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BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
Asunto(s)
Anemia Hemolítica , Factor B del Complemento , Inactivadores del Complemento , Hemoglobinas , Hemoglobinuria Paroxística , Humanos , Administración Oral , Anemia Hemolítica/complicaciones , Complemento C5/antagonistas & inhibidores , Factor B del Complemento/antagonistas & inhibidores , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/efectos adversos , Inactivadores del Complemento/uso terapéutico , Transfusión de Eritrocitos , Cefalea/inducido químicamente , Hemoglobinas/análisis , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemoglobinuria Paroxística/etiología , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: Describe the real-world clinical profile of eculizumab-treated patients by characterizing their short- and long-term clinical and laboratory outcomes. METHODS: This retrospective study used preexisting medical records of eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) at the University Hospital Essen. Hematologic response, breakthrough hemolysis, transfusion dependence, and other outcomes were assessed. RESULTS: Of 85 patients with PNH, 76 received eculizumab for ≥24 weeks (mean follow-up: 5.59 years; total: 425 person-years). At 24 weeks (n = 57 patients with data), 7% and 9% had complete and major hematologic response, respectively. Breakthrough hemolysis occurred in 8%, and 38% required a blood transfusion. Over long-term follow-up (25-264 weeks), 70%-82% of patients did not achieve complete or major hematologic response in any 24-week period. Breakthrough symptoms, breakthrough hemolysis, and transfusion dependence occurred in 63%, 43%, and 63% of patients, respectively, at any point during follow-up. The majority (79%-89%) of patients did not achieve normalized hemoglobin, with 76%-93% having elevated bilirubin or absolute reticulocyte count in any 24-week window. Mean percentage reduction in lactate dehydrogenase (baseline to end of follow-up) was 80.3% (95% CI, 64.0-96.6). CONCLUSIONS: A considerable proportion of patients with PNH receiving eculizumab did not achieve optimal clinical outcomes and had an ongoing disease burden.
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Hemoglobinuria Paroxística , Humanos , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemólisis , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
INTRODUCTION: Patients with hematologic disease are at high risk of morbidity and mortality from COVID-19 due to disease-inherent and therapy-related immunodeficiency. Whether infection with the SARS-CoV2 omicron variant leads to attenuated disease severity in these patients is currently unknown. METHODS: We assessed clinical and laboratory parameters in 61 patients with underlying hematologic conditions with a SARS-CoV2 omicron variant infection confirmed by nucleic acid amplification testing. RESULTS: Fifty patients reported symptoms of COVID-19, most commonly fatigue (37 patients, 60.66%) and cough (32 patients, 52.46%). 39.34% of patients reported fever. Dyspnea was reported by 10 patients and 7 patients (11.48%) required oxygen therapy. Anosmia and ageusia were relatively rare, occurring in less than 10% of patients. Severity of SARS-CoV2 infection could be assessed in 60 patients. Five cases of critical illness leading to ICU admission occurred during the observation period. Overall mortality was 9.84% in this patient cohort, with heterogeneous causes of death. The majority of omicron-infected hematologic patients experienced mild symptoms or remained asymptomatic. DISCUSSION: In this study, symptoms of COVID-19 tended to be milder than described for previous SARS-CoV2 variants. However, the extent to which attenuated severity of omicron-variant SARS-CoV2 infection is caused by altered viral pathogenicity or pre-existing host immunity cannot be inferred from our data and should be investigated in larger prospective studies.
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COVID-19 , Humanos , Estudios Prospectivos , ARN Viral , SARS-CoV-2RESUMEN
COVID-19 is a potential life-threatening viral disease caused by SARS-CoV-2 and was declared a pandemic by the WHO in March 2020. mRNA-based SARS-CoV-2 vaccines are routinely recommended in immune-compromised patients, including patients with AA, as these patients are at increased risk of contracting COVID-19 and developing a more severe course of disease. Between March 2021 and November 2021 relapse of AA occurred in four (age [median]: 53 years, range 30-84 years) out of 135 patients currently registered at our department and two de novo cases of AA in temporal context to vaccination against SARS-CoV-2, were documented. Median time after first COVID-19 vaccination and relapse of AA was 77 days. All relapsed patients were vaccinated with the mRNA-based vaccine Comirnaty®. Relapse in two out of the four patients was refractory to CsA/eltrombopag, favoring IST with hATG/CsA or BMT, respectively. Our observations should prompt clinicians to take vaccine-induced relapse of AA or de novo AA after SARS-CoV-2 vaccination into account. Furthermore, careful clinical monitoring and vigilance for signs or symptoms that may indicate relapse of AA (e.g., bleeding complications) are indicated.
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Anemia Aplásica , Vacunas contra la COVID-19 , COVID-19 , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/inducido químicamente , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Persona de Mediana Edad , ARN Mensajero , Recurrencia , SARS-CoV-2 , Vacunación/efectos adversosRESUMEN
Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.
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Receptores de Activinas Tipo II , Talasemia beta , Adulto , Humanos , Receptores de Activinas Tipo II/efectos adversos , Receptores de Activinas Tipo II/uso terapéutico , Talasemia beta/complicaciones , Talasemia beta/diagnóstico , Talasemia beta/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max ) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4 . For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4 , and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Linfoma de Células T Periférico/patología , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células T Periférico/diagnóstico por imagen , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Acute chest syndrome (ACS) in adult patients with sickle cell disease represents a leading cause of death. It is characterized by a new density on chest X-ray accompanied by fever and/or respiratory symptoms. Currently, 49 adult patients with sickle cell disease are registered at our department. By now, 12 patients (24.5%) suffered from ACS and two patients showed multiple/recurrent (>2) episodes. Death in one patient was related to acute respiratory failure secondary to ACS. In three patients with ACS, invasive mechanical ventilation and subsequent veno-venous extracorporeal membrane oxygenation (VV-ECMO) was mandatory. Veno-venous ECMO was applied within 24 hours upon arrival to the intensive care unit (ICU). All patients were treated aggressively for ACS including exchange transfusions [packed red blood cell (pRBC) units 5-16] maintaining a Hb S threshold of <30.0% in addition to broad-spectrum antibiotics, resulting in a successful outcome following decannulation from VV-ECMO (49 hours, 251 hours, 30 min., and 98 hours, respectively). Limited information is presently available on the use of VV-ECMO in adult patients with sickle cell disease in the context of acute respiratory failure secondary to ACS. The adequate timing of the decision to place ECMO in critically ill adults with sickle cell disease, incapable of being treated by conventional mechanical ventilation secondary to very severe vaso-occlusive crisis (VOC), might further reduce mortality rates while treating the underlying condition.
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Síndrome Torácico Agudo/complicaciones , Anemia de Células Falciformes/complicaciones , Oxigenación por Membrana Extracorpórea , Síndrome Torácico Agudo/patología , Síndrome Torácico Agudo/terapia , Adolescente , Adulto , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/terapia , Enfermedad Crítica , Transfusión de Eritrocitos , Oxigenación por Membrana Extracorpórea/métodos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Despite significant advances in the treatment of complications requiring intensive care unit (ICU) admission, ICU mortality remains high for patients after allogeneic stem cell transplantation. We evaluated the role of thrombocytopenia and poor graft function in allogeneic stem cell recipients receiving ICU treatments along with established prognostic ICU markers in order to identify patients at risk for severe complications. At ICU admission, clinical and laboratory data of 108 allogeneic stem cell transplanted ICU patients were collected and retrospectively analyzed. Platelet counts (≤ 50,000/µl, p < 0.0005), hemoglobin levels (≤ 8.5 mg/dl, p = 0.019), and leukocyte count (≤ 1500/µl, p = 0.025) along with sepsis (p = 0.002) and acute myeloid leukemia (p < 0.0005) correlated significantly with survival. Multivariate analysis confirmed thrombocytopenia (hazard ratio (HR) 2.79 (1.58-4.92, 95% confidence interval (CI)) and anemia (HR 1.82, 1.06-3.11, 95% CI) as independent mortality risk factors. Predominant ICU diagnoses were acute respiratory failure (75%), acute kidney injury (47%), and septic shock (30%). Acute graft versus host disease was diagnosed in 42% of patients, and 47% required vasopressors. Low platelet (≤ 50,000/µl) and poor graft function are independent prognostic factors for impaired survival in critically ill stem cell transplanted patients. The underlying pathophysiology of poor graft function is not fully understood and currently under investigation. High-risk patients may be identified and ICU treatments stratified according to allogeneic stem cell patients' individual risk profiles. In contrast to previous studies involving medical or surgical ICU patients, the fraction of thrombocytopenic patients was larger and low platelets were a better differentiating factor in multivariate analysis than any other parameter.
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Supervivencia de Injerto , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Enfermedad Aguda , Adulto , Anciano , Aloinjertos , Cuidados Críticos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The author name Philipp Wohlfarth was incorrectly spelled as Philipp Wohlfahrth in the original version of this article.
RESUMEN
Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fluorodesoxiglucosa F18/administración & dosificación , Linfoma de Células B , Tomografía de Emisión de Positrones , Rituximab/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
OBJECTIVE: Immunosuppressive therapy (IST) with horse anti-thymocyte globulin (hATG) and cyclosporine (CsA) is considered one of the first-line therapies in patients (pts) with acquired aplastic anemia (AA). METHODS: In our single-center, retrospective analysis response rates (RRs) to ATG/CsA at a minimum of 6 mo were evaluated in 67 treatment-naïve (TN) AA pts (52.2% (35/67) females; median age 45 y (range 18-89 y)) being treated at the West German Cancer Center at the Department of Hematology at the University Hospital of Essen between April 2000 and December 2015. RESULTS: Overall 6 mo RRs in TN pts following ATG/CsA were 67.2% (45/67) (5-year OS: 79.5%). In TN hATG-treated pts 6 mo RRs were 75.5% (37/49) (5-year OS: 81%) compared to 44.4% (8/18) (5-year OS 73.5%) following rabbit ATG (rATG). Response to ATG/CsA was dependent of age, absolute reticulocyte count (ARC), and disease severity. Six mo RRs to salvage ATG/CsA in relapsed/refractory (R/R) pts were 37.5% (6/16). CONCLUSION: Our data independently confirm the findings of previous studies that hATG/CsA is superior to rATG/CsA in TN pts. The lack of hATG availability should not result in abstaining it from an indicated ATG therapy, even though ATGAM® is not registered in Germany.
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Anemia Aplásica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anemia Aplásica/diagnóstico , Anemia Aplásica/etiología , Anemia Aplásica/mortalidad , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/efectos adversos , Suero Antilinfocítico/uso terapéutico , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Índices de Eritrocitos , Femenino , Humanos , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to Neisseria meningitidis infections. The two mainstays to reduce the risk of infection are vaccination and antibiotic prophylaxis. In this retrospective study, serologic response was analyzed after vaccination with a meningococcal vaccine in 23 PNH patients (median age 36 years; range 25 - 88 years; 15 males, 8 females) by measuring serum bactericidal assay (SBA) using rabbit complement (rSBA) titers against meningococcal serogroups A, C, W, and Y. Serologic protection was defined by an rSBA titer ≥1:8. Forty-three percent (10/23) were vaccinated more than once due to chronic eculizumab treatment. Overall serologic response for the meningococcal serogroups was A: 78% (18/23), C: 87% (20/23), W: 48% (11/23), and Y: 70% (16/23). No meningococcal infections have been observed. As immunological response to vaccines varies, the use of serologic response analyses is warranted. Re-vaccination with a tetravalent conjugate vaccine under eculizumab therapy every 3 years is essential or should be based on response rates. If meningococcal infection is suspected, standby therapy with ciprofloxacin and immediate medical evaluation are recommended. The novel vaccines covering serogroup B may even further reduce the risk for infection.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Hemoglobinuria Paroxística/sangre , Hemoglobinuria Paroxística/terapia , Vacunas Meningococicas/administración & dosificación , Prueba Bactericida de Suero/métodos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Cohortes , Esquema de Medicación , Femenino , Hemoglobinuria Paroxística/diagnóstico , Humanos , Masculino , Infecciones Meningocócicas/sangre , Infecciones Meningocócicas/diagnóstico , Infecciones Meningocócicas/prevención & control , Persona de Mediana Edad , Conejos , Estudios Retrospectivos , Pruebas Serológicas/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Eculizumab-treated paroxysmal nocturnal hemoglobinuria (PNH) patients (pts) show a dramatic decrease in serum lactate dehydrogenase (LDH) activities and bilirubin concentrations. However, some pts remain hyperbilirubinemic, possibly indicating an inadequate response due to extravascular hemolysis. METHODS: Mutation analyses of hepatocanalicular transporter/nuclear receptor variants (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight (five of eight males; mean age 38 years [range 26-68 years]) out of the 174 pts with PNH/-clone at our department due to a persistent increase in total bilirubin concentrations (median 3.4 mg/dL; range 2.1-8.1 mg/dL) during chronic eculizumab treatment and normal/or slightly increased serum aminotransferase activities. Median observation time was 70.1 months (range 10.6-135.2 months). All pts were treated according to German PNH guidelines. RESULTS: Homozygous and heterozygous procholestatic variants in the ABCB4, ABCB11, and ATP8B1 genes were identified in all eight pts. All carried the common ABCB4 c.787A>T polymorphism. The A(TA)7 TAA variant in the UGT1A1 promoter causing Gilbert syndrome was detected in three pts (5/8). CONCLUSIONS: Hyperbilirubinemia in PNH pts treated with eculizumab might not only be due to an insufficient response but rather a combination of mutations in hepatocanalicular transporter variants, Gilbert syndrome, and extravascular hemolysis. Our findings warrant further studies concerning transporter and enzyme variants in PNH to determine their clinical significance.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/tratamiento farmacológico , Hiperbilirrubinemia/etiología , Adulto , Anciano , Alelos , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genotipo , Hemoglobinuria Paroxística/sangre , Hemoglobinuria Paroxística/genética , Hemólisis , Humanos , Hiperbilirrubinemia/diagnóstico , L-Lactato Deshidrogenasa/sangre , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Mutación , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
We present the case of a 64-yr-old female paroxysmal nocturnal hemoglobinuria (PNH) patient with subsequent transition to severe aplastic anemia in whom a concomitant successful immunosuppressive therapy (horse anti-thymocyte globulin (hATG) and cyclosporin A) in addition to an ongoing long-term treatment with the terminal complement inhibitor eculizumab was initiated. No reduced ATG efficacy or severe adverse events were observed in the presence of eculizumab. In addition, the possible reoccurrence of PNH symptoms (thromboembolic events and/or intravascular hemolysis) was prevented, while T-cell depletion was similar to non-eculizumab-treated patients with partial remission being evident by day 83.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Hemoglobinuria Paroxística/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/efectos adversos , Quimioterapia Combinada , Femenino , Hemoglobinuria Paroxística/diagnóstico , Hemólisis/efectos de los fármacos , Caballos , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disorder characterised by persistent haemolysis and platelet activation, severe end-organ damage, an increased risk of thrombosis and early mortality. We present the case of a 56-year-old male with long-standing PNH and significant disease-related morbidity who underwent steroid therapy for approximately 15 yrs before treatment with eculizumab, a humanized monoclonal antibody that blocks the terminal phase of the complement cascade at the C5 level. CASE HISTORY: The patient presented with a severely impaired quality of life in 1997 and was diagnosed with PNH 8 months later, soon after which he was commenced on steroid therapy with prednisone. During long-term steroid therapy with progressive increases in prednisone dose, the patient had frequent haemolytic episodes as well as thrombosis and renal complications. He also experienced Cushing's syndrome with arterial hypertension, insulin-dependent diabetes mellitus, osteoporosis, acne and portal fibrosis. Eculizumab therapy was started in late-2009 and led to rapid improvements in haemoglobin and lactate dehydrogenase levels with a complete cessation of haemolytic episodes. Eculizumab has been well tolerated. CONCLUSIONS: Long-term steroid therapy was not effective in controlling PNH in this patient and was associated with significant comorbidities. Treatment with eculizumab led to major improvements, even after such a long period with relatively uncontrolled disease.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Hemoglobinuria Paroxística/tratamiento farmacológico , Prednisona/uso terapéutico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Sickle cell disease is a rare, but complex multi-systemic disorder with high need of interdisciplinary and specialized care and new structural requirements. Besides care of those chronically sick patients, transition process is a vulnerable phase which highly influences further treatment. To make matters worse, patients often have migration background with subsequent communication problems. A national guidance for a standardized transition process is lacking in Germany. In context of a structured consensus process, the "transition initiative sickle cell disease" developed specific recommendations for a structured transition of sickle cell patients on the basis of the S3 transition guideline of the DGfTM. These recommendations should improve this vulnerable process in this complex disease to ensure adequate further treatment and to avoid acute and chronic complications but also mental, social or job-related issues. Besides improvement of quality of life, medical treatment and survival, health economic aspects arise. Documents were developed to support and facilitate the transition process and are available under www.sichelzellkrankheit.info/transition/.
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Anemia de Células Falciformes , Humanos , Anemia de Células Falciformes/terapia , Alemania , Transición a la Atención de Adultos , Guías de Práctica Clínica como AsuntoRESUMEN
Sickle cell disease (SCD) is considered a rare disease in Germany. Due to the increasing prevalence, the acute and chronic morbidities associated with the disease and the sharp increase in the mortality rate of young adults, a need-based transition structure for patients with SCD in Germany is explicitly required. This is the first multicenter German consensus statement addressing the importance of implementing a standardized transition guideline that allows adolescents and young adults to safely transition from pediatric to adult care. Early identification of medical needs and intervention remains important in the context of chronic diseases. Effective measures can improve health care in general, as they lead to a reduction in disease and the consequential economic burden. It is noteworthy that improving structural barriers remains a key challenge even in highly developed countries such as Germany. Inclusion of these transition services for patients with SCD into the regular care of chronically ill adolescents and young adults should be ensured, as well as the coverage of costs associated with a structured transition process.
RESUMEN
This monocentric study conducted at the Pediatric and Adult Hemoglobinopathy Outpatient Units of the University Hospital of Essen summarizes the results of hemoglobinopathies diagnosed between August 2018 and September 2021, prior to the introduction of a general newborn screening (NBS) for SCD in Germany (October 2021). In total, 339 patients (pts.), 182 pediatric [50.5% males (92/182)] and 157 adult pts. [75.8% females (119/157)] were diagnosed by molecular analysis. The most common (parental) descent among affected pts. were the Middle Eastern and North African/Turkey (Turkey: 19.8%, Syria: 11.8%, and Iraq: 5.9%), and the sub-Saharan African region (21.3%). Median age at diagnosis in pediatric carriers [N = 157; 54.1% males (85/157)] was 6.2 yrs. (range 1 (months) mos.-17.8 yrs.) and 31 yrs. (range 18-65 yrs.) in adults [N = 53; 75.2% females (115/153)]. Median age at diagnosis of homozygous or compound-heterozygous disease in pediatric pts. (72% (18/25) females) was 3.7 yrs., range 4 mos.-17 yrs. (HbSS (N = 13): 2.5 yrs., range 5 mos.-7.8 yrs.; HbS/C disease (N = 5): 8 yrs., range 1-8 yrs.; homozygous/compound heterozygous ß-thalassemia (N = 5): 8 yrs., range 3-13 yrs.), in contrast to HbH disease (N = 5): 18 yrs. (median), range 12-40 yrs. Hemoglobinopathies represent a relevant health problem in Germany due to immigration and late diagnosis of second/third generation migrants. SCD-NBS will accelerate diagnosis and might result in reduction of disease-associated morbidity. However, diagnosis of carriers and/or disease-states (i.e. thalassemic syndromes) in newly immigrated and undiagnosed patients will further be delayed. A first major step has been taken, but further steps are required.
Asunto(s)
Anemia de Células Falciformes , Hemoglobinopatías , Talasemia , Talasemia beta , Adulto , Niño , Femenino , Alemania/epidemiología , Hemoglobinopatías/diagnóstico , Hemoglobinopatías/epidemiología , Hemoglobinopatías/genética , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , TurquíaRESUMEN
Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse, is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in vivo T cell depletion with antithymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (P = .0002) than for patients in first complete remission (CR1, P = .0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (P = .796), while it inverted its effect into increased relapse for CR1 patients (P = .0428). CMV reactivation was associated with significantly increased nonrelapse mortality in CR1 patients without ATG (P = .0187) but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared with patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between antivirus and antitumor immunity.
Asunto(s)
Infecciones por Citomegalovirus , Leucemia Mieloide Aguda , Suero Antilinfocítico/uso terapéutico , Infecciones por Citomegalovirus/complicaciones , Humanos , Recurrencia , Estudios Retrospectivos , Activación ViralRESUMEN
BACKGROUND: This monocentric study conducted at the University Hospital of Essen aims to describe maternal and fetal/neonatal outcomes in sickle cell disease (SCD) documented between 1996 to 2021 (N = 53), reflecting the largest monocentric analysis carried out in Germany. METHODS/RESULTS: 46 pregnancies in 22 patients were followed. None of the patients died. In total, 35% (11/31) of pregnancies were preterm. 15 pregnancies in eight patients were conceived on hydroxycarbamide (HC), of which nine had a successful outcome and three were terminated prematurely. There was no difference regarding the rate of spontaneous abortions in patients receiving HC compared to HC-naive patients prior to conception. In patients other than HbS/C disease, pregnancies were complicated by vaso-occlusive crises (VOCs)/acute pain crises (APCs) (96%, 23/24); acute chest syndrome (ACS) (13%, 3/24), transfusion demand (79%, 19/24), urinary tract infections (UTIs) (42%, 10/24) and thromboembolic events (8%, 2/24). In HbS/C patients complications included: VOCs/APCs (43%, 3/7; ACS: 14%, 1/7), transfusion demand (14%, 1/7), and UTIs (14%, 1/7). Independent of preterm deliveries, a significant difference with respect to neonatal growth in favor of neonates from HbS/C mothers was observed. CONCLUSION: Our data support the results of previous studies, highlighting the high rate of maternal and fetal/neonatal complications in pregnant SCD patients.