Burden of immune thrombocytopenia (ITP): Special considerations for refractory ITP.

It is known that patients with immune thrombocytopenia (ITP) have fatigue and impairment of health-related quality of life (HRQoL). However, it is hypothesized that patients with refractory ITP have additional burdens that should be considered. Specifically, fatigue is more pronounced in patients with refractory disease, there are additional side effects from second- and third-line treatments, additional anxiety about the long-term course of the disease, impairment in HRQoL resulting from heavy menstrual bleeding and concerns related to family planning. The burden of disease, therefore, should be carefully assessed and considered in these patients. However, researchers have utilized numerous tools for evaluating HRQoL and fatigue, making comparison of data across studies challenging. There is a need to standardize assessment using either disease-specific or generic instruments that can be easily implemented in routine clinical practice. Additionally, whether treatment of low platelet count and bleeding symptoms will have a positive influence on HRQoL remains to be seen and published evidence is conflicting. Nevertheless, improvement of HRQoL is a major treatment goal for both patients and physicians and should be especially considered when treating patients with refractory ITP.

Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-ß levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.

Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

[The spleen in non-malignant haematological disorders]. / Die Milz bei nicht-malignen hämatologischen Erkrankungen.

The spleen functions as a filter of the circulating blood, removing aging or abnormal red blood cells, intraerythrocyte inclusions as well as foreign particals. As the spleen is composed of lymphocytic tissue, circulatory elements and mononuclear phagocytic cells it plays an important role in the nonspecific as well as the specific immune response. Additionally, the spleen serves as a reservoir for circulating blood cells, especially platelet sequestration by the spleen is well do cumented. The spleen produces blood cells during fetal development and in certain haematological disorders such as myelofibrosis. The destruction of red blood cells within the splenic cords releases iron in the circulation, which is recycled and used to manufacture new erythrocytes in the bone marrow. In several non-malignant haematological disorders antibody-coated cells are cleared from the circulation by phagocytic cells of the spleen. This involves erythrocytes in autoimmunhaemolytic anaemias, platelets in immunthrombocytopenia and neutrophils in Felty syndrome. In hereditary spherocytosis the spleen destroys the resulting defective, spherical red cells. In pyruvate kinase deficiency impaired production of adenosine triphosphate leads to destruction of red blood cells in the spleen or in the liver. In sickle cell anaemia the defective erythrocytes cause sludging and thrombosis in small vessels with infarcts for instance in the spleen, which over time can result in autosplenectomy. In thalassaemia major abnormal haemoglobin forms protein precipitates in the red cells with development of a severe hypochromic anaemia with haemolysis and intramedullary inef fective erythropoiesis. Therapeutic splenectomy can be an option in all of these mentioned non-malignant haematological disorders. The rationale and the pathophysiology of its role in thrombotic thrombocytopenic purpura is probably at least well understood. The use of new and effective drugs such as the monoclonal antibody rituximab or thrombopoietin agonists in immunthrombocytopenia as well as the option of a laparoscopic rather than an open splenectomy have changed our view on benefits and risks of splenectomy in recent years. To minimize these risks such as overwhelming postsplenectomy infection or abdominal vein thrombosis, prophylactic vaccination, postoperative thromboembolism prophylaxis and patient education is mandatory.

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

Real-world impact of primary immune thrombocytopenia and treatment with thrombopoietin receptor agonists on quality of life based on patient-reported experience: Results from a questionnaire conducted in Switzerland, Austria, and Belgium.

AIMS OF THE STUDY: Thrombopoietin receptor agonists (TPO-RAs) are approved for immune thrombocytopenia (ITP), but their impact on health-related quality of life (HRQoL) remains poorly investigated in clinical practice. This observational study aimed to gain insight into real-world patient-reported experiences of the burden of ITP and TPO-RAs. METHOD: An online questionnaire of closed questions was used to collect views of patients with primary ITP from Switzerland, Austria, and Belgium, between September 2018 and April 2020. RESULTS: Of 46 patients who completed the questionnaire (total cohort), 41% were receiving TPO-RAs. A numerically higher proportion of patients reported being free from symptoms at the time of the questionnaire (54%) than at diagnosis (24%), irrespective of treatment type. Bleeding, the most frequently reported symptom at diagnosis (59%), was reduced at the time of the questionnaire (7%). Conversely, fatigue was reported by approximately 40% of patients at both diagnosis and the time of the questionnaire. Having a normal life and their disease under control was reported by 83% and 76%, respectively, but 41% were worried/anxious about their condition. Nearly 50% reported that ITP impaired their engagement in hobbies/sport or energy levels and 63% reported no impact on employment. When stratified by TPO-RA use, bleeding was better controlled in those receiving TPO-RAs than not (0% vs 11%). A numerically lower proportion receiving TPO-RAs than not reported worry/anxiety about their condition (16% vs 59%) and shifting from full-time to part-time employment (11% vs 22%). Similar proportions were satisfied with their therapy whether they were receiving TPO-RAs or not (89% vs 85%). CONCLUSIONS: Many factors affect HRQoL in patients with ITP. Of patients receiving TPO-RAs, none experienced bleeding at the time of the questionnaire; they also showed a more positive perspective for some outcomes than those not using TPO-RAs. However, fatigue was not reduced by any treatment.

Hereditary hyperferritinemia-cataract syndrome (HHCS) presenting with iron deficiency anemia associated with a new mutation in the iron responsive element of the L ferritin gene in a Swiss family.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is one of the differential diagnoses of hyperferritinemia (HF) with low or normal transferrin saturation but is usually not associated with anemia. Here, we report a case of a microcytic, hypochromic anemia with hyperferritinemia as the initial presentation of a combination of iron deficiency anemia and HHCS. The latter is an autosomal dominant disorder characterized by distinctive cataracts and HF in the absence of iron overload. Sequencing studies were carried out to look for mutations in the iron responsive element (IRE) of the L ferritin gene. A heterozygous single point mutation for a +24T to C substitution in the IRE of the L ferritin gene (=HGVS c.-176T>C) was detected which has not been described before. To evaluate the pathogenetic relevance of this new mutation, we performed family studies of parents and siblings. We could identify the father and one brother with HF, cataract, and the heterozygous +24T>C mutation. Neither the mother nor the five other siblings had HF, cataract or that mutation. We therefore conclude that this newly described heterozygous +24T>C mutation in the IRE of the L ferritin gene causes HHCS.

Management of transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Expert recommendation from the Swiss Amyloidosis Network (SAN) for systemic AL-amyloidosis.

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis.

Trends of incidence and survival of patients with chronic myelomonocytic leukemia between 1999 and 2014: A comparison between Swiss and American population-based cancer registries.

BACKGROUND: Chronic myelomonocytic leukemia (CMML) is a rare hematopoietic malignancy. Treatment with hypomethylating agents (HMA) was introduced between 2004 and 2006 but its impact on population-based survival remains controversial. The aim of this study was to investigate epidemiological characteristics and survival before and after introduction of HMA treatment. METHODS: We performed a population-based analysis of CMML cases reported to the Cantonal Cancer Registries in Switzerland (SWISS) and the Surveillance, Epidemiology, and End Results (SEER) Program from the United States for 1999-2006 (before HMA) and 2007-2014 (after HMA). Time trends were compared for these two time periods. RESULTS: 423 and 4144 new CMML cases were reported to the SWISS and SEER registries, respectively. We observed an increasing proportion of older patients ≥75 years in the SWISS (50.3%-62.3%) compared to a decreasing one in the SEER population (59.1%-55.1%). Age standardized incidence-rates were similar and remained stable in both countries (0.32-0.38 per 100'000 py). Relative survival (RS) improved significantly in the SEER (3 years 27%-37%; 5 years 19%-23%; p < 0.001 for both) but remained stable in the SWISS population (3 years 48% to 40%; 5 years 34% to 26%; n.s. for both). CONCLUSIONS: With the exception of opposing age-trends, epidemiologic characteristics are similar in both countries and comparable to other population-based registries. RS remains poor and different time trends of population-based survival cannot be faithfully explained by HMA but most likely by changes in diagnostic accuracy within prognostically distinct age-groups.

Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is a rare disease which responds well to plasma exchange treatment in the majority of patients. We report on a patient with acute TTP caused by severe autoantibody-mediated ADAMTS-13 deficiency, in whom remission was not achieved by initial treatment consisting of plasma exchange (PE), plasma infusion and corticosteroids, followed by vincristine and splenectomy. In view of the ongoing activity of TTP, treatment was initiated with rituximab, a chimaeric monoclonal antibody directed against the CD 20 antigen present on B lymphocytes. The patient received 4 weekly infusions of 375 mg/m2, each administered after the daily PE session and withholding PE until 48 hours later. Three weeks after the last infusion of rituximab a complete clinical and laboratory remission of this first episode of acute refractory TTP was documented. A concise review of the literature on the role of rituximab in patients with a first episode of acute plasma-refractory TTP suggests that rituximab in that situation may produce clinical remission in a significant proportion of patients, result in a lowered plasma requirement and avoid the complications of salvage immunosuppressive therapy. The use of rituximab in acute refractory TTP appears to be safe, with no excess infectious complications. We conclude that rituximab should be considered in TTP patients with acquired ADAMTS-13 deficiency who fail to respond clinically after 7-14 days of standard treatment with daily PE and glucocorticoids.

Reference values for oral iron absorption of bivalent iron in healthy volunteers.

BACKROUND: It is a challenge to establish the cause of iron deficiency in the absence of obvious reasons. There has been no prospectively validated oral iron absorption test (OIAT) that could confidently confirm or exclude iron malabsorption. The aim, therefore, was the establishment of an OIAT with defining reference values of plasma iron in healthy volunteers. METHODS: We included 49 healthy volunteers who received 200 mg of bivalent ferrous fumarate in fasting condition and measured plasma iron after 2 and 4 hours as well as after 3 and 5 days. After a wash-out phase, 23 healthy volunteers proceeded to receive trivalent iron hydroxide polymaltose in fasting condition, and 11 participants were tested without iron. RESULTS: Reference values of absolute and relative plasma iron after oral iron ingestion could be established. There was a significant increase of plasma iron after bivalent iron intake within 4 hours after ingestion (absolute increase after 4h: from initially 17 ± 4 µmol/l to 35 ± 12 µmol/l in females and from 21 ± 7 µmol/l to 33 ± 11 µmol/l in males, relative plasma iron concentration (defined reference: 1.0) after 4 h: 2.1 ± 0.7 in females and 1.7 ± 0.6 in males). There was no relevant increase with trivalent iron nor without iron. Relative iron increase correlates to iron storage. In general, females had lower ferritin levels and thus higher increases of plasma iron. CONCLUSION: An OIAT in healthy volunteers could be established. Its prospective validation using bivalent iron in iron deficiency is desirable.