[How did the survival of acute myeloid leukemia change over the last ten years in our unit?] / Hogyan változott az akut myeloid leukaemiás betegek túlélése a terápiás lehetoségek bovülésével az elmúlt 10 évben klinikánkon?

INTRODUCTION: Acute myeloid leukemia (AML) is a hematological malignancy with high mortality rate. The treatment is especially challenging in patients older than 65 years, which is the large majority of those. For patients unfit for intensive chemotherapy regimens, only palliative cytoreduction and basic supportive care used to be the options in our unit. However, from 2018, the azacitidine-venetoclax combination has been a new therapeutic alternative. This treatment resulted in marked survival benefit in clinical trials, however, its impact on the daily clinical practice and the entire patient population is unclear. OBJECTIVE: Our goal was to evaluate how the application of azacitidine-venetoclax changed the treatment and survival of AML patients in our practice. METHOD: We retrospectively analyzed the available clinical data of all AML patients treated consecutively between January 1, 2011 and December 31, 2021 at the 3rd Department of Internal Medicine (from 2020 onward called Department of Internal Medicine and Hematology), examining their treatment depending on the time period of therapy (2011-2017 and 2018-2021). Patients with acute promyelocytic leukemia were excluded. RESULTS: 423 patients were diagnosed during this period. The number of cases showed a marked increase: in the first 7 years of our study, 184 patients were diagnosed, while this rose to 239 during the subsequent 4 years. The median age of patients was 67.6 years, with more than 60% of patients aged over 65. An improving trend can be observed in the overall survival: between 2011 and 2017, the median overall survival was 4.8 ± 0.9 months, while between 2018 and 2021, it was 8.3 ± 1.4 months (p = 0.051). Moreover, in the case of patients over 65 there was a significant overall survival improvement: 3.1 ± 0.5 vs. 4.9 ± 0.6 months (p = 0,01). The main factor behind this improvement could be that a large proportion of over 65 patients previously only fit for supportive care could now be treated with azacitidine-venetoclax: the percentage of actively treated patients grew from 57.1% to 75.3% in the second period. CONCLUSION: The survival of patients unfit for curative therapy and older than 65 showed a steady increase which can be attributed to the introduction of new therapeutic alternatives. Orv Hetil. 2023; 164(45): 1787-1794.

C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency.

BACKGROUND: Autoantibodies against C1-inhibitor (C1-INH-Ab) have a diagnostic value in acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), even though antibodies can circulate in complexes, which can be undetectable by proven methods. Our aim was to measure C1-INH/C1-INH-Ab complexes (CAC) and investigate their connection to C1-INH-Ab and the changes in their titer over time. RESULTS: 19 patients were diagnosed with C1-INH-AAE in the Hungarian Angioedema Center of Reference and Excellence; 79% of them had an underlying disease. Samples were examined with a newly developed in-house complex ELISA method. Patients with high C1-INH-Ab titer had a CAC titer which did not exceed the normal level and the ones with high CAC titer had a C1-INH-Ab titer which did not exceed the normal level. In case of those patients who had C1-INH-Ab and CAC of the same type of immunoglobulin, the increasing titer of C1-INH-Ab went together with the decreasing level of CAC and vice versa. CAC titer was already increased before the diagnosis of the underlying disease. CONCLUSIONS: Free circulating and complex antibodies are in a dynamically changing equilibrium. CAC measurements can help to predict the development of an underlying disease. The efficiency of the treatment for underlying disease can be monitored by the decreasing CAC titers. Our results show that the CAC can be of important additional information besides the complement panel examination in case of C1-INH-AAE. Measurement of CAC is recommended to be done parallelly with C1-INH-Ab, so as to detect both free and bound antibodies.

Long term follow-up of complement parameters to improve the management of acquired angioedema due to C1-inhibitor deficiency.

Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease that can be diagnosed via complement testing. It often accompanies lymphoproliferative underlying diseases. Our study aimed to examine if there is a connection between complement parameters and the clinical symptoms of C1-INH-AAE, and, in case of a known underlying disease, its activity. The other question is how a connection, if proven, could help in the development of the therapeutic strategy of C1-INH-AAE patients. In the past 30 years, out of the 3938 patients sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1-INH-AAE in 19 cases. An underlying disease was diagnosed in 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found. Angioedema specific long-term prophylaxis did not result in an improvement in neither the frequency of the attacks nor in the complement parameters. A connection has been found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Decreasing complement parameters warn about the appearance or the worsening of the underlying disease. The treatment of the underlying disease brings improvement in the complement parameters. Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Complement parameters supported the long-term efficacy of rituximab treatment for C1-INH-AAE. The change in complement parameters predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In C1-INH-AAE, it is essential to examine the patients for underlying diseases, and to regularly follow up the patient's complement parameters.

Changes of coagulation parameters during erythema marginatum in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of subcutaneous/submucosal edema, which may be preceded by erythema marginatum (EM) as a prodromal symptom. Our aim was to analyze the changes occurring in the parameters of the coagulation system during the development of EM and HAE attacks. MATERIALS AND METHODS: Eight C1-INH-HAE patients (1 male, 7 females, median age: 41.7 years) were studied. Blood samples were obtained from all patients (during symptom-free periods, EM, and HAE attacks), as well as from 20 sex- and age-matched healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Factor V, Factor VII, Factor X, Factor XI, and Factor XII levels were measured. RESULTS: D-dimer levels were significantly lower, whereas aPTT was significantly prolonged in healthy controls vs. the values measured during the symptom-free period (p = 0.0497; p = 0.0043), in the presence of EM (p = 0.002; p = 0.0002), or during HAE attacks (p < 0.0001; p = 0.0002). We observed the following differences between samples taken during HAE attacks vs. in symptom-free periods: D-dimer levels were significantly elevated (p = 0.0391), while aPTT was significantly shorter during HAE attacks (p = 0.0159). D-dimer levels were significantly higher during EM than in symptom-free periods (p = 0.0078). Comparing the samples drawn during EM or during HAE attacks, there were no significant differences in the study parameters. CONCLUSIONS: D-dimer levels were elevated during EM and this suggests that EM may be part of the HAE attack. Nevertheless, further research into the complement and kinin-kallikrein systems is needed in more patients for a better understanding of the pathomechanism of EM.

[Thalidomide therapy in relapsed diffuse large B-cell lymphoma in elderly patients. Three cases]. / Thalidomidkezelés relabált, diffúz nagy B-sejtes lymphomában idos betegekben. Három eset bemutatása.

Diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoproliferative disease, is the most common lymphoma in adults, representing 31% of non-Hodgkin lymphomas (NHL). In elderly patients treatment is problematic because of the high toxicity of standard chemotherapy protocols, especially in relapsed cases, where high-dose chemotherapy and haematopoietic stem cell transplantation would be the best choice. More and more data is becoming available on alternative treatment of refractory/relapsed NHL, including studies on the positive effect of thalidomide and second generation IMiDs in DLBCL, which are already part of the standard treatment protocol in myeloma multiplex and myelodysplasia. The broadening use of IMiDs is due to their anti-angiogenetic, immunmodulatory and anti-inflammatory properties. In addition, a component of the E3-ubiquitin ligase complex, named cereblon, has been described in 2010 as the molecular effector of the thalidomide signal transduction pathway. We initiated thalidomide treatment in three elderly patients with relapsed DLBCL. In two cases, patients had CNS involvement, in the third case the patient had primary mediastinal disease. Patients received 100 mg thalidomide in combination with corticosteroids. Two patients showed an excellent response reaching complete remission on imaging; these patients are progression-free 12 and 20 months after the beginning of treatment. One patient with CNS involvement progressed and deceased despite therapy. According to the literature, IMiDs have significant activity in relapsed DLBCL. Our case-report presents promising results in an elderly patient population with aggressive relapsed NHL that usually has very poor outcome, as high-toxicity treatment cannot be given to these patients. Consequently, because of its efficiency, low-cost and low-toxicity, it is recommended to consider thalidomide therapy in elderly patients with high-grade DLBCL. Orv Hetil. 2017; 158(41): 1642-1648.

The effect of long-term danazol treatment on haematological parameters in hereditary angioedema.

BACKGROUND: The 17-alpha-alkylated derivatives of testosterone are often used for the prevention of oedematous episodes in hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). However, these agents can have many adverse effects, including erythrocytosis and polyglobulia. Our aim was to investigate occurrence of erythrocytosis and polyglobulia after long-term danazol prophylaxis in C1-INH-HAE. METHODS: During the initial stage of our retrospective study, we explored whether C1-INH-HAE is associated with susceptibility to erythrocytosis and/or polyglobulia. In the second stage, we analyzed the haematological parameters of 39 C1-INH-HAE patients before, as well as after treatment with danazol for 1, 3, or 5 years. In the third stage, we studied the incidence of erythrocytosis and of polyglobulia after dosing with danazol for more than 5 years. RESULTS: We did not find any significant difference between C1-INH-HAE patients not receiving danazol and healthy controls as regards the occurrence of erythrocytosis or polyglobulia. The haematological parameters did not change after treatment with danazol for 1, 3, or 5 years. Platelet count was an exception-it decreased significantly (p = 0.0115) versus baseline, but within the reference range. Treatment-related polyglobulia did not occur. We observed erythrocytosis in a single female patient after 1-year-and in three female patients after more than 5-year long-treatment with danazol. Erythrocytosis did not require intervention or the discontinuation of danazol therapy. CONCLUSIONS: We conclude that neither erythrocytosis, nor polyglobulia occurs more often in C1-INH-HAE patients than in healthy individuals; it can be observed only sporadically even after treatment with danazol.

Multiple Valvular Complications of Hypereosinophilic Syndrome.

Endomyocardial fibrosis (EMF) is the most common cardiac abnormality in hyeperosinophilic syndrome (HES), sometimes complicated with mitral valve disease. Mitral valve disease without ventricular manifestation is very rare, however. Case reports link HES to prosthetic valve thrombosis (PVT), but the optimal type of prosthetic valve in HES is not known. Herein is reported the case of a young female HES patient with secondary mitral valve degeneration and severe regurgitation. A mechanical prosthetic valve was implanted six months after she was diagnosed with HES, but despite anticoagulation and antiplatelet therapy she developed PVT three months later. Partially successful thrombolysis was followed by biological prosthetic valve implantation, with no further complications during the subsequent four years. The eosinophil count and treatment for HES was basically unchanged during the follow up period, following the initiation of treatment. Based on these findings it is suggested that, in HES, the implantation of a biological prosthetic valve might be preferable over a mechanical valve.

Neutrophil activation during attacks in patients with hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: Earlier studies have shown that the absolute number of neutrophil granulocytes (NGs) may increase during attack of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). Whether NGs undergo activation during attack has not yet been investigated. However, as neutrophil elastase (NE) can cleave and inactivate C1-INH which may contribute to the dysregulation of the kallikrein-kinin system and hence, to edema formation. Our aim was to investigate the possible activation of NGs during attacks. METHODS: We studied blood samples obtained from 26 patients with C1-INH-HAE during symptom-free periods and during attacks, along with samples from 26 healthy volunteers. NG count (NGC), NE, myeloperoxidase (MPO), pentraxin 3 (PTX3), CRP, C5a, factor H, IL-8, and TNF-α levels were measured. RESULTS: NGC was higher during attacks than during symptom-free periods (p = 0.0132), and the same was observed for NE (p = 0.0026), MPO (p = 0.0008), and PTX3 levels (p = 0.0409). There was a strong positive correlation between NE and MPO levels during attacks (p < 0.0001, R = 0.709). Furthermore, IL-8 (p = 0.0061) and TNF-α (p = 0.0186) levels were also elevated during attacks, compared with symptom-free periods. By contrast, C5a and factor H levels were similar in samples obtained during attacks or in symptom-free periods. CONCLUSION: Increased NGC was associated with elevated NE and MPO levels - this suggests neutrophil activation during attacks. The strong positive correlation between NE and MPO levels, together with the elevated PTX3 concentration, may indicate the expression of neutrophil extracellular traps. All these processes may contribute to the activation of kallikrein-kinin system, which leads to the onset of an edematous episode.

[Severe nephrotic syndrome in a young man taking anabolic steroid and creatine long term]. / Súlyos fokú nephrosis szindróma kialakulása anabolikus szteroidot és kreatint tartósan szedó fiatal férfiban.

Anabolic steroids and creatine supplementation is one of the current abuse used by body builders. It is less known that this combination beside of many deleterious effects may also cause renal damage. Authors report a case of diffuse membranoproliferative glomerulonephritis type I in a 22-year-old man who had been taking continuously methandion in a large quantity and 200 grams of creatine daily, and was sent to the outpatient nephrologic unit with typical clinical signs of nephrosis syndrome. They also call attention to the role of the continuously consumed creatine in the renal failure.