The problem of immune thrombocytopenia refractory to both eltrombopag and romiplostim.

Immune thrombocytopenia refractory to multiple thrombopoietin receptor agonists remains a challenging clinical problem. This commentary discusses and contextualizes the recent report on this entity from Moulis and colleagues, and how to move forward with these patients. Commentary on: Moulis et al. Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France Registry. Br J Haematol 2024;204:1476-1482.

Chronic health conditions after childhood Langerhans cell histiocytosis: Results from the Swiss Childhood Cancer Survivor Study.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare disease characterized by dysregulated proliferation of myeloid marrow progenitors and subsequent organ infiltration. While LCH is associated with a favorable prognosis, some survivors may develop chronic health conditions (CHC) because of the disease. In this study, we aimed to assess the spectrum and prevalence of CHC among LCH survivors compared with siblings and identify factors associated with the development of CHC. METHODS: The Swiss Childhood Cancer Survivor Study sent questionnaires to all ≥ 5-year LCH survivors registered in the Swiss Childhood Cancer Registry and diagnosed between 1976 and 2015. Siblings also received similar questionnaires. We compared CHC prevalence between LCH survivors and siblings and used logistic regression to identify determinants of CHC. RESULTS: A total of 123 LCH survivors participated in the study, with a response rate of 69%. Median time since diagnosis was 13 years (interquartile range 9-20). Among LCH survivors, 59% had at least one CHC. Cardiovascular (13% vs. 6%), endocrine (15% vs. 2%), musculoskeletal (22% vs. 13%), and digestive (15% vs. 8%) CHC were more common among LCH survivors compared to siblings (all p < 0.05). Factors most strongly associated with the occurrence of CHC were multisystem LCH, multifocal bone involvement, and involvement of the pituitary gland. CONCLUSIONS: More than half of long-term LCH survivors suffered from one or more CHC and were affected considerably more than siblings. IMPLICATIONS FOR CANCER SURVIVORS: LCH survivors in follow-up care should be screened especially for cardiovascular, endocrine, musculoskeletal, and digestive conditions.

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.

Early immunomodulation in immune thrombocytopenia-A report of the ICIS meeting in Lenzerheide, Switzerland 2022.

The only way to prevent immune thrombocytopenia (ITP) from becoming refractory would be to restore tolerance to platelets at an early phase of the disease. Numerous immune alterations probably accumulate in chronic ITP; thus, the chances of cure decrease significantly with time. Currently, sustained remission off treatment (SROT) is a clinical definition describing patients who can discontinue their ITP treatment without risk and maintain a state of remission. Different treatment strategies are presently being evaluated with the goal of attaining SROT, mostly combining drugs targeting the innate and/or the adaptive immune system, the inflammation state, so as increasing the platelet load. In this sense, thrombopoietin receptor agonists (TPO-RAs) have shown promising results if used as upfront treatment. TPO-RAs seem to exhibit immunomodulation and immune tolerance properties, increasing not only the platelet antigen mass but also increasing the transforming growth factor-ß concentration, and stimulating regulatory T and B lymphocytes. However, more immunological studies are needed to establish accurate molecular alterations in ITP that are potentially reversed with treatments.

Chronic refractory immune thrombocytopenia in adolescents and young adults.

Defining immune thrombocytopenia (ITP) in two age groups-children and adults-overlooks the specific clinical features and needs of adolescents and young adults (AYAS). We previously reported a high risk of chronic disease at 12 months (50%); however, data on the course of chronic ITP, the risk of refractoriness and treatment strategies in AYAS are limited. Data from patients aged 12-25 years with chronic primary ITP at 12 months were extracted from three large registries between 2004 and 2021. Clinical and laboratory data were evaluated until 48 months of follow-up (FU). Refractory ITP was defined as the administration of ≥3 different lines of therapy. A total of 427 AYAS (64% female) with chronic ITP were included. Overall, 7% and 14% were classified as 'refractory' at 12 and 48 months of FU respectively. The proportion of males was greater in the refractory group than in the non-refractory group (43% vs. 35%). AYAS with refractory disease displayed lower median platelet counts, more bleeding and a higher need for treatment at initial diagnosis and FU than non-refractory patients. This study reveals that refractory ITP is uncommon in AYAS; however, AYAS with refractory ITP display a high disease burden at all time points, including at initial diagnosis.

Adolescents and young adults with newly diagnosed primary immune thrombocytopenia.

Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with an initial platelet counts of <100×109/L. Patients with secondary ITP or non-immune thrombocytopenia (n=57) and pregnant women (n=10) were excluded. Of the 656 cases of AYAS with primary ITP registered from 2004 up to 2021, 12-month follow-up data were available for 72%. The initial median platelet count was 12×109/L. In 109 patients (17%), the diagnosis was incidental, without documented bleeding. Apart from gynecological bleeding, the clinical and therapeutical characteristics of females and males were similar. Platelet-enhancing drugs were reported in 66%, 45%, and 30% of patients at diagnosis, 1-6 months, and 6-12 months after diagnosis, respectively. Corticosteroids were the preferred treatment at all time points. At 12 months, 50% of all patients developed chronic ITP. In the subgroup of patients with initial severe thrombocytopenia (<20×109/L), those receiving frontline treatment had a higher remission rate at 1 year than those who followed an initial watch-and-wait strategy (53% and 32%; P<0.05). Our analysis indicates that the remission rate at 1 year may be associated with the initial treatment strategy. This hypothesis must be confirmed in prospective studies.

Understanding Immune Thrombocytopenia: Looking Out of the Box.

The pathogenesis of immune thrombocytopenia (ITP) is increasingly being elucidated, and its etiology is becoming more frequently identified, leading to a diagnostic shift from primary to secondary ITP. The overlap between autoimmunity, immunodeficiency, and cancer is evident, implying more interdisciplinarity in daily care. This mini-review is based on an expert meeting on ITP organized by the Intercontinental Cooperative ITP Study Group and presents the challenges of hematologists in understanding and investigating "out of the box" concepts associated with ITP.

Misdiagnosed thrombocytopenia in children and adolescents: analysis of the Pediatric and Adult Registry on Chronic ITP.

Primary immune thrombocytopenia (ITP) in children is a diagnosis of exclusion, but cases of secondary ITP and nonimmune thrombocytopenia (non-IT) are generally difficult to recognize in a timely fashion. We describe a pediatric population with a revised diagnosis of secondary ITP or non-IT within 24 months of follow-up. Data were extracted from the Pediatric and Adult Registry on Chronic ITP, an international multicenter registry collecting data prospectively in patients with newly diagnosed primary ITP. Between 2004 and 2019, a total of 3974 children aged 3 months to 16 years were included. Secondary ITP and non-IT were reported in 113 patients (63 female subjects). Infectious (n = 53) and autoimmune (n = 42) diseases were identified as the main causes, with median ages at diagnosis of 3.2 years (interquartile range: 1.2; 6.7 years) and 12.4 years (interquartile range: 7.6; 13.7 years), respectively. Other causes included malignancies, aplastic anemia, immunodeficiency, and drug use. Patients with malignancy and aplastic anemia had significantly higher initial platelet counts (37 and 52 × 109/L) than did those with infection or autoimmune diseases (12 and 13 × 109/L). Characteristics of patients with secondary ITP due to infection were similar to those of children with primary ITP at first presentation, indicating similar mechanisms. Significant differences were found for age, sex, comorbidities, initial bleeding, sustained need for treatment, and disease persistence for the remaining noninfectious group compared with primary ITP. Based on our findings, we propose a diagnostic algorithm that may serve as a basis for further discussion and prospective trials.

Sialoblastoma of the submandibular gland: a distinct entity?

Sialoblastoma is a rare congenital malignant tumor of the salivary glands. A case of a submandibular sialoblastoma in a 1.5-year-old child is presented. A comparative analysis on 79 pediatric cases reported in the literature suggests a less aggressive behavior for submandibular sialoblastoma in comparison with other sites. Classically, diagnosis is confirmed by open biopsy, but fine-needle aspiration may offer an alternative with reduced morbidity. Expression of AFP and high levels of Ki-67 have been associated with poor prognosis. Whilst early surgical resection with negative margins is widely accepted as first-line treatment, there is no consensus on therapy of recurrence and follow-up. MRI and sonography represent valid tools for the follow-up, which is usually restricted to 3-5 years.Conclusion: Submandibular sialoblastomas may have a different biological profile in comparison with parotid tumors with the absence of metastasis and much lower rate of recurrence. Comprehensive diagnostics should include additional options such as fine-needle aspiration and markers to assess cell proliferation and AFP. Literature suggests that surgery alone is sufficient for the treatment of tumors with low malignancy. Follow-up should be tailored according to the tumor site and might be limited to 3-5 years. What is Known: • Sialoblastoma is a rare congenital malignant tumor with an unpredictable clinical outcome. What is New: • Sialoblastoma of submandibular origin seems to have a less aggressive behavior in comparison with other sites. • Fine-needle aspiration and markers to assess proliferation index (i.e., suggestive of potential more aggressive course/malignancy) should be strongly considered in the diagnostic work-up. • Radical surgery as first-line therapy and a 3-5-year follow-up are acceptable for tumors with a low malignancy.

Immunomodulation in Primary Immune Thrombocytopenia: A Possible Role of the Fc Fragment of Romiplostim?

Fc fusion proteins and Fc fusion peptides or peptibodies are chimeric molecules composed of an active pharmacological protein or peptide and the Fc fragment of an immunoglobulin. The primary aim of this drug construct is to prolong the half-life of the active component. This molecular architecture is seen in drugs, such as etanercept, romiplostim, and the recombinant factor VIII (efmoroctocog alfa). A considerable number of Fc fusion proteins and peptibodies are currently in pre-clinical and clinical development. The isolated effect of the Fc fragment has been studied intensively during last years, but is still poorly understood in the clinical setting and in relation with the active drug and underlying disease. In this short review, we will propose new hypotheses of possible immunomodulatory functions of the Fc fragment of romiplostim in patients with primary immune thrombocytopenia.

Double trouble: visceral leishmaniasis in twins after traveling to Tuscany - a case report.

BACKGROUND: Leishmaniasis is endemic in many countries worldwide, with a prevalence of 12 million people infected, and an estimated annual incidence of 500 000 visceral leishmaniasis cases. In Europe visceral leishmaniasis is considered endemic mainly in the Mediterranean countries and cases in non-endemic European countries north of the Alps have primarily been reported in returning travellers. The incubation period is typically described between 6 weeks to 6 months. The cases presented highlight the occurrence of longer incubation periods and illustrate the individual variability for progression from infection to disease. CASE PRESENTATION: We report the cases of 18-months-old twin girls living at the German-Swiss border, who developed visceral leishmaniasis 7 and 15 months after travelling to Tuscany. They presented with fever of unknown origin and pancytopenia. Both had splenomegaly and in the first case haemophagocytic lymphohistiocytosis or leukaemia was initially included in the differential diagnosis. Diagnosis of visceral leishmaniasis was confirmed by presence of intracytoplasmic localised leishmania parasites on bone marrow aspirate and/or positive leishmania serology. Both girls responded well to treatment with liposomal amphotericin B. The mother and two older siblings remained uninfected, while the father was diagnosed to be an asymptomatic carrier. CONCLUSION: Visceral leishmaniasis is an important differential diagnosis for fever of unknown origin and pancytopenia in young children living in countries with endemic disease and highlights the importance of obtaining a detailed travel history. Hemophagocytic lymphohistiocytosis and acute leukaemia present with similar symptoms and consequently are important differential diagnoses. Factors determining progression from infection to disease are not fully understood but younger age seems to be an important risk factor. Screening of siblings from affected individuals therefore may be warranted.

A comparative prospective observational study of children and adults with immune thrombocytopenia: 2-year follow-up.

Comparative clinical studies of children and adults with immune thrombocytopenia (ITP) are poorly covered in the literature. However, the accepted classification of ITP-childhood ITP and adult ITP-results in considerable differences in treatment protocols and practice guidelines. The analysis of the Pediatric and Adult Registry on Chronic ITP (PARC-ITP) of patients at first presentation demonstrated fewer differences in clinical and laboratory findings at initial diagnosis between children and adults than expected. The present report of 2-year follow-up data supports the hypothesis that there are common aspects of childhood and adult ITP. Data of 3360 children and 420 adults were collected during the time of 2004 until 2015 at initial diagnosis. Follow-up information was available for 51% and 33% of children and 66% and 49% of adults at 12- and 24-months, respectively. Similarities were found in unexpected areas of ITP, such as the rate of late remission at 12 and 24 months, reported bleeding sites, platelet count in bleeders, and the frequency of treated patients with persistent or chronic ITP. Differences were confirmed for the overall rate of remission and treatment modalities. Unexpected differences were found in the percentage of nonbleeders, with more adults in the nonbleeder group. More studies are needed to investigate different age groups with the aim to optimize their management.

Thrombopoietin receptor agonists: a new immune modulatory strategy in immune thrombocytopenia?

In 2008, new drugs that mimic the effects of thrombopoietin became available for the treatment of primary immune thrombocytopenia, eg, romiplostim and eltrombopag. These drugs activate the thrombopoietin receptor, stimulate the production of megakaryocytes, and increase the production of platelets. Important clinical observation has been gained, such as unexpected long-term remission after stopping thrombopoietin receptor agonists. The pathophysiology of this unforeseen cure is currently the subject of discussion and is investigated in clinical trials and laboratory research projects. Here we evaluate the different hypotheses on how thrombopoietin receptor agonists can affect the immune system, particularly the induction of tolerance, and by which mechanisms this may be achieved.

Intracranial Hemorrhage as the First Manifestation of Severe Congenital Factor X Deficiency in a 20-Month-Old Male: Case Report and Review of the Literature.

Factor X deficiency (FXD) is a rare bleeding disorder, which can result in severe bleeding symptoms such as intracranial hemorrhage (ICH). The most common bleeding symptoms are epistaxis and gum bleeding. ICH is reported in 9-26% of all patients with FXD, mostly during the first month of life. Here, we present a rare case of a male presenting with ICH at the age of 20 months as the first manifestation of FXD. Secondary prophylaxis with factor X substitution once weekly prevented further bleeding.

Fanconi Anemia: Overview of the Disease and the Role of Hematopoietic Transplantation.

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by congenital abnormalities and chromosomal breakages with the occurrence of hematological and solid malignancies. FA is the most common type of inherited bone marrow failure and poses tremendous challenges. FA patients are uniquely hypersensitive to hematopoietic stem cell transplantation (HSCT) conditioning agents due to the underling chromosomal instability. HSCT has shown important progress in the last years, especially after the introduction of fludarabine and the reduction of cyclophosphamide in the preparative regimen. For patients with HLA-identical-related donors HSCT should be performed as first-line therapy, for patients with alternative donors HSCT remains a therapy with increased morbidity and mortality.

Tumor-associated FGF-23-induced hypophosphatemic rickets in children: a case report and review of the literature.

BACKGROUND: Tumor-associated fibroblast growth factor 23 (FGF-23)-induced hypophosphatemic rickets is a rare but known pediatric entity first described in 1959. It results from local production of phosphatonins by benign and malignant mesenchymal tumors. CASE-DIAGNOSIS/TREATMENT: We report an 8-year-old boy with tumor-associated hypophosphatemic rickets due to paraneoplastic FGF-23 secretion from a benign mesenchymal pelvic-bone tumor. Excessive FGF-23 production was visualized by immunohistochemistry in the resected tumor. Phosphate wasting stopped immediately after tumor resection. We reviewed 26 reports of pediatric patients with tumor-induced hypophosphatemic rickets; paraneoplastic FGF-23 secretion was documented in only three of them. All tumors developed inside bone, were benign in 21/26 cases, and were localized in femur/tibia (13/26), radius/ulna/humerus (7/26), pelvis (4/26), rib (1/26), and craniofacial (1/26) bones. Mean interval between onset of signs and/or symptoms and diagnosis was 34 months. CONCLUSIONS: In patients with hypophosphatemic rickets acquired beyond infancy, radiologic investigations for bone tumors need to be performed rapidly. In contrast to biochemical screening for increased circulating FGF-23 levels, immunohistochemical confirmation of FGF-23 production in resected tumor tissue can be regarded as being well established.

Transient myeloproliferative disorder in neonates without Down syndrome: case report and review.

Transient myeloproliferative disorder (TMD) is a clonal proliferation of megakaryoblasts, typically occurring in newborns with Down syndrome. It is believed that TMD occurs in the presence of GATA1 mutation together with trisomy 21. However, a limited number of patients with TMD but without Down syndrome have been reported, all with a blast population with numeric or rarely structural chromosome 21 abnormalities. We present the first case of a newborn boy with a TMD without trisomy 21 and without any of the mentioned molecular or cytogenetic abnormalities. This case report suggests that unknown disease mechanisms may provoke or mimic TMD. This case report is followed by a concise review of the literature discussing the different entities and pathomechanisms of TMD and acute megakaryocytic leukaemia in patients with or without Down syndrome.

Chronic immune thrombocytopenia in children: who needs splenectomy?

In the field of emerging innovative therapies, such as thrombopoietin mimetics, the question of who needs splenectomy remains highly relevant. Removal of the spleen is an accepted and potentially curative treatment of immune thrombocytopenia (ITP) after decades with a favorable economical-effect ratio but with relevant morbidity particularly in the young patients. ITP is rare and splenectomy is performed in a minority of children, which makes its research almost impossible, resulting in a poor standardization of the procedure. Hence, in children, recommendation and decision for splenectomy is individually based and rests on expert opinions. Furthermore, local practice and availability of health products affect the frequency of splenectomy. Current guidelines agree on one point: splenectomy should be postponed for at least 12 months after the initial diagnosis of ITP, due to the high probability of improvement or even spontaneous remission. However, evidence-based data are lacking and splenectomy remains controversial. This article reviews the current literature and delineates controversies and complexities of splenectomy in children with ITP. There is an urgent need for consensus of this procedure in pediatric patients.