Screening and monitoring of the BTKC481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTKC481S , sensitive (10-4 ) time-resolved screening was performed in 83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. With a median follow-up time of 40 months, BTKC481S was detected in 48·2% (40/83) of the patients, with 80·0% (32/40) of them showing disease progression during the examined period. In these 32 cases, representing 72·7% (32/44) of all patients experiencing relapse, emergence of the BTKC481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl-2 inhibition therapy applied in 28/32 patients harbouring BTKC481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTKC481S monitoring with the largest longitudinally analysed real-world patient cohort reported to date and validates the feasibility of an early prediction of relapse in the majority of ibrutinib-treated relapsed/refractory CLL patients experiencing disease progression.

Anagrelide influences thrombotic risk, and prolongs progression-free and overall survival in essential thrombocythaemia vs hydroxyurea plus aspirin.

OBJECTIVE: We report an extension study of patients with essential thrombocythaemia (ET) in the Hungarian Myeloproliferative Neoplasm (HUMYPRON) Registry, which demonstrated that over 6 years anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous thrombotic events (TEs) vs hydroxyurea+aspirin. METHODS: Data on patients with ET were collected through completion of a questionnaire developed according to 2008 WHO diagnostic criteria and with regard to Landolfi, Tefferi and IPSET criteria for thrombotic risk. Data were entered into the registry from 14 haematological centres. TEs, secondary malignancies, disease progression and survival were compared between patients with ET treated with anagrelide (n = 116) and with hydroxyurea+aspirin (n = 121). RESULTS: Patients were followed for (median) 10 years. A between-group difference in the number of patients with TEs was observed (25.9% anagrelide vs 38.0% hydroxyurea+aspirin; P = .052). Minor arterial events were more frequently reported in the hydroxyurea+aspirin group (P < .001); there were marginally more reports of major arterial events in the anagrelide group (P = .049). TE prior to diagnosis was found to significantly influence TE incidence (P > .001). Progression-free survival (P = .004) and survival (P = .001) were significantly increased for the anagrelide group vs hydroxyurea+aspirin. CONCLUSIONS: Anagrelide reduced TEs, and increased progression-free and overall survival vs hydroxyurea+aspirin over (median) 10 years.

[Systemic mastocytosis with progressive disease course]. / Progresszív kórlefolyást mutató szisztémás mastocytosis.

Authors report on a case of a male patient of systemic mastocytosis that was associated with extensive cutaneous lesions. Chronic diarrhoea worsening his quality of life was well managed by the administration of antihistamines. The pleural fluid recurrence soon after drainage has been controlled by the administration of alpha interferon. 40 years after the onset of the first skin signs progression has been manifested in the development of "B" (bone marrow infiltration rate >30%, dysmyelopoiesis, serum tryptase >20 µg/L, hepato- and splenomegaly) and "C" symptoms (liver function test abnormalities, cytopenia, malabsorption, osteoporosis). The patient died at age of 87. The authors' aim was to attract attention on this rare disease and emphasize that symptomatic therapy with antihistamines and drugs available based on customised rights by the National Health Insurance Fund might provide good quality of life. Orv Hetil. 2018; 159(5): 192-196.

[Anteposition in malignant hematologic diseases of siblings in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 34-year period]. / Antepozíció testvérekben észlelt malignus hematológiai betegségekben. A 34 éves Szabolcs-Szatmár-Bereg megyei leukaemia/lymphoma regiszter adataiból levonható következtetések.

INTRODUCTION: In their previous works, the authors reported findings from familial hematologic malignancies in Szabolcs-Szatmár-Bereg county, Hungary. So far there are no other studies on this topic available in Hungary. AIM: Detailed analysis of epidemiologic features of hematologic malignancies of siblings. METHOD: During a 34-year period (between January 1, 1983 and December 31, 2016), 86 families with hematologic malignancies were recorded in Szabolcs-Szatmár-Bereg county. Among them, 19 cases of the affected siblings were registered. RESULTS: In one family there were three sisters with polycythaemia vera, hence the number of analysed disease associations was 21. In all of the 21 cases, the younger sibling's disease developed earlier. The average anteposition was 10.8 (1-33) years (median: 10 years). CONCLUSION: The anticipation was earlier observed in multigeneration hematological malignancies between direct and collateral descendants. On the basis of the above data, anteposition of the disease was observed in younger siblings. Orv Hetil. 2017; 158(33): 1283-1287.

[Epidemiologic features of Philadelphia-negative chronic myeloproliferative disorders in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 33-year period]. / A Philadelphia-negatív krónikus myeloproliferativ kórképek epidemiológiai jellemzoi Szabolcs-Szatmár-Bereg megyében. 33 év adatainak elemzése.

INTRODUCTION: In their previous work, the authors reported findings from 30 years on the incidence of hematological malignancies in Szabolcs-Szatmár-Bereg county, Hungary. Until now there are no other studies on this topic available in Hungary. AIM: Detailed analysis of epidemiologic features of patients with Philadelphia-negative chronic myeloproliferative disorders was carried out. METHOD: During a 33-year period (between January 1, 1983 and December 31, 2015) 4523 adult patients with hematologic malignancies were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. Among them, 255 patients with polycytaemia vera, 102 with primary myelofibrosis, and 331 with essential thrombocytaemia were registered. RESULTS: The incidence of polycythaemia vera and essential thrombocythaemia in Szabolcs-Szatmár-Bereg county showed an increasing tendency, with an overall incidence rate of 1.35 and 1.75/100 000 inhabitants/year, respectively; while the incidence of primary myelofibrosis decreased in the course of years (0.54/100 000 inhabitants/year). In cases of polycythaemia vera and primary myelofibrosis the male:female ratio was found to be equal, however essential thrombocythaemia showed a female dominance. The mean age of patients with polycythaemia vera was 65 (21-95) years, similar to essential thrombocythaemia with 65 (19-85) years, and to primary myelofibrosis with 65.5 (33-84) years. There were only two villages found in this county where the occurrence of patients with Philadelphia-negative chronic myeloproliferative disorders per one thousand inhabitants was significantly higher, than the average (1.22). In every familial cases of these, the manifestation of the disease in the second and the third generations became earlier than in the first genetration. The perceived average degree of the anteposition (anticipation) was found to be 22 years. CONCLUSION: The epidemiologic features of Philadelphia-negative chronic myeloproliferative disorders in Szabolcs-Szatmár-Bereg county are essentially similar to data published in the literature. Orv. Hetil., 2017, 158(15), 572-578.

[Epidemiologic features of myeloma in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 33-year period]. / A myeloma epidemiológiai jellemzoi Szabolcs-Szatmár-Bereg megyében. 33 év adatainak elemzése.

INTRODUCTION: In their previous work, the authors reported findings from 30 years on the incidence of hematological malignancies in Szabolcs-Szatmár-Bereg county, Hungary. Until now there are no other studies on this topic available in Hungary. AIM: Detailed analysis of epidemiologic features of patients with myeloma. METHOD: During a 33-year period (between January 1, 1983 and December 31, 2015) 4521 adult patients with hematologic malignancies were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. Among them 440 patients with myeloma (9.73%) were registered (397 multiple myeloma, 38 solitary, bone/soft tissue plasmocytoma, 5 primary plasma cell leukaemia). RESULTS: The incidence of myeloma in Szabolcs-Szatmár-Bereg county showed an increasing tendency, with an overall incidence rate of 2.33/100 000 inhabitants/year. The male:female ratio was 45.9%:54.1%, the average age of patients was 65.1 (28-90) years, and 59.4% of the patients with multiple myeloma had IgG-type monoclonal immunoglobulin. There was no town or village in this county where the occurrence of patients with myeloma in one thousand inhabitants was significantly higher, than the average (0.78). CONCLUSIONS: The epidemiologic features of myeloma in Szabolcs-Szatmár-Bereg county - except a moderate female dominance - is essentially similar to data published in the literature. Orv. Hetil., 2016, 157(34), 1357-1360.

[Occurrence of associated tumours in chronic lymphocytic leukemia]. / Társult tumorok elofordulása krónikus lymphoid leukaemiában.

INTRODUCTION: Chronic lymphocytic leukemia is one of the most common hematologic malignancy. AIM: The aim of the authors was to investigate the characteristics of malignancies associated with chronic lymphocytic leukemia in patients diagnozed between 2000 and 2015. METHOD: Data of patients with chronic lymphocytic leukemia who had other associated tumours were analysed using the Leukemia/Lymphoma Registry of the Szabolcs-Szatmár-Bereg County, Hungary and patient records. RESULTS: Between January 1, 2000 and December 31, 2015, 526 patients with chronic lymphocytic leukemia were diagnosed. 95 patients of the 526 patients (18.06%) were diagnosed as having associated other tumours. In 48/95 patients (50.5%) the first diagnosed tumour was chronic lymphocytic leukemia, in 23/95 patients (24.2%) the first recognized malignancy was the associated tumour, whereas in 24/95 patients (25.3%) synchron tumours were diagnosed. The number of patients with more than one associated tumour was 10/95 (10.5%). The total number of tumours was 107. The incidence of chronic lymphoid leukemia increased in the period between 2000 and 2015 as compared to the period between 1983 and 1999 (3.19 vs 5.65/100 000 person/year). The occurrence of associated malignancies increased as well (8.06% vs 18.06%). In addition to the most common tumours (colorectal, breast, lung, prostate), skin squamous cell carcinoma (17/95 patients; 17.9%) and melanoma (6/95 patients; 6.3%) also frequently occurred. The second malignancies were most frequently discovered after the diagnosis of chronic lymphocytic leukemia and synchron tumours accounting for 78.5% (84/107) of all associated tumours. The incidence of second malignancies decreased 10 years after the diagnosis of chronic lymphocytic leukemia. CONCLUSIONS: The possible reasons for the high frequency of other tumours associated with chronic lymphocytic leukemia are elderly age of patients, immunsuppressed state and, presumably, chemotherapy of patients with chronic lymphocytic leukemia. During the follow up of patients the high risk for the development of associated tumours should be considered. Therapy of patients should be initiated when it is neccessary. Orv. Hetil., 2016, 157(44), 1752-1756.

[Extranodal lymphomas in adults in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of 30 years' epidemiologic data]. / Extranodalis lymphomák Szabolcs-Szatmár-Bereg megye felnott lakossága körében. 30 év adatainak elemzése.

INTRODUCTION: In their previous work, the authors reported 27-year' findings on the epidemiology of extranodal lymphomas in Szabolcs-Szatmár-Bereg county, Hungary. There are no other studies on this topic available in Hungary. AIM: The aim of this study was to analyse in detail the epidemiologic data of patients with non-Hodgkin's lymphoma who were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county during a 30-year period, to compare the main epidemiologic features of the extranodal and nodal forms, and compare the results with data reported in the international literature. METHOD: Between January 1, 1983 and December 31, 2012, 1123 adult patients with newly diagnosed non-Hodgkin's lymphoma were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. Of those, 347 patients suffered from extranodal, and 776 patients from nodal form of non-Hodgkin's lymphoma. The authors compared the incidence of the extranodal and nodal forms, the age and sex distribution of patients, the ratio of B- and T-cell, as well as the indolent and aggressive forms, the geographic distribution and the association with carcinomas. In addition, they studied the occurrence of familial appearance and the localisation of extranodal forms. RESULTS: The occurrence of non-Hodgkin's lymphomas indicated an increasing tendency in their county. This tendency was true for both the extranodal and nodal forms, but it was more remarkable in the extranodal form of lymphomas. They found no substantial difference between the main epidemiologic features of the two forms. The gastrointestinal tract was the most frequent site of presentation for extranodal lymphomas. CONCLUSIONS: These observations are in line with data reported in the international literature. The data are essentially similar to those published in populations from Western European countries and the United States.

[Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia]. / Az abszolút monocytaszám prognosztikus értéke krónikus lymphoid leukaemiában.

INTRODUCTION: The low peripheral absolute lymphocyte and high monocyte count have been reported to correlate with poor clinical outcome in various lymphomas and other cancers. However, a few data known about the prognostic value of absolute monocyte count in chronic lymphocytic leukaemia. AIM: The aim of the authors was to investigate the impact of absolute monocyte count measured at the time of diagnosis in patients with chronic lymphocytic leukaemia on the time to treatment and overal survival. METHOD: Between January 1, 2005 and December 31, 2012, 223 patients with newly-diagnosed chronic lymphocytic leukaemia were included. The rate of patients needing treatment, time to treatment, overal survival and causes of mortality based on Rai stages, CD38, ZAP-70 positivity and absolute monocyte count were analyzed. RESULTS: Therapy was necessary in 21.1%, 57.4%, 88.9%, 88.9% and 100% of patients in Rai stage 0, I, II, III an IV, respectively; in 61.9% and 60.8% of patients exhibiting CD38 and ZAP-70 positivity, respectively; and in 76.9%, 21.2% and 66.2% of patients if the absolute monocyte count was <0.25 G/l, between 0.25-0.75 G/l and >0.75 G/l, respectively. The median time to treatment and the median overal survival were 19.5, 65, and 35.5 months; and 41.5, 65, and 49.5 months according to the three groups of monocyte counts. The relative risk of beginning the therapy was 1.62 (p<0.01) in patients with absolute monocyte count <0.25 G/l or >0.75 G/l, as compared to those with 0.25-0.75 G/l, and the risk of overal survival was 2.41 (p<0.01) in patients with absolute monocyte count lower than 0.25 G/l as compared to those with higher than 0.25 G/l. The relative risks remained significant in Rai 0 patients, too. The leading causes of mortality were infections (41.7%) and the chronic lymphocytic leukaemia (58.3%) in patients with low monocyte count, while tumours (25.9-35.3%) and other events (48.1 and 11.8%) occurred in patients with medium or high monocyte counts. CONCLUSIONS: Patients with low and high monocyte counts had a shorter time to treatment compared to patients who belonged to the intermediate monocyte count group. The low absolute monocyte count was associated with increased mortality caused by infectious complications and chronic lymphocytic leukaemia. The absolute monocyte count may give additional prognostic information in Rai stage 0, too.

Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

[Incidence of haematological malignancies in adults in Szabolcs-Szatmár-Bereg county, Hungary, between 1983 and 2012. Analysis of data from a thirty-year period]. / Malignus hematológiai betegségek gyakorisága 1983-2012 között Szabolcs-Szatmár-Bereg megye felnott lakossága körében. 30 év adatainak elemzése.

INTRODUCTION: In their previous work the authors reported 25 years' findings on the incidence of haematological malignancies in Szabolcs-Szatmár-Bereg county, Hungary. However, there are no other studies on this topic available in Hungary. AIM: The aim of the authors was to analyze the incidence of malignant haematological disorders between 1983 and 2012 using data obtained from the leukaemia/lymphoma registry of the Szabolcs-Szatmár-Bereg county. METHOD: Between January 1, 1983 and December 31, 2012, 3964 adult patients with newly diagnosed haematological malignancy were recorded in the registry. Patients with myelodysplastic syndrome or monoclonal gammopathy were not registered. RESULTS: The annual number of newly diagnosed patients indicated an increasing tendency of malignant haematological disorders. The increase was primarily due to the increasing number of patients with non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, and essential thrombocythaemia. CONCLUSIONS: These observations are in line with data reported in the international literature. The incidence rate of haematological malignancies in this region of Hungary was similar to data published in populations from Western European countries and the United States.

[Leukemia- and lymphoma-associated flow cytometric, cytogenetic, and molecular genetic aberrations in healthy individuals]. / Leukaemia/lymphoma specifikus áramláscitometriai, citogenetikai és molekuláris genetikai eltérések egészségesekben.

Most leukemia and lymphoma cases are characterized by specific flow cytometric, cytogenetic and molecular genetic aberrations, which can also be detected in healthy individuals in some cases. The authors review the literature concerning monoclonal B-cell lymphocytosis, and the occurrence of chromosomal translocations t(14;18) and t(11;14), NPM-ALK fusion gene, JAK2 V617F mutation, BCR-ABL1 fusion gene, ETV6-RUNX1(TEL-AML1), MLL-AF4 and PML-RARA fusion gene in healthy individuals. At present, we do not know the importance of these aberrations. From the authors review it is evident that this phenomenon has both theoretical and practical (diagnostic, prognostic, and therapeutic) significance.

[The prognostic value of smudge cells (Gumprecht shadows) in chronic lymphocytic leukaemia]. / A Gumprecht-rögök arányának prognosztikus értéke krónikus lymphoid leukaemiában.

INTRODUCTION: Smudge cells (Gumprecht shadows) are chronic lymphocytic leukaemic cells ruptured during peripheral blood smear preparation. It has been demonstrated to be linked to reduced expression of the cytoskeletal protein vimentin and its inverse correlation with the clinical outcome of the disease. AIMS: Investigation of the percentage of smudge cells, CD38-, ZAP-70-positive cells and the time to treatment in patients with chronic lymphocytic leukaemia. METHODS: Authors investigated the percentage of smudge cells, CD38- and ZAP-70-positive cells in the peripheral blood of 50 patients with chronic lymphocytic leukaemia and their correlation with the time to treatment. RESULTS: 21 patients required treatment in the follow-up period. Their median smudge cell percentage was 9.9%, while it was 26.8% in the non-treated group. The cut-off value of smudge cell positivity was set to 20%. 59.3% of the patients with less than cut-off had to be treated in the follow-up time compared to 21.7% of patients with more smudge cells. These findings were similar to the prognostic value of CD38 and ZAP-70. The necessity of treatment increased to 75-77.8% with the combination of investigated markers. The time to treatment was 19 months when smudge cells were less than 20%, but above 20% it was 36.15 months. In case of low smudge cell percentage and CD38 positivity the time to treatment was 14.14 months and in case of high smudge cell percentage and CD38 negativity it was 32.92 months. In discordant cases the time to treatment was 18.43 months. The authors also present a case report that demonstrates the relationship between the percentage of smudge cells and apoptotic cells with annexin V and 7-AAD staining. CONCLUSIONS: Estimation of smudge cells on a blood smear could be a simple and cheap prognostic test in chronic lymphocytic leukaemia with sensitivity similar to CD38 and ZAP-70 estimation. Combination of these tests raised the sensitivity of their prognostic value.

Revealing a Phenotypical Appearance of Ibrutinib Resistance in Patients With Chronic Lymphocytic Leukaemia by Flow Cytometry.

Background: Ibrutinib is widely known as an effective and well-tolerated therapeutical choice of the chronic lymphocytic leukaemia (CLL). However, acquired resistance may occur during the treatment, causing relapse. Early detection of ibrutinib resistance is an important issue, therefore we aimed to find phenotypic markers on CLL cells the expression of which may correlate with the appearance of ibrutinib resistance. Methods: We examined 28 patients' peripheral blood (PB) samples (treatment naïve, ibrutinib sensitive, clinically ibrutinib resistant). The surface markers' expression (CD27, CD69, CD86, CD184, CD185) were measured by flow cytometry. Furthermore, the BTKC481S resistance mutation was assessed by digital droplet PCR. Moreover, the CLL cells' phenotype of a patient with acquired ibrutinib resistance was observed during the ibrutinib treatment. Results: The expression of CD27 (p = 0.030) and CD86 (p = 0.031) became higher in the clinically resistant cohort than in the ibrutinib sensitive cohort. Besides, we found that high CD86 and CD27 expressions were accompanied by BTKC481S mutation. Our prospective study showed that the increase of the expression of CD27, CD69 and CD86 was noticed ahead of the clinical resistance with 3 months. Conclusion: Our study suggests that the changes of the expression of these markers could indicate ibrutinib resistance and the examination of these phenotypic changes may become a part of the patients' follow-up in the future.

Detection of internal tandem duplications in the FLT3 gene by different electrophoretic methods.

BACKGROUND: In acute myeloid leukemia (AML), the internal tandem duplication (ITD) in the juxtamembrane domain of the FLT3 (Fms-like tyrosine kinase 3) gene is one of the most frequent genetic alterations associated with poor prognosis. METHODS: A complex evaluation of the analytical properties of the three most frequently used detection methods--PCR followed by agarose (AGE), polyacrylamide (PAGE) or capillary electrophoresis (CE)--was performed on 95 DNA samples obtained from 73 AML patients. RESULTS: All the three methods verified the presence of a mutant allele in 20 samples from 18 patients. AGE and PAGE could detect the presence of 1%-2% mutant allele, while the detection limit of CE was 0.28%. However, acceptable reproducibility (inter-assay CV <25%) of the mutant allele rate determination was only achievable above 1.5% mutant/total allele rate. The reproducibility of the ITD size determination by CE was much better, but the ITD size calculated by PeakScanner or GeneScan analysis was 7% lower as compared to values obtained by DNA sequencing. The presence of multiple ITD was over-estimated by PAGE and AGE due to the formation of heteroduplexes. CONCLUSIONS: This study suggests the use of PCR+CE in the diagnostics and the follow-up of AML patients. The data further supports the importance of proper analytical evaluation of home-made molecular biological diagnostic tests.

Laboratory evaluation of a flow cytometric BCR-ABL immunobead assay.

BACKGROUND: A new flow cytometric (FC) BCR-ABL immunobead assay has been developed recently. Here we present the laboratory evaluation of the commercially available kit. METHODS: Mononuclear cells were isolated, lysed and processed according to the instructions of the manufacturer. Anti-BCR antibodies adsorbed to capture beads bind the BCR-ABL fusion proteins of the lysed cells, a phycoerythrin (PE)-conjugated anti-ABL antibody is the detector reagent and mean fluorescence intensity (MFI) signals were recorded by flow cytometry. Detection of t(9;22)(q34;q11) translocation was carried out with a quantitative PCR assay. RESULTS: MFI results of 20 normal peripheral blood samples were 88±8 (mean±SD), CV 9%. K562 cells were used as positive control. Within-batch imprecision was excellent (3.7% in the normal and 10% in the pathological range). Cut-off was chosen at MFI 112, where both sensitivity and specificity were 100%. Altogether 17 chronic myeloid leukemia (CML) and 16 acute leukemia samples were analyzed. All PCR positive samples (n=14) were positive with the FC method and negative results were also concordant (n=15). Frozen cell lysates can be stored up to 4 weeks without significant decrease of MFI signal. CONCLUSIONS: The FC BCR-ABL assay is a fast, reproducible and reliable method that may be incorporated into standard flow cytometric protocols to help clinical decision-making.

[Anemia in pregnancy: characteristics in Szabolcs-Szatmár-Bereg County, Hungary]. / Terhességi anaemiák jellemzoi Szabolcs-Szatmár-Bereg megyében.

UNLABELLED: Nowadays anemia is the most common disease of internal medicine during pregnancy. It could cause harmful consequences both to mother and to child. AIM: authors examined connection between the blood count data (hemoglobin, red cell mean corpuscular volume), the ferritin level and the pregnancy age, the mothers' age, schooling, the number of earlier pregnancies, abortions and miscarriages frequency of women who gave birth in 2008 at Szabolcs-Szatmár-Bereg County, Hungary. METHODS: Authors analyzed the records of health visitors in 2008 year in their county. RESULTS: rate of anemia's occurrence in the first trimester was 2.54%, 0.71% in the second and 1.87% in the third trimester, and it was significantly frequented among the youthful (10.30%), the low schooled (5.55%), and the multipara women (2.56%). There was no difference in the rate of abortions; however, miscarriages were more frequent among pregnant women with anemia (7.14% vs. 5.46%). Low mean red cell corpuscular volume values were more frequent in all groups (6.06-22.88%) then the number of pregnant women with anemia. This fact refers to decreased iron stores in most cases. Ferritin level determination was made in 2.42% of cases only, but among these pathological low values was found in 93.1%. CONCLUSIONS: Authors draw attention to the careful nursing of youthful, low schooled and multipara pregnant women, majority of them suffer from iron deficiency. They call attention to the right analysis of blood count, the start of correct iron supplementation in early pregnancy and the need of correction of iron stores before conception, too. Authors also give recommendations to this work on the basis of references.

Incidence of haematological malignancies in adults in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 36-year period / A felnottkori malignus hematológiai megbetegedések gyakorisága Szabolcs-Szatmár-Bereg megyében. 36 év adatainak elemzése.

INTRODUCTION: During a 36-year period (between January 1, 1983 and December 31, 2018), 5159 adult patients with newly diagnosed haematological malignancy were registered in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. AIM: The review of the incidence of different haematological malignancy in the authors' county, and the changes of incidence from time to time, the associated haematological malignancies, and familial occurrence of malignant haematological diseases. METHOD: Detailed analysis of the data of the registry, with statistical analysis of incidence. RESULTS: The incidence of Hodgkin disease and non-Hodgkin's lymphoma (1.49 and 7.12 new cases, respectively/100 000 inhabitants/year) was a little smaller, that of essential thrombocythaemia was larger than in the published data. The incidence of all other haematological malignancies corresponded to the data of the literature. The change of incidence of all malignant haematological diseases was similar to the published data. In the registry, there were 35 patients with two different malignant haematological diseases appearing simultaneously or successively. During the 36-year period, 88 families with haematological malignancies were recorded in the registry. CONCLUSION: With the exception of Hodgkin disease, non-Hodgkin's lymphoma, and essential thrombocythaemia, the incidence of other haematological malignancies corresponded to the data of the literature. The change of incidence in all entities was similar to that observed by other authors. The authors in their country do not know other published data related to associated malignant haematological diseases. The observed anteposition in familial haematological diseases of uncle/aunt and nephew/cousin, and anteposition in malignant haematological diseases of siblings are equally new in the literature. Orv Hetil. 2020; 161(34): 1400-1413.

[Haematological aspects of the gut flora]. / A bélflóra hematológiai vonatkozásai.

The relationship between the gut flora and various diseases (obesity, diabetes mellitus, metabolic disorders, allergic and autoimmune diseases, inflammatory bowel diseases, liver failure, infections, certain neuropsychiatric disorders, tumors) has been highlighted in recent years. Depletion of microbiotics inhibits bone marrow healing. Infections and their antibiotic treatment may also affect hematopoiesis. Intestinal flora may also affect the severity of the graft-versus-host disease and may also play a role in the pathogenesis of immunthrombocytopenia through the T-regulator cells. The study summarizes the features of the gut flora, the effects of microbiotics on bone marrow healing, the course of infections, allogeneic bone marrow transplantation, graft-versus-host disease, lymphoma and the results of related research and therapeutic options. The authors briefly discuss the possible linkage between intestinal flora and immunthrombocytopenia and the effectiveness of the immunotherapy of tumors and its effect on the von Willebrand-factor synthesis. They draw attention on the importance of maintaining microbiotics diversity. Orv Hetil. 2019; 160(20): 774-779.

Effectiveness of the Combination of Rituximab and Standard Chemotherapeutic Regimens in Previously Untreated Patients with Chronic Lymphocytic Leukaemia in Real-Life: Results from a Noninterventional Study (CILI Study).

Chronic lymphocytic leukemia (CLL) is one of the most common haematological malignancies exhibiting remarkable heterogeneity in clinical course. Rituximab added to standard chemotherapy has been proven to increase response rate and eventually survival among previously untreated CLL patients. CILI was an open-label, non-randomized, single arm, multicentric, observational study aimed to collect real-life effectiveness data for rituximab used according to the current label in combination with standard chemotherapy in previously untreated CLL patients. Overall response rates (ORR) in the entire study population as well as in various subgroups were estimated. Adverse events were recorded during the entire course of the study. A total number of 150 patients were enrolled by 15 Hungarian study sites. Out of these, 82 patients received 6 cycles of rituximab containing treatment. Overall response rates of 88.24% (CI95%: 81.6-93.12%) and 94.59% (CI95%: 86.73-98.51%) were recorded in the intent-to-treat (ITT) and per-protocol (PP) populations, respectively. In both study populations, somewhat higher ORR was observed in patients aged ≥65 years. Subgroups defined according to either chromosomal aberrations (presence of 11q and 17p deletions) showed apparently high ORRs, though these rates were most probably biased by low patient numbers. 144 adverse events were reported during the study, of which 15 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those previously reported by controlled clinical trials.