Inheritance of the chronic myeloproliferative neoplasms. A systematic review.

This systematic review investigated the inheritance of the classical chronic myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia (CML). Sixty-one articles were included and provided 135 families with a total of 341 participants distributed to various subtypes of MPN: 50% PV, 23% ET, 14% PMF, 10% CML and 3% non-MPN hematological disorder. Women developed the disease earlier than men (43.1 years vs 47.3 years; p = 0.074), while the general average age of onset was 46 years, notably younger than sporadic cases. The clinical phenotype of the families showed a homogenous (67%) and a heterogeneous (33%) pattern, with the majority being PV-PV pairs (36%) and PV-PMF pairs (17%), respectively. This observation suggests that the susceptibility gene (or genes) is not restricted to one subtype supporting the hypothesis of a mutation in an early multipotent stem cell. Furthermore, a major subgroup of families provided evidence of an autosomal dominant (AD) inheritance with reduced penetrance. This study suggests that the origin of MPNs may occur in at least three different settings: (i) a sporadic, (ii) genetic heterogeneity with polygenetic and environmental impact and (iii) a familial phenotype following an AD inheritance.

Characterization of blood donors with high haemoglobin concentration.

BACKGROUND AND OBJECTIVES: The literature contains little on the prevalence and causes of high predonation haemoglobin levels among blood donors. This study aimed to characterize and develop an algorithm to manage would-be donors with polycythaemia. MATERIALS AND METHODS: Between November 2009 and November 2011, we offered haematology consultations to blood donors with repeated haemoglobin concentration (Hb) above the WHO limit for polycythaemia vera (PV) (10·2 and 11·5 mm/16·5 and 18·5 g/dl for women and men, respectively). Investigation of such donors included Hb, haematocrit, mean cell volume, erythropoietin, ferritin, platelet count and leucocyte count, JAK2 V617 and JAK2 exon12 analysis, as well as other routine measurements. RESULTS: Among 46 such donors, 39 had a history of smoking, which contributes to erythrocytosis. Two had PV, five had severe hypertension, one of them because of renal artery stenosis, and two had diabetes mellitus. Thus, we found a high morbidity among such donors. Of the 36 others, 30 donated again before May 2012, at which time the Hb was significantly lower. CONCLUSION: We recommend JAK2 V617 and JAK2 exon12 screening and clinical investigation for donors with concurrently high Hb, high haematocrit and iron deficiency. We also recommend that they stop or cut down on smoking to reduce the risk of thrombosis in general. We disqualified 10 of the donors.

Systemic adverse events following rituximab therapy in patients with Graves' disease.

BACKGROUND AND AIM: Rituximab (RTX) therapy has shown promising results in Graves' disease (GD), with or without ophthalmopathy. We examined the occurrence of adverse events in GD patients treated with RTX. SUBJECTS AND METHODS: Ten patients received RTX and methimazole, while 10 patients received methimazole only. Adverse events were recorded, and the presence of circulating immune complexes (CIC) was measured as IgG, IgM and complement component 3 (C3) depositing on normal monocytes following incubation with patient plasma. RESULTS: Five patients had benign infusion-related adverse events at first infusion. Two patients developed a serum sickness-like reaction 11 days after the first RTX-infusion. One of these patients developed diarrhea, raised orosomucoid levels, lowgrade inflammation in colonoscopic biopsies, and iridocyclitis 1 yr later. At day 14, the most pronounced immunoglobulin/ C3-adherent to the test monocytes, indicative of CIC, was observed in the presence of plasma from these 2 patients (p=0.003 to p=0.01 vs asymptomatic patients). A 3rd patient had recurrent fever and symmetric polyarthritis from day 38, and colonoscopy-verified ulcerative colitis at day 68. This patient had the 3rd highest increase in Ig deposition on monocytes by day 14. The arthralgias persisted in 2 of the patients, despite glucocorticoid rescue therapy. CONCLUSIONS: We report articular adverse events in 3 and gastrointestinal symptoms in 2 out of 10 GD patients who received RTX without concurrent immunosupression. The joint symptoms were related to CIC formation.

COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.

Distinguishing myelofibrosis from polycythemia vera and essential thrombocythemia: The utility of enumerating circulating stem cells with aberrant hMICL expression by flow cytometry.

INTRODUCTION: Diagnosing BCR-ABL negative myeloproliferative neoplasms (MPN) may be challenging due to overlapping features and lack of robust discriminatory parameters, especially between essential thrombocythemia (ET) and prefibrotic myelofibrosis (MF). Circulating immature hematopoietic cells are variably present in polycythemia vera (PV), ET, and MF. The C-type lectin hMICL is aberrantly expressed on hematopoietic stem cells in the majority of acute myeloid leukemia patients. However, the hMICL expression in MPN, having varying propensity of leukemic transformation, is unsettled. We hypothesized that enumeration of immature cells by flow cytometry (FCM) could be a discriminatory tool in MPN diagnostics. METHODS: By FCM, we quantified circulating stem cells with aberrant hMICL expression in 39 MPN patients, 10 age-matched controls, and in leukapheresis products from 10 patients with lymphoproliferative neoplasms. The utility of the FCM assay for discriminating MPN entities was evaluated by applying ROC curve analysis. RESULTS: While hMICL was absent in control samples, MF patients had significantly more hMICL+ stem cells (median 15.2%) than PV and ET (0.0%, P = .001 and 0.0%, P = .002, respectively). By ROC curve analysis, the presence of hMICL+ stem cells (>0 cells) in peripheral blood reliably discriminates MF from ET and PV with a sensitivity of 80% and a specificity of 97%. CONCLUSION: Enumeration of circulating hMICL+ stem cells by FCM can discriminate between MPN phenotypes and holds potential for monitoring disease evolution.

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy.

The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T cells were able to recognize several epitopes in the CALRmut C terminus. Next, we established a CALRmut-specific CD4+ T-cell clone by limiting dilution. These CD4+ T cells recognized autologous CALRmut monocytes and hematopoietic stem cells, and T-cell recognition of target cells was dependent on the presence of CALR. Furthermore, we showed that the CALRmut response was human leukocyte antigen (HLA)-DR restricted. Finally, we demonstrated that the CALRmut-specific CD4+ T cells, despite their phenotype, were cytotoxic to autologous CALRmut cells, and that the cytotoxicity was mediated by degranulation of the T cells. In conclusion, the CALR exon 9 mutations are targets for specific T cells and thus are promising targets for cancer immune therapy such as peptide vaccination in patients harboring CALR exon 9 mutations.

Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.

Corrigendum to "Combination therapy with interferon and JAK1-2 inhibitor is feasible. Proof of concept with rapid reduction in JAK2V617F-allele burden in Polycythemia Vera" [Leuk. Res. Rep. 3 (2) (2014) 73-75].

[This corrects the article DOI: 10.1016/j.lrr.2014.05.003.].

SU6668 in idiopathic myelofibrosis--a rational therapeutic approach targeting several tyrosine kinases of importance for the myeloproliferation and the development of bone marrow fibrosis and angiogenesis.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder being featured by progressive accumulation of connective tissue in concert with marked neovascularization (angiogenesis) of the bone marrow. Both fibrogenesis and angiogenesis are considered to develop consequent to the intramedullary release of various growth-promoting factors from rapidly proliferating and dysplastic megakaryocytes. Among these growth factors are platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF). The protein kinase inhibitor SU6668 is a potent antiangiogenic inhibitor of receptor tyrosine kinases, including those of VEGFR, PDGFR, bFGFR, and c-kit. The hypothesis is that SU6668 may be an effective agent in the treatment of idiopathic myelofibrosis. This compound has an inhibitory target profile on several tyrosine kinases involved in the myeloproliferation, the development of myeloid metaplasia (bFGFR, PDGFR, VEGFR, and c-kit) and the development of the major stromal changes in the bone marrow - fibrosis and angiogenesis (bFGFR, PDGFR, and VEGFR).

[Toxic shock syndrome in group A streptococcal infection]. / Toksisk shock syndrom ved gruppe A streptokokinfektion.

Three new cases of toxic shock syndrome due to infection with group A beta-hemolytic streptococci are described and similar cases in the literature are reviewed. The typical features of this disease include rapid development of multiorgan failure with renal impairment and, in many patients, also the respiratory distress syndrome. Cardiac dysfunction with myocardial depression is a prominent feature which is most reasonably explained by an effect of the septicaemia per se but may also be toxic cardiomyopathy mediated by circulating toxins. Other major findings include exanthema--often with the development of haemorrhagic bullae as part of toxic epidermal necrolysis. In patients with initial soft tissue infection this is rapidly progressive and often associated with necrotizing fasciitis and myositis, which may give rise to a compartment syndrome with rhabdomyolysis. In addition to conventional therapy with antibiotics, fluid replacement and inotropics, most patients with extensive soft tissue infection also require surgical intervention with debridement and occasionally fasciotomy.

[Hematological abnormalities in alcoholism]. / Haematologiske abnormiteter ved alkoholisme.

The most common haematological abnormalities in alcoholism are raised mean corpuscular volume of the erythrocytes and thrombocytopenia. The etiology is multifactorial including malnutrition with folate deficiency, a direct toxic influence of alcohol and sequestration in an enlarged spleen. Sideroblastic anaemia caused by interference of alcohol with the metabolism of pyridoxine is common and so is haemolytic anaemia caused by hypersplenism and megaloblastic anaemia. Leucopenia can be seen and is probably caused by a direct toxic effect of alcohol on the bone marrow. Other potentially toxic changes are impaired chemotaxis, motility and adherence of the granulocytes and impaired blast-transformation of the lymphocytes. In the bone marrow, vacuolized precursors of myelo- and erythropoiesis are seen. The bone marrow may be hypocellular. Other changes in the bone marrow are increased but ineffective erythropoiesis with defective iron metabolism, vacuolized pro-erythroblasts, multinucleated erythroblasts, megaloblasts and iron-containing plasma cells.

[Hematological changes associated with human immunodeficiency virus (HIV-1) infection]. / Haematologiske forandringer ved infektion med human immundefekt virus (HIV-1).

Infection with human immunodeficiency virus type 1 (HIV-1) primarily involves a subgroup of T-lymphocytic cells, but other cell types are also invaded by the virus, including cell lines within the haematopoietic system. Together with infectious, inflammatory and neoplasic processes, invasion of haematopoietic tissue explains the haematological alterations which are seen during the course of infection with HIV-1. Anaemia develops in the large proportion of patients. Thrombocytopenia frequently occurs during the course of the disease, but may be seen in some patients already at the time of diagnosis, where the condition may be misdiagnosed as "idiopathic" thrombocytopenic purpura. Neutropenia is seen in all disease stages, but is most severe in patients with advanced disease. Bone marrow changes include varying degrees of dysplasia in one or more cell lines, which in some patients may mimic a myelodysplastic syndrome. The number of plasma cells is always increased. In many patients the bone marrow stroma exhibits an increased amount of reticular fibres. HIV-1 infection is associated with an increased risk of non-Hodgkin malignant lymphoma. Acute myelogenous leukaemia and myelomatosis have been described in patients with advanced disease. Treatment of the above mentioned haematological abnormalities aims primarily at reducing replication of HIV-1, thereby diminishing suppression of haematopoiesis by the virus infection, and at controlling the opportunistic infections during the course of the disease. Specific antiviral therapy (AZT) is most successful in correcting thrombocytopenia. The possibility of bone marrow suppression mediated by a toxic drug effect should always be considered in this patient group.

[Desmopressin in the treatment of hemorrhagic diathesis]. / Desmopressin i behandling af haemoragisk diatese.

Over the past several years, the use of 1-deamino-8-D-arginine vasopressin (DDAVP), a synthetic analogue of vasopressin, has been found to be useful in the treatment of patients with abnormal bleeding tendency. This article is a review of inherited and acquired disorders with prolonged bleeding time in which DDAVP is supposed to shorten the bleeding time. DDAVP is established as effective therapy of the abnormal haemostasis in mild or moderate haemophilia A and von Willebrand's disease. Frequently, DDAVP infusions are used to control bleeding in patients with uraemia. Bleeding time is also significantly shortened in patients with liver cirrhosis, although randomized trials of DDAVP therapy of gastrointestinal bleeding in this group of patients are still needed. Shortening or normalization of the bleeding time with DDAVP has also been observed in patients with inherited platelet dysfunctions, acquired disorders of haemostasis and abnormal haemostasis in chronic myeloproliferative diseases. In addition, preoperative treatment with DDAVP seems to reduce blood loss during surgery.

[Clinical use of recombinant human thrombopoietin. Status and perspectives]. / Klinisk anvendelse af rekombinant humant trombopoietin. Status og perspektiver.

Thrombopoietin (TPO) is primarily produced by hepatocytes and regulates the production and differentiation of megakaryocytes and platelets in the bone marrow. The endogenous TPO level is increased when the megakaryocyte count is low, and high in aplastic anaemia and after myeloablative chemotherapy. TPO is cloned and manufactured by a recombinant technique for clinical use. Treatment with recombinant human TPO (rhTPO) after intensive chemotherapy may reduce the need for platelet transfusions. Administration of granulocyte colony-stimulating factor in combination with rhTPO has enhanced the mobilisation and harvest product of haematopoietic stem cells. Whether rhTPO is effective in the treatment of the myelodysplastic syndrome, aplastic anaemia, and other conditions with bone marrow insufficiency (including AIDS) is not yet known. In liver cirrhosis, the endogenous TPO level rapidly increases after liver transplantation. Accordingly, substitution of rhTPO may be indicated in advanced liver failure complicated by thrombocytopenia and bleeding.

["Blue rubber bleb nevus syndrome"--or Bean's syndrome]. / "Blue rubber bleb naevus syndrome"--eller Beans syndrom.

We describe a case of the blue rubber bleb naevus syndrome, an uncommon systemic disorder characterized by multiple bluish haemangiomas of the skin and gastrointestinal tract. The syndrome is commonly associated with iron deficiency anaemia due to gastrointestinal bleeding. The syndrome is likely to be caused by a gene mapping to chromosome 9p and showing autosomal dominant inheritance. This is the first Danish report of this unusual disease. We hope that this case will heighten the awareness of this condition, because early recognition is essential for appropriate medical intervention and genetic counselling.

[Metabolic disorders in the treatment of malignant hematologic diseases--the acute tumor lysis syndrome]. / Metaboliske forstyrrelser ved behandling af maligne haematologiske sygdomme--det akutte tumorlysesyndrom.

The acute tumor-lysis syndrome is a potentially fatal complication which characteristically arises during initial chemotherapy of malignant hematological diseases with large tumor burdens. The syndrome is characterized by hyperphosphatemia, hypocalcemia, hyperuricemia and often acute renal failure. Prior to chemotherapy the patient should be treated for 12-24 hour with intensified diuresis to ensure optimal renal function. The treatment of the fully developed syndrome is hemodialysis. Three cases of TLS which developed during initial chemotherapy of patients with acute lymnphoblastic leukemia and non-Hodgkin lymphoma are presented.

[Virus-associated hemophagocytic syndrome. Diagnosis and treatment]. / Virusassocieret haemofagocytose-syndrom. Diagnostik og behandling.

Virus-associated haemophagocytic syndrome (VAHS) is a rare disease characterized by fever, splenomegaly, cytopenia and histiocytic proliferation with haemophagocytosis in the reticuloendothelial system. The clinical course of VAHS can be dramatic and the prognosis is often poor. The pathogenesis of VAHS is not well understood. Many believe that viral infection provokes an abnormal immune response in predisposed individuals leading to hyperactivation of Th1 helper cells, macrophage proliferation and secretion of large amounts of cytokines. The resultant hypercytokinaemia may be responsible for the clinical and biochemical manifestations of VAHS. In this article the clinical features, presumed pathogenesis, diagnostic criteria and treatment of VAHS are discussed.

[The chronic Philadelphia chromosome-negative myeloproliferative syndrome I. Pathogenesis and pathophysiology]. / Det kroniske Philadelphia-kromosom-negative myeloproliferative syndrom I. Patogenese og patofysiologi.

In polycythaemia vera (PV) the erythroid progenitors proliferate autonomously independently of the circulating erythropoietin. The progenitors are hypersensitive to various growth factors, including insulin-like growth factor 1, which inhibits apoptosis in erythroid and myeloid progenitor cells. No change has been found in the erythropoietin (EPO) receptor. Thrombopoietin (Tpo) regulates the production of haematopoietic progenitor cells, particularly of platelets. By inhibiting apoptosis, this growth factor may be responsible for the autonomous proliferation of the megakaryocyte cell lineage in PV and idiopathic myelofibrosis (IMF), which are featured by highly elevated circulating Tpo levels. Thrombopoietin may also be involved in the pathogenesis of myelofibrosis and development of extramedullary haematopoiesis. Both fibrogenesis and angiogenesis in the bone marrow, spleen, and liver develop secondary to the release of various growth-promoting factors from the megakaryocyte cell lineage. The lesion of the pluripotent stem cell in PV and IMF seems to imply several defects, including lack of or decreased expression of the Tpo receptor, alterations in the sensitivity of progenitor cells to various growth factors, and alterations in important gene systems (Bcl-2), which govern cell survival. Essential thrombocytosis seems to be a heterogeneous disease entity, as about 50% of the patients have polyclonal haematopoiesis.

[The chronic Philadelphia chromosome-negative myeloproliferative syndrome II. Clinical findings, diagnostics and treatment]. / Det kroniske Philadelphia-kromosom-negative myeloproliferative syndrom II. Klinik, diagnostik og behandling.

Polycythaemia vera (PV) and essential thrombocytosis (ET) are clinically characterised by non-specific neurologic symptoms, peripheral circulatory disturbances (acrocyanosis, wounds, erythromelalgia) or abdominal symptoms. The treatment of PV includes phlebotomy, antiaggregation and cytoreduction. In ET, the primary treatment is also low-dose aspirin except for patients presenting with a haemorrhagic diathesis. Hydroxyurea may be associated with an increased risk of acute leukaemia or myelodysplasia. Therefore alpha-interferon and anagrelide should be considered in younger patients. Early cytoreductive therapy is advocated in patients with idiopathic myelofibrosis (IMF) to inhibit further progression of bone marrow fibrosis and further expansion of myeloid metaplasia in the spleen and liver. Treatment with androgens (danazol) and glucocorticoids may improve severe anaemia and thrombocytopenia. In younger patients, allogeneic bone marrow transplantation should be considered.