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.

Immune thrombotic thrombocytopenic purpura: clinical suspicion and basic management in emergency departments - an expert review and consensus statement from the Spanish societies of hematology and hemotherapy (SEHH) and emergency medicine (SEMES). / Púrpura trombocitopénica trombótica inmune: sospecha y manejo básico en los servicios de urgencias. Revisión y consenso de un grupo de expertos de las sociedades científicas SEHH y SEMES.

TEXT: Acquired or immune thrombotic thrombocytopenic purpura (TTP) are thrombotic microangiopathies associated with high mortality if treatment is not started early. Onset is usually sudden, meaning that the condition is often diagnosed in hospital emergency departments, where TTP must be suspected as early as possible. These guidelines were drafted by specialists in emergency medicine and hematology to cover the diagnosis, referral, and treatment of patients suspected of immune-mediated TTP who require emergency care. Immune TTP should be suspected whenever a patient presents with hemolytic microangiopathy and has a negative Coombs test, and thrombocytopenia, possibly in conjunction with fever and neurologic and cardiac alterations. If one of the existing diagnostic algorithms indicates there is a high probability that the patient has immune TTP, plasma exchange therapy should be started along with immunosuppressants. Treatment with caplacizumab should also be considered. The patient should be referred immediately to the hematology department within the same hospital or a referral hospital.

TEXTO: La púrpura trombótica trombocitopénica adquirida o inmune (PTTi) es una microangiopatía trombótica (MAT) con una elevada mortalidad si no se instaura un tratamiento precoz. El inicio habitualmente brusco de la enfermedad hace que, en la mayoría de los pacientes, el diagnóstico inicial se haga en los servicios de urgencias hospitalarios (SUH), donde se debe sospechar esta entidad con la mayor inmediatez posible. Esta guía, elaborada por profesionales de Medicina de Urgencias y de Hematología, establece unas recomendaciones en cuanto al diagnóstico, derivación y tratamiento de los pacientes con sospecha de PTTi en los SUH. Se debe sospechar PTTi en todo paciente que presente una anemia hemolítica microangiopática, prueba de Coombs directo negativa y trombocitopenia pudiendo asociar, además, fiebre, alteraciones neurológicas y cardiacas. Si tras la aplicación de alguno de los algoritmos diagnósticos existentes, hay una alta probabilidad de que el paciente presente una PTTi, debería iniciarse tratamiento con recambio plasmático, inmunosupresores y valorar el inicio de caplacizumab. Además, debe gestionarse el traslado inmediato de los pacientes al Servicio de Hematología, bien del mismo centro o a uno de referencia.

Púrpura trombocitopénica trombótica inmune: sospecha y manejo básico en los servicios de urgencias. Revisión y consenso de un grupo de expertos de las sociedades científicas SEHH y SEMES / Immune thrombotic thrombocytopenic purpura: clinical suspicion and basic management in emergency departments — an expert review and consensus statement from the Spanish societies of hematology and hemotherapy (SEHH) and emergency medicine (SEMES)

La púrpura trombótica trombocitopénica adquirida o inmune (PTTi) es una microangiopatía trombótica (MAT) con una elevada mortalidad si no se instaura un tratamiento precoz. El inicio habitualmente brusco de la enfermedad hace que, en la mayoría de los pacientes, el diagnóstico inicial se haga en los servicios de urgencias hospitalarios (SUH), donde se debe sospechar esta entidad con la mayor inmediatez posible. Esta guía, elaborada por profesionales de Medicina de Urgencias y de Hematología, establece unas recomendaciones en cuanto al diagnóstico, derivación y tratamiento de los pacientes con sospecha de PTTi en los SUH. Se debe sospechar PTTi en todo paciente que presente una anemia hemolítica microangiopática, prueba de Coombs directo negativa y trombocitopenia pudiendo asociar, además, fiebre, alteraciones neurológicas y cardiacas. Si tras la aplicación de alguno de los algoritmos diagnósticos existentes, hay una alta probabilidad de que el paciente presente una PTTi, debería iniciarse tratamiento con recambio plasmático, inmunosupresores y valorar el inicio de caplacizumab. Además, debe gestionarse el traslado inmediato de los pacientes al Servicio de Hematología, bien del mismo centro o a uno de referencia. (AU)

Acquired or immune thrombotic thrombocytopenic purpura (TTP) are thrombotic microangiopathies associated with high mortality if treatment is not started early. Onset is usually sudden, meaning that the condition is often diagnosed in hospital emergency departments, where TTP must be suspected as early as possible. These guidelines were drafted by specialists in emergency medicine and hematology to cover the diagnosis, referral, and treatment of patients suspected of immune-mediated TTP who require emergency care. Immune TTP should be suspected whenever a patient presents with hemolytic microangiopathy and has a negative Coombs test, and thrombocytopenia, possibly in conjunction with fever and neurologic and cardiac alterations. If one of the existing diagnostic algorithms indicates there is a high probability that the patient has immune TTP, plasma exchange therapy should be started along with immunosuppressants. Treatment with caplacizumab should also be considered. The patient should be referred immediately to the hematology department within the same hospital or a referral hospital. (AU)

Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica / Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura

La púrpura trombocitopénica trombótica (PTT) es una microangiopatía trombótica (MAT) caracterizada por el desarrollo de anemia hemolítica microangiopática, trombocitopenia y disfunción orgánica isquémica asociada a niveles de ADAMTS13 inferiores al 10% en la mayoría de los casos.Recientemente se han producido numerosos avances en el campo de la PTT. Se han desarrollado nuevas técnicas rápidas y accesibles capaces de cuantificar los niveles de ADAMTS13 y los posibles inhibidores. Los sistemas de secuenciación masiva del gen ADAMTS13 facilitan la identificación de polimorfismos en este gen. Además, han aparecido nuevos fármacos como caplacizumab y se plantean estrategias de prevención de recaídas con el uso de rituximab.Los registros de pacientes con PTT permiten ahondar en el conocimiento de esta enfermedad, pero la gran variabilidad en el diagnóstico y tratamiento hace necesaria la elaboración de un documento que homogenice la terminología y la práctica clínica.Las recomendaciones recogidas en el presente documento se han elaborado siguiendo la metodología AGREE. Las preguntas de investigación se formularon de acuerdo con el formato PICO. Se realizó una búsqueda bibliográfica de la literatura publicada durante los últimos 10 años. Las recomendaciones se establecieron por consenso entre todo el grupo puntualizando las fortalezas y limitaciones existentes de acuerdo al nivel de evidencia obtenido.En conclusión, en el presente documento se recogen recomendaciones sobre el tratamiento, diagnóstico y tratamiento de la PTT con el objetivo final de elaborar pautas basadas en la evidencia publicada hasta la fecha que permitan a los profesionales sanitarios optimizar el tratamiento de la PTT. (AU)

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) characterized by the development of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10% in most cases.Recently there have been numerous advances in the field of PTT, new, rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors. The massive sequencing systems facilitate the identification of polymorphisms in the ADAMTS13 gene. In addition, new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab.The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice.The recommendations set out in this document were prepared following the AGREE methodology. The research questions were formulated according to the PICO format. A search of the literature published during the last 10 years was carried out. The recommendations were established by consensus among the entire group, specifying the existing strengths and limitations according to the level of evidence obtained.In conclusion, this document contains recommendations on the management, diagnosis, and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment. (AU)

Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura. / Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) characterized by the development of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10% in most cases. Recently there have been numerous advances in the field of PTT, new, rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors. The massive sequencing systems facilitate the identification of polymorphisms in the ADAMTS13 gene. In addition, new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab. The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice. The recommendations set out in this document were prepared following the AGREE methodology. The research questions were formulated according to the PICO format. A search of the literature published during the last 10 years was carried out. The recommendations were established by consensus among the entire group, specifying the existing strengths and limitations according to the level of evidence obtained. In conclusion, this document contains recommendations on the management, diagnosis, and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment.

Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study.

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1-5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1-10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23-67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63-89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients.

Sustained Remission in Patients with Primary Immune Thrombocytopenia after Romiplostim Tapering and Discontinuation: A Case Series in Real Life Management in Spain.

Romiplostim, a thrombopoietin-receptor agonist (TPO-ra), is a highly effective option in primary immune thrombocytopenia (ITP), with 80-90% of patients achieving platelet responses after few weeks of treatment. The evidence showing remissions, that is, sustained platelet counts after romiplostim discontinuation, in patients with ITP refractory to immunosuppressive therapy is steadily increasing. However, there is a lack of guidelines or recommendations addressing how and when to taper romiplostim in clinical practice in patients maintaining elevated and stable platelet counts. Furthermore, given the high heterogeneity of ITP patients, no associated predictive factors have been currently identified. Here, we present 4 representative clinical cases of the daily clinical practice in Spain comprising newly diagnosed, persistent, and both splenectomized and nonsplenectomized chronic ITP patients treated with romiplostim, achieving and maintaining clinical remission (platelet count ≥ 50 × 109/L for 24 consecutive weeks in the absence of any treatment for ITP) after treatment tapering and discontinuation, without observed safety concerns. Prospective studies identifying clinical and biological predictive factors of sustained response are warranted.

Comparación de guías internacionales sobre púrpura trombocitopénica autoinmunitaria primaria / Comparison of international guidelines for primary autoimmune thrombocytopenia

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Recommendations for the treatment of invasive fungal infection caused by filamentous fungi in the hematological patient

El tratamiento antifúngico del paciente hematológico ha alcanzado una gran complejidad con la llegada de nuevos antifúngicos y pruebas diagnósticas que han dado lugar a diferentes estrategias terapéuticas. La utilización del tratamiento más adecuado en cada caso es fundamental en infecciones con tanta mortalidad. La disponibilidad de recomendaciones como éstas, realizadas con la mejor evidencia por un amplio panel de 48 expertos, en las que se intenta responder a cuándo está indicado tratar y con qué hacerlo considerando diferentes aspectos del paciente (riesgo de infección fúngica, manifestaciones clínicas, galactomanano, TC de tórax y profilaxis realizada), puede ayudar a los clínicos a mejorar los resultados(AU)

Antifungal treatment in the hematological patient has reached a high complexity with the advent of new antifungals and diagnostic tests, which have resulted in different therapeutic strategies. The use of the most appropriate treatment in each case is essential in infections with such a high mortality. The availability of recommendations as those here reported based on the best evidence and developed by a large panel of 48 specialists aimed to answer when is indicated to treat and which agents should be used, considering different aspects of the patient (risk of fungal infection, clinical manifestations, galactomanann test, chest CT scan and previous prophylaxis) may help clinicians to improve the results(AU)