Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia.

OBJECTIVES: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological disease whose clinical management includes caplacizumab along with plasma exchange and immunosuppression, according to international guidelines. Caplacizumab has been available in Colombia since 2022. This study seeks to determine the therapeutic classification of caplacizumab according to the methodology of the Instituto de Evaluación Tecnológica en Salud. METHODS: The classification was carried out through a deliberative process following the modified Delphi technique, with a panel of experts, made up of four hemato-oncologists, a pharmaceutical chemist, and a patient. The results of effectiveness and safety obtained through a systematic review, therapeutic thresholds (clinical significance), and degree of acceptability (willingness to use the technology) were used for the classification. RESULTS: Fourteen effectiveness and safety outcomes were submitted for the classification process. Caplacizumab showed clinical significance for some effectiveness outcomes, was not considered inferior in terms of safety, and displayed acceptability of use. Through consensus, the panel determined that caplacizumab plus the standard regimen is superior to the standard regimen in terms of treatment response and composite outcome, and no different for the other effectiveness and safety outcomes. Likewise, in overall terms, the panel determined that caplacizumab together with the standard regimen is superior to the standard regimen. CONCLUSION: Treatment with caplacizumab together with the standard regimen was considered superior to the standard regimen for the treatment of patients with aTTP, as it showed clinically significant benefits in critical outcomes for decision making, and a safety profile no different to its comparator.

Brazilian experience with caplacizumab in acquired thrombotic thrombocytopenic purpura: outcomes of the expanded access program.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare disease with an acute and severe clinical presentation. The anti-von Willebrand factor caplacizumab was licensed for adults with aTTP based on prospective controlled trials. However, until now, there was no Brazilian experience with this new treatment modality. This retrospective, multicenter, single-arm, expanded access program (EAP) with caplacizumab, plasma exchange (PEX), and immunosuppression was conducted between 02/24/21 and 04/14/21, and enrolled 5 Brazilian patients with aTTP. EAP allowed access to caplacizumab in Brazil and real-world data was collected, at a time when the medication was not commercially available in Brazil. The median age was 31 years old, most patients were women (80%), and neurological manifestation was observed in 80% of cases. The median of laboratory tests was hemoglobin (Hb) of 11 g/dL, platelets (16.1 × 109/L), lactic dehydrogenase (LDH) of 1471 U/L, creatinine (0.7 mg/dL), ADAMTS13 activity lower than 0.71%, and PLASMIC score of 6. All patients received immunosuppression, PEX, and caplacizumab. Until clinical response was achieved, the median was 3 sessions of PEX and 3 days of treatment. The median time of caplacizumab use was 35 days, with platelet normalization in 2 days after starting the drug. The median total length of stay was 8 days. All patients achieved clinical response and clinical remission, with a good safety profile. There was rapid clinical response, few PEX sessions were necessary, and there were short hospital stay, absence of refractoriness, little exacerbation, no death, and resolution of signs and symptoms at diagnosis.

Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.

Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time to response, and improves exacerbation rates at the expense of increased relapse and bleeding risk.

[Treatment of thrombotic thrombocytopenic purpura with rituximab. Report of eight cases]. / Experiencia de un hospital universitario en el manejo de púrpura trombótico trombocitopénico-microangiopatía trombótica no inmune refractaria o en recaída tratado con rituximab: report of eight cases.

Thrombotic thrombocytopenic purpura, an immune/non-immune thrombotic microangiopathy (TTP/TMA) is associated with high morbidity and mortality, even with appropriate treatment. In patients refractory to standard treatment with plasmapheresis there is no certainty about the best therapeutic strategy. This report shows our experience in eight refractory patients who survived after treatment with rituximab.

Experiencia de un hospital universitario en el manejo de púrpura trombótico trombocitopénico-microangiopatía trombótica no inmune refractaria o en recaída tratado con rituximab: Report of eight cases / Treatment of thrombotic thrombocytopenic purpura with rituximab

Thrombotic thrombocytopenic purpura, an immune/non-immune thrombotic microangiopathy (TTP/TMA) is associated with high morbidity and mortality, even with appropriate treatment. In patients refractory to standard treatment with plasmapheresis there is no certainty about the best therapeutic strategy. This report shows our experience in eight refractory patients who survived after treatment with rituximab.

Púrpura trombótica trombocitopenica en adultos / Trombocitopenica trombótica purple in adults

Se revisa la presentación de 6 pacientes adultos con púrpura trombótica trombocitopénica (PTT), que fueron atendidos en el Servicio de Clínica Médica del Hospital Escuela de Corrientes durante un período de 11 años. La púrpura trombótica trombocitopénica es una anemia hemolítica microangiopática caracterizada por una pentada clínica típica: trombocitopenia, anemia hemolítica microangiopática, fallo renal, fiebre y manifestaciones neurológicas. Todos los pacientes presentaron trombocitopenia y anemia hemolítica microangiopática. El compromiso neurológico fue la segunda característica más frecuente. Todos los pacientes fueron tratados con plasmaféresis. Tres pacientes se recuperaron completamente y 3 fallecieron. El pilar del tratamiento es la transfusión de plasma y la plasmaféresis. Se hace hincapié en su implementación inmediata dada la alta mortalidad de esta patología.

Cerebellar degeneration and immune thrombocytopenic purpura associated with human immunodeficiency virus infection (HIV).

Cerebellar disorders associated with HIV infection are usually caused by opportunistic infections, central nervous system lymphoma, and toxic effects of medicines, nutritional and metabolic disorders, and cerebrovascular disease. We present an unusual association of cerebellar degeneration and immune thrombocytopenic purpura in a 28-years-old woman HIV infected. An autoimmune aetiology is likely.

Púrpura trombocitopénico trombótico con respuesta exitosa a vincristina / Successful treatment of thrombotic thrombocytopenic purpura with vincristine report of one case

Thrombotic thrombocytopenic purpura presents as a multisystemic disease with thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological and renal involvement. We report a 24 years-old male presenting with purpura and a generalized seizure. His blood tests showed an hemolytic anemia, unconjungated hyperbilirubinemia, increased lactated dehydrogenase, thrombocytopenia and impairment of renal function. He was initially treated with daily plasmapheresis and steroids without improvement. Due to persistence of the disease, he was treated with two doses of intravenous vincristine in four days, with clinical and laboratory improvement. He was discharged 40 days after the last dose of vincristine, in good conditions.

Cerebellar degeneration and immune thrombocytopenic purpura associated with human immunodefi ciency virus infection (HIV)

Cerebellar disorders associated with HIV infection are usually caused by opportunistic infections, central nervous system lymphoma, and toxic effects of medicines, nutritional and metabolic disorders, and cerebrovascular disease. We present an unusual association of cerebellar degeneration and immune thrombocytopenic purpura in a 28-years-old woman HIV infected. An autoimmune aetiology is likely.

Transtornos cerebelares associados a infecção pelo HIV são comumente causados por infecções oportunistas, linfoma do sistema nervoso central, efeitos tóxicos de medicamentos anti-retrovirais, alterações metabólicas e nutricionais, e doença cerebrovascular. Apresentamos um caso incomum de associação de degeneração cerebelar e púrpura trombocitopênica imunológica em um mulher de 28 anos infectada pelo HIV. Discutimos uma possível etiologia autoimune para justificar o quadro.

[Successful treatment of thrombotic thrombocytopenic purpura with vincristine report of one case]. / Púrpura trombocitopénico trombótico con respuesta exitosa a vincristina.

Thrombotic thrombocytopenic purpura presents as a multisystemic disease with thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological and renal involvement. We report a 24 years-old male presenting with purpura and a generalized seizure. His blood tests showed an hemolytic anemia, unconjugated hyperbilirubinemia, increased lactated dehydrogenase, thrombocytopenia and impairment of renal function. He was initially treated with daily plasmapheresis and steroids without improvement. Due to persistence of the disease, he was treated with two doses of intravenous vincristine in four days, with clinical and laboratory improvement. He was discharged 40 days after the last dose of vincristine, in good conditions.

Eficacia de la asociación rituximab-vindesina en el tratamiento de un caso de púrpura trombótico-trombopénico (PTT) adquirido idiopático refractario / Successful treatment of idiopathic acquired refractory thrombotic thrombocytopenic purpura with an association of rituximab - vindesine. Report of one case

We report a 23 years old female who presented a second episode of thrombotic thrombocytopenic purpura (TTP). She was treated with fresh frozen plasma infusions and 14 plasma exchange (PE) sessions without response. Therefore a second-line therapy was started, associating a weekly cycle administration of vindesine (Vds) 2 mg/m2 and rituximab (R) 375 mg/m2. Five cycles of this association plus one cycle of R exclusively, were administered. After the third course, biological signs of improvement were observed and complete normalization of blood cell counts and other specific parameters was seen after 8 weeks. From the beginning of her second relapse we detected a severe deficit (<5%) in von Willebrand-cleaving factor (ADAMTS13) associated to the presence of ADAMTS13 inhibitors. The combined treatment induced an improvement in ADAMTS13 values without detectable inhibitors. After 21 months of follow-up the patient was well, without signs of relapse but ADAMTS13 values were still under normal, which may be an unfavorable prognostic factor. PE is the treatment of choice for acquired idiopathic TTP, but for refractory cases or TTP cases with severe ADAMTS13 values/high inhibitor titers, PE associated to an immunosuppressive treatment should be considered.

[Successful treatment of idiopathic acquired refractory thrombotic thrombocytopenic purpura with an association of rituximab-vindesine. Report of one case]. / Eficacia de la asociación rituximab-vindesina en el tratamiento de un caso de púrpura trombótico-trombopénico (PTT) adquirido idiopático refractario.

We report a 23 years old female who presented a second episode of thrombotic thrombocytopenic purpura (TTP). She was treated with fresh frozen plasma infusions and 14 plasma exchange (PE) sessions without response. Therefore a second-line therapy was started, associating a weekly cycle administration of vindesine (Vds) 2 mg/m2 and rituximab (R) 375 mg/m2. Five cycles of this association plus one cycle of R exclusively, were administered. After the third course, biological signs of improvement were observed and complete normalization of blood cell counts and other specific parameters was seen after 8 weeks. From the beginning of her second relapse we detected a severe deficit (<5%) in von Willebrand-cleaving factor (ADAMTS13) associated to the presence of ADAMTS13 inhibitors. The combined treatment induced an improvement in ADAMTS13 values without detectable inhibitors. After 21 months of follow-up the patient was well, without signs of relapse but ADAMTS13 values were still under normal, which may be an unfavorable prognostic factor. PE is the treatment of choice for acquired idiopathic TTP, but for refractory cases or TTP cases with severe ADAMTS13 values/high inhibitor titers, PE associated to an immunosuppressive treatment should be considered.

Púrpura trombocitopénica trombótica y síndrome hemolítico urémico en el adulto

La púrpura trombocitopénica trombótica y el síndrome hemolítico urémico en el adulto son expresiones distintas de una misma enfermedad. Su incidencia es muy baja, aproximadamente uno en un millón de habitantes, pero su mortalidad sin tratamiento adecuado es alta. Las manifestaciones clínicas son heterogéneas y se pueden confundir con las producidas por otras entidades. En este informe se presentan y discuten las características clínicas de nueve pacientes vistos en seis años en un hospital universitario de referencia y se enfatizan los hallazgos que deben hacer sospechar la existencia de la enfermedad.

Chronic relapsing thrombotic thrombocytopenic purpura in infants with large von Willebrand factor multimers during remission.

We studied two children with recurrent schistocytic hemolytic anemia and thrombocytopenia beginning in the neonatal period. One patient had a stroke during one of the episodes of thrombotic thrombocytopenic purpura. The presence of unusually large von Willebrand factor multimers was demonstrated in both children during clinical and hematologic remissions. Treatment with corticosteroids and intravenous injections of immune globulin was unsuccessful in the one patient who received it. Immediate improvement occurred in both patients after the infusion of fresh-frozen plasma. Symptoms of thrombocytopenia continue to recur at regular intervals in the absence of periodic fresh-frozen plasma infusions. One of these children apparently has chronic relapsing thrombotic thrombocytopenic purpura; the second has a chronic relapsing disorder similar to thrombotic thrombocytopenic purpura.