence brought novel issues into some specific topics. Consensus-based recommendations ameliorate the appropriateness in daily clinical practice and, in turn, optimize the use of health care resources. Study Design and Methods Two Italian scientific societies, the Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and the Italian Group for Bone Marrow Transplantation (GITMO), joined to develop and disseminate recommendations on appropriate application of ECP treatment in patients with GVHD. Accordingly, SIdEM and GITMO named an expert panel that first selected 16 questions that were considered relevant for clinical practice: the questions were subsequently addressed through a revision of the available literature and in consensus meetings. The whole group discussed the proposed recommendations according to the nominal group technique. Results The above-described approach in turn allowed the panel to agree on 47 practice recommendations. SIdEM and GITMO will disseminate such recommendations to the national transplant centers. Conclusion In conclusion, SIdEM and GITMO have made a scientific effort to provide a useful tool to physicians involved in the field, thus supporting daily clinical practice, as well as strategic decisions in the setting of ECP treatment of GVHD. \ua9 2013 American Association of Blood Banks

An attempt to induce transient immunosuppression pre-erythrocytapheresis in a girl with sickle cell disease, a history of severe delayed hemolytic transfusion reactions and need for hip prosthesis

We report on a case of delayed hemolytic transfusion reaction (DHTR) occurred 7 days after an erythrocytapheresis or eritroexchange procedure (EEX) treated with rituximab and glucocorticoids in a 15-years old patient with sickle cell disease. EEX was performed despite a previous diagnosis of alloimmunization, in order to reduce hemoglobin S rate before a major surgery for avascular necrosis of the femoral head. A first dose of rituximab was administered before EEX. However, rituximab couldn’t prevent DHTR that occurred with acute hemolysis, hemoglobinuria and hyper-bilirubinemia. A further dose of rituximab and three boli of methylprednisolone were given after the onset of the reaction. It is likely that the combined use of rituximab and steroids managed to gradually improve both patient’s general conditions and hemoglobin levels. Nor early or late side effects were registered in a 33-months follow-up period. This report suggests the potential effectiveness and safety of rituximab in combination with steroids in managing and mitigating the symptoms of delayed post-transfusional hemolytic reactions in alloimmunized patients affected by sickle cell disease with absolute need for erythrocytapheresis

Compassionate use of ruxolitinib in patients with SARS‐Cov‐2 infection not on mechanical ventilation: Short‐term effects on inflammation and ventilation

Abstract Ruxolitinib is an anti‐inflammatory drug that inhibits the Janus kinase‐signal transducer (JAK‐STAT) pathway on the surface of immune cells. The potential targeting of this pathway using JAK inhibitors is a promising approach in patients affected by coronavirus disease 2019 (COVID‐19). Ruxolitinib was provided as a compassionate use in patients consecutively admitted to our institution for severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Inclusion criteria were oxygen saturation less than or equal to 92%, signs of interstitial pneumonia, and no need of mechanical ventilation. Patients received 5 mg b.i.d. of ruxolitinib for 15 days, data were collected at baseline and on days 4, 7, and 15 during treatment. Two main targets were identified, C‐reactive protein (CRP) and PaO2/FiO2 ratio. In the 31 patients who received ruxolitinib, symptoms improved (dyspnea scale) on day 7 in 25 of 31 patients (80.6%); CRP decreased progressively from baseline (79.1 ± 73.4 mg/dl) to day 15 (18.6 ± 33.2, p = 0.022). In parallel with CRP, PO2/FiO2 ratio increased progressively during the 3 steps from 183 ± 95 to 361 ± 144 mmHg (p < 0.001). In those patients with a reduction of polymerase chain reaction less than or equal to 80%, delta increase of the PO2/FiO2 ratio was significantly more pronounced (129 ± 118 vs. 45 ± 35 mmHg, p = 0.02). No adverse side effects were recorded during treatment. In patients hospitalized for COVID‐19, compassionate‐use of ruxolitinib determined a significant reduction of biomarkers of inflammation, which was associated with a more effective ventilation and reduced need for oxygen support. Data on ruxolitinib reinforces the hypothesis that targeting the hyperinflammation state, may be of prognostic benefit in patients with SARS‐CoV‐2 infection. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Some evidence suggest that patients affected by coronavirus disease 2019 (COVID‐19) present an exuberant inflammatory response represented by a massive production of type I interferons and different pro‐inflammatory cytokines. Nonetheless, as for the present, there are no proven therapeutic agents for COVID‐19, in particular anti‐inflammatory and antiviral, with a significant and reproducible positive clinical response. WHAT QUESTION DID THIS STUDY ADDRESS? Targeted therapeutic management of pro‐inflammatory pathways appears to be a promising strategy against COVID‐19, and ruxolitinib, due to its established broad and fast anti‐inflammatory effect, appears to be a promising candidate worthy of focused investigations in this field. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Ruxolitinib rapidly reduces the systemic inflammation, which accompanies the disease, thereby improving respiratory function and the need of oxygen support. This effect may contribute to avoid progression of the disease and the use of invasive ventilation. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Data on ruxolitinib contributes the reinforcement of the hypothesis that it is crucial to counteract the early hyperinflammation state, particularly of the lungs, induced by COVID‐19 infection