Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients.

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

The seasonal distribution of immune thrombotic thrombocytopenic purpura is influenced by geography: Epidemiologic findings from a multi-center analysis of 719 disease episodes.

Prior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5-year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere-winter (December-February); spring (March-May); summer (June-August); autumn (September-November) and Southern Hemisphere-winter (June-August); spring (September-November); summer (December-February); autumn (March-May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%-31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Humanistic burden of haemophilia A without inhibitors: A cross-sectional analysis of the HemoLIFE study.

AIM: To evaluate the impact of haemophilia A without inhibitors on humanistic outcomes in patients and caregivers. Herein, we report a cross-sectional analysis of the baseline data of persons with haemophilia (PWH) participating in the prospective study HEMOLIFE. METHODS: These data are part of a prospective, observational, and multicentre study currently being conducted in 20 hospitals in Spain by haematologists. We included subjects 12 years or older diagnosed with haemophilia. The evaluations included the Maladjustment Scale, Haemophilia-Specific Quality of Life Questionnaire for Adults (HaemoQol)/HaemoQol Short Form (Children), haemophilia-specific version of the Work Productivity and Impairment Questionnaire plus the Classroom Impairment Questionnaire (WPAI+CIQ:HS), Haemophilia Activity List (HAL)/Paediatric Haemophilia Activities List (pedHAL), visual analogue scale (VAS) for evaluating pain, Coping Pain Questionnaire-Reduced (CAD-R), and Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 81 PWH were recruited at 18 centres; 66 PWH were ≥18 years (i.e., adults), and PWH 15 were <18 years (i.e., paediatric patients). Out of the 79 evaluable subjects, 16 (20%) showed an impact of haemophilia on daily life, and the areas most affected were "leisure time" (58% showed maladjustment) and "work/studies" (47% showed maladjustment). Patients reported a higher impact of haemophilia on quality of life (mean [SD] of the transformed score) in the dimensions of "sport" (49.4 [28.6]), "physical health" (40.5 [25.8]) and "future" (37.7 [28.9]). In adults, according to HAL scores, greater impairment of function was observed in "lying/sitting/kneeling/standing," "function of legs" and "leisure activities and sports," with mean normalized scores of 64.7, 65.1 and 69.0, respectively. Productivity was mostly impacted by presenteeism. The pain was infrequent and moderate. According to the HADS scores, nine (11.5%) patients had clinical anxiety and depression. CONCLUSION: PWH without inhibitors exhibited impairments in adjustment, quality of life and functionality, especially related to leisure and sports activities, and exhibit relevant levels of anxiety and depression.

Avatrombopag plus fostamatinib combination as treatment in patients with multirefractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) refractory to multiple therapies may require a combination of drugs targeting different mechanisms and targets. In this retrospective, multicentre, international study, we report the safety and effectiveness of avatrombopag and fostamatininb in combination administered to 18 patients with multirefractory ITP. Overall, the combination response was achieved in 15 patients (83.3%), with a median time from combination start to best response of 15 days (IQR: 8-35 days). After a median follow-up of 256 days (IQR: 142.8-319), 5 patients relapsed (26.7%), all during tapering or stopping one drug. Adverse events were described in 6 of 18 patients (33%).

Treatment with fostamatinib in patients with immune thrombocytopenia: Experience from the Andalusian region in Spain-The Fostasur Study.

Immune thrombocytopenia (ITP) is characterized by low platelet counts (PLTs) and an increased risk of bleeding. Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved as a second-line treatment for ITP. Real-world data on fostamatinib are lacking. This observational, retrospective, multicentre study, conducted in the Andalusia region of Spain, evaluated 44 adult primary ITP patients (47.7% female; median age 58 years; newly diagnosed ITP 6.8%; persistent 13.6%; chronic 79.5%; median four prior treatments) after ≥ 4 weeks of fostamatinib therapy. The median PLT at the initiation of fostamatinib was 15 × 109/L. Common reasons for starting fostamatinib were refractoriness or intolerance to prior therapy, oral medication preference, history of thrombosis and cardiovascular risk. Dosing was individualized based on efficacy and tolerance. After 2 weeks, global response rate was 56.8% (response and complete response). Response rates were 70.5%, 62.5% and 64% at 4 weeks, 12 weeks and at the end of the study respectively. Adverse events were mild, and no patients discontinued as a result. This real-world study demonstrated a response rate similar to fostamatinib as seen in the pivotal clinical trials while including newly diagnosed patients and allowing for individualized dosing.

Should we consider caplacizumab as routine treatment for acute thrombotic thrombocytopenic purpura? An expert perspective on the pros and cons.

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disorder. Caplacizumab has been the latest drug incorporated into the initial treatment of acute episodes, allowing for faster platelet recovery and a decrease in refractoriness, exacerbation, thromboembolic events, and mortality. However, caplacizumab is also associated with a bleeding risk and higher treatment costs, which prevent many centers from using it universally. AREAS COVERED: Studies that included iTTP and/or caplacizumab to date were selected for this review using PubMed and MEDLINE platforms. We describe outcomes in the pre-caplacizumab era and after it, highlighting the benefits and risks of its use early in frontline, and also pointing out special situations that require careful management. EXPERT OPINION: It is clear that the availability of caplacizumab has significantly and favorably impacted the management of iTTP patients. Whether this improvement is cost-effective still remains uncertain, and data on long-term sequelae and different healthcare systems will help to clarify this point. In addition, evidence of the bleeding/thrombotic risk of iTTP patients under this drug needs to be better addressed in future studies.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapy.

ABSTRACT: Caplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.

Recommendations for the Clinical Approach to Immune Thrombocytopenia: Spanish ITP Working Group (GEPTI).

Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to increased destruction and reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management. In 2021, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH) updated a consensus document that had been launched in 2011. The updated guidelines have been the reference for the diagnosis and management of primary ITP in Spain ever since. Nevertheless, the emergence of new tools and strategies makes it advisable to review them again. For this reason, we have updated the main recommendations appropriately. Our aim is to provide a practical tool to facilitate the integral management of all aspects of primary ITP management.

Spanish registry of thrombotic thrombocytopenic purpura (REPTT): Data evidence and new developments.

Immuno Thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially fatal disorder characterized by systemic microvascular thrombosis because of a severe deficiency of ADAMTS13. It is difficult to generate knowledge about TTP because of its low incidence and the lack of clinical trials. Most of the evidence on diagnosis, treatment, and prognosis has been generated from real-world data registries. In 2004, the Spanish Apheresis Group (GEA) implemented the Spanish registry of TTP (REPTT) with 438 patients suffering 684 acute episodes in 53 hospitals up to January 2022. REPTT has studied several aspects of TTP in Spain. The iTTP incidence in Spain our country is 2.67 (95 % CI 1.90-3.45) and the prevalence is 21.44 (95 % CI % 19.10-23.73) patients per million inhabitants. The refractoriness incidence is 4.8 % and exacerbation incidence was 8.4 %, with a median of follow-up of 131.5 months (IQR: 14-178 months). In a 2018 review, the mortality in the first episode due to TTP was 7.8 %. We have also found that de novo episodes require fewer PEX procedures than relapses. Since June 2023, REPTT will involve Spain and Portugal, with a recommended sampling protocol and new variables to improve the neurological, vascular and quality of life evaluation of these patients. The main strength of this project will be the involvement of a combined population of more than 57 million inhabitants, which implies an annual incidence of close to 180 acute episodes per year. This will allow us to provide better answers to questions like treatment efficacy, associated morbidity and mortality, and the possible neurocognitive and cardiac sequelae.

Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura.

INTRODUCTION: Severe ADAMTS13 deficiency defines thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is responsible for VWF cleavage. In the absence of this enzyme, widespread thrombi formation occurs, causing microangiopathic anemia and thrombocytopenia and leading to ischemic organ injury. Understanding ADAMTS13 function is crucial to diagnose and manage TTP, both in the immune and hereditary forms. AREAS COVERED: The role of ADAMTS13 in coagulation homeostasis and the consequences of its deficiency are detailed. Other factors that modulate the consequences of ADAMTS13 deficiency are explained, such as complement system activation, genetic predisposition, or the presence of an inflammatory status. Clinical suspicion of TTP is crucial to start prompt treatment and avoid mortality and sequelae. Available techniques to diagnose this deficiency and detect autoantibodies or gene mutations are presented, as they have become faster and more available in recent years. EXPERT OPINION: A better knowledge of TTP pathophysiology is leading to an improvement in diagnosis and follow-up, as well as a customized treatment in patients with TTP. This scenario is necessary to define the role of new targeted therapies already available or coming soon and the need to better diagnose and monitor at the molecular level the evolution of the disease.

Acquired Haemophilia A: A Review of What We Know.

Autoantibodies against plasma coagulation factors could be developed by some individuals inducing severe and sometimes fatal bleedings. This clinical entity is called acquired haemophilia. It should be suspected in subjects with acute abnormal bleedings, without personal or familiar history of congenital bleeding disorders with an unexplained prolonged aPTT. It is rare disease, although its incidence may be underestimated due to the low knowledge about it by many specialists, the frequent use of anticoagulant or antiplatelet therapies in the affected population that can mask the diagnosis and, sometimes, a so withering effect that avoid its confirmation. Mortality ranges between 9% and 33% depending on the series in the first 2 months after diagnosis. This mortality is attributed in up to 40% of the cases to infections in the context of immunosuppressive treatments used to eliminate the inhibitor. Factor VIII levels below 1% and high inhibitor titers are conditions of worse response rates. Advanced age, patient's ECOG, and underlying conditions are key prognostic factors for response to treatment and patient survival. To reduce morbidity and mortality in these patients, it is important to have clinical knowledge and access to guidelines to achieve an early diagnosis and to optimize the haemostatic and immunosuppressive treatment. This review aims to contribute to the dissemination of basic concepts on the epidemiology etiopathogenesis, diagnosis, treatment and management of these patients, as well as risk factors to get remission and the longest overall survival to allow individualized care. Especial awareness will be proposed in patients with some underlying conditions like cancer, autoimmune diseases, children, pregnancy or drugs.

Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura.

Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX.

Novel Therapies to Address Unmet Needs in ITP.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that causes low platelet counts and subsequent bleeding risk. Although current corticosteroid-based ITP therapies are able to improve platelet counts, up to 70% of subjects with an ITP diagnosis do not achieve a sustained clinical response in the absence of treatment, thus requiring a second-line therapy option as well as additional care to prevent bleeding. Less than 40% of patients treated with thrombopoietin analogs, 60% of those treated with splenectomy, and 20% or fewer of those treated with rituximab or fostamatinib reach sustained remission in the absence of treatment. Therefore, optimizing therapeutic options for ITP management is mandatory. The pathophysiology of ITP is complex and involves several mechanisms that are apparently unrelated. These include the clearance of autoantibody-coated platelets by splenic macrophages or by the complement system, hepatic desialylated platelet destruction, and the inhibition of platelet production from megakaryocytes. The number of pathways involved may challenge treatment, but, at the same time, offer the possibility of unveiling a variety of new targets as the knowledge of the involved mechanisms progresses. The aim of this work, after revising the limitations of the current treatments, is to perform a thorough review of the mechanisms of action, pharmacokinetics/pharmacodynamics, efficacy, safety, and development stage of the novel ITP therapies under investigation. Hopefully, several of the options included herein may allow us to personalize ITP management according to the needs of each patient in the near future.

COVID-19 Vaccines and Autoimmune Hematologic Disorders.

Worldwide vaccination against SARS-CoV-2 has allowed the detection of hematologic autoimmune complications. Adverse events (AEs) of this nature had been previously observed in association with other vaccines. The underlying mechanisms are not totally understood, although mimicry between viral and self-antigens plays a relevant role. It is important to remark that, although the incidence of these AEs is extremely low, their evolution may lead to life-threatening scenarios if treatment is not readily initiated. Hematologic autoimmune AEs have been associated with both mRNA and adenoviral vector-based SARS-CoV-2 vaccines. The main reported entities are secondary immune thrombocytopenia, immune thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, Evans syndrome, and a newly described disorder, so-called vaccine-induced immune thrombotic thrombocytopenia (VITT). The hallmark of VITT is the presence of anti-platelet factor 4 autoantibodies able to trigger platelet activation. Patients with VITT present with thrombocytopenia and may develop thrombosis in unusual locations such as cerebral beds. The management of hematologic autoimmune AEs does not differ significantly from that of these disorders in a non-vaccine context, thus addressing autoantibody production and bleeding/thromboembolic risk. This means that clinicians must be aware of their distinctive signs in order to diagnose them and initiate treatment as soon as possible.

New treatments for primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoimmune disease leading to a decreased platelet count and an ensuing haemorrhagic risk. First-line treatment against ITP consists in the administration of immunomodulators aimed at decreasing platelet destruction. Up to 70% of individuals with an ITP diagnosis treated with corticosteroids do not achieve a clinical response or demonstrate a high relapse rate, requiring treatment to prevent a haemorrhagic risk. Less than 30% of patients treated with thrombopoietin analogues, 60% of those treated with splenectomy and 20% of those treated with rituximab reach sustained remission in the absence of treatment. Because of these reasons, it is unquestionable that treatment of patients with ITP should be optimized. Through this study, we will review new actual and future options of treatment.