Morphologic and molecular analysis of Richter syndrome in chronic lymphocytic leukaemia patients treated with ibrutinib or venetoclax.

Richter syndrome (RS) represents the development of high-grade lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and presents a diagnostic and therapeutic challenge with an adverse prognosis. The genetic background and morphology of RS in CLL patients treated with chemoimmunotherapy is extensively characterised; however, our knowledge about RS in patients treated with targeted oral therapies should be extended. To understand the morphologic and molecular changes leading to RS in CLL patients treated with the Bruton's tyrosine kinase inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, sequential samples from six CLL/SLL patients undergoing RS were collected in both the CLL and RS phases. A detailed immunophenotypic analysis of formalin-fixed, paraffin-embedded tissue specimens of RS phase was performed, followed by extensive molecular characterisation of CLL and RS samples, including the immunoglobulin heavy chain gene (IGH) rearrangement, TP53 mutations, drug-induced resistance mutations in BTK and BCL2 genes and various copy number changes and point mutations detectable with multiplex ligation-dependent probe amplification (MLPA). Rare, non-diffuse large B-cell lymphoma phenotypes of RS were observed in 3/6 cases, including plasmablastic lymphoma and a transitory entity between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The majority of cases were clonally related and harboured an unmutated variable region of the immunoglobulin heavy chain gene. Abnormalities affecting the TP53 gene occurred in all patients, and every patient carried at least one genetic abnormality conferring susceptibility to RS. In the background of RS, 2/5 patients treated with ibrutinib showed a BTK C481S resistance mutation. One patient developed a BCL2 G101V mutation leading to venetoclax resistance and RS. In conclusion, our findings contribute to better understanding of RS pathogenesis in the era of targeted oral therapies. Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax.

Retrospective analysis of chronic myeloid leukemia patients treated in the Department of Internal Medicine and Oncology, Semmelweis University, between 2003 and 2019 / Krónikus myeloid leukaemia miatt 2003 és 2019 között a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján kezelt betegek adatainak elemzése

Összefoglaló. Bevezetés: A krónikus myeloid leukaemia a diagnosztika fejlodésének és a tirozin-kináz-gátlók bevezetésének köszönhetoen az elmúlt évtizedekben kiváló prognózisú betegséggé vált. Célkituzés: A betegséggel kapcsolatos ismereteink nagy része klinikai vizsgálatokból származik, emiatt kiemelt szerepük van a nem szelektált beteganyagon végzett elemzéseknek. Módszer: Retrospektív elemzésünkben a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján 2003 és 2019 között tirozin-kináz-gátló kezelésben részesült betegek adatait tekintettük át. Eredmények: Klinikánkon összesen 88 beteg részesült terápiában, közülük 73 beteg az analízis idopontjában is kezelés alatt állt. A betegek 5 éves össztúlélése 86%, 5 éves progressziómentes túlélése 70% volt. 9 beteg halt meg, közülük 2 betegnél a halál oka a progrediáló alapbetegség volt. 38 betegnél volt szükség az elso vonalban terápiaváltásra, a váltás oka akkor elsosorban az elégtelen terápiás válasz volt. A késobbi terápiaváltásokra elsosorban intolerancia miatt került sor. Az elso vonalban a betegek több mint fele major molekuláris választ ért el, a jelenlegi kezelés mellett a betegek 85%-ánál major molekuláris választ detektáltunk. Megbeszélés: Adataink alapján az intézményünkben kezelt betegek túlélése és a betegek által elért terápiás válasz megfelel a nemzetközi adatoknak. Következtetés: Mivel nem válogatott beteganyagról van szó, a kapott eredmények pontosabb képet adhatnak a krónikus myeloid leukaemia tirozin-kináz-gátlóval történt kezelésének eredményeirol. Orv Hetil. 2021; 162(32): 1297-1302. INTRODUCTION: As a result of advances in diagnostic techniques and the introduction of tyrosine kinase inhibitors, the prognosis of chronic myeloid leukemia has improved over the last decades. OBJECTIVE: Most of our knowledge about chronic myeloid leukemia results from clinical trials, therefore data derived from non-selected patient population is substantial. METHOD: Data of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors at the Department of Internal Medicine and Oncology, Semmelweis University, between 2003 and 2019 were analysed retrospectively. RESULTS: 88 patients received treatment, 73 patients were on therapy at the time of the analysis. Overall survival at 5 years was 86%, progression-free survival at 5 years was 70%. 9 patients died, 2 of them due to progressive disease. 38 patients needed 2nd line therapy, the main reason of treatment change was failure of therapy. Subsequent treatment modifications were conducted mostly because of intolerance. More than half of the patients on 1st line treatment reached major molecular response and 85% of the patients on treatment at the end of the analysis are in major molecular response. DISCUSSION: Based on our data, survival and therapeutic response of patients in our center are similar to the international results. CONCLUSION: This analysis provides real-world data about treatment results of chronic myeloid leukemia in the tyrosine kinase inhibitor era. Orv Hetil. 2021; 162(32): 1297-1302.

Management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia / Akut coronaria szindrómán átesett thrombocytopeniás betegek thrombocytaaggregáció-gátló gyógyszeres kezelése.

Összefoglaló. Az akut coronaria szindrómán (ACS) átesett betegek kezelésének alappillére a kettos (aszpirin + klopidogrél ) thrombocytaaggregáció-gátló kezelés. Az immunthrombocytopeniás purpurás (ITP-s) betegek - és különösen azok, akik refrakter ITP miatt thrombopoetinanalóg kezelésben részesülnek - külön elbírálást igényelnek. 50-100 G/l thrombocytaszám közötti és vérzéses szövodménnyel nem rendelkezo ACS-s betegeken a gyógyszerkibocsátó stent beültetését követoen kettos thrombocytaaggregáció-gátló kezelést csak 1 hónapig kell alkalmazni (ez az idotartam átlagos vérzéses rizikójú betegeken 1 év), majd klopidogrél-monoterápia javasolt. Munkánk során a 2015. január 1. és 2020. október 1. között a Semmelweis Egyetem I. Belgyógyászati Klinikáján kezelt ITP-s betegek körében vizsgáltuk az ACS elofordulását és lefolyását. Klinikánkon az elmúlt 5 évben gondozott, 168 ITP-s beteg közül 3 beteg esetében alakult ki ACS. A refrakter ITP kezelésének részeként mind a 3 beteg thrombopoetinanalóg - (2 beteg romiplosztim-, 1 beteg eltrombopág-) kezelésben részesült. A 3 ITP-s betegünk egyikénél sem alakult ki vérzéses szövodmény a thrombopoetinanalóg-kezelés és a thrombocytaaggregáció-gátlás mellett. Elso betegünk esetében 5 év alatt három alkalommal alakult ki ACS (egy ízben fémstentet és két alkalommal gyógyszerkibocsátó stentet kapott). A második betegnél két alkalommal (1 év különbséggel), a harmadik betegnél egy esetben történt gyógyszerkibocsátó stent beültetése. ITP és ACS együttes fennállása esetén az akut és a hosszú távú gyógyszeres kezelés egyéni mérlegelést igényel. Ezen speciális betegcsoport számára a kezelési irányelv kidolgozása megfontolandó. Orv Hetil. 2021; 162(33): 1335-1340. Summary. Dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is essential in the treatment of acute coronary syndrome (ACS). Immune thrombocytopenic purpura (ITP) patients - and especially those receiving thrombopoietin analog (TPO) treatment - deserve special attention. In ACS patients with platelet counts between 50 G/L and 100 G/L and no bleeding symptoms, DAPT is indicated for 1 month after the placement of new generation drug-eluting stents (the length of treatment is 1 year in the case of patients with average bleeding risk) followed by clopidogrel monotherapy. In patients with average bleeding risk, DAPT is recommended for 1 year after the ACS. Our aim was to investigate the incidence and outcome of ACS in ITP patients, who were treated in our clinic between 1st January 2015 and 1st October 2020. Out of 168 patients treated for ITP, 3 patients suffered from ACS in the last 5 years. These patients received TPO treatment (2 patients subcutan romiplostim, 1 patient oral eltrombopag). None of these ITP patients treated with DAPT and with TPO analog suffered from bleeding complications. 1 patient developed ACS three times within the last 5 years (he received bare-metal stent once and drug-eluting stent twice). Drug-eluting stent was placed once in the third, and twice (with 1 year difference) in the second patient. Acute and long-term medication of patients suffering from both ITP and ACS is a challenging task and needs individual evaluation. Establishment of treatment guidelines for this special group is warranted. Orv Hetil. 2021; 162(33): 1335-1340.

P53 Overexpression as an Indicator of Overall Survival and Response to Treatment in Osteosarcomas.

The p53 gene located at chromosome 17p13 is found to be altered (allelic loss or other mutation) in multiple human cancers, including osteosarcomas. The mutated gene produces a protein with a prolonged half-life thus rendering it detectable by conventional immunohistochemistry. We examined the correlation between p53 expression and clinical prognosis as well as response to therapy. Twenty-one patients with previously untreated and histologically verified highly malignant osteosarcoma were used for this study. Biopsy material taken both prior to the start of COSS 91 protocol and at the time of surgery (ten weeks later) was examined for alterations in p53 protein expression and drug resistance. Two patients who had strong (+++) p53 protein expression and three others who became positive during the chemotherapy had significantly worse prognosis (all of them died within one year) than those who showed no p53 expression both at biopsy and after chemotherapy (all 11 patients are alive, average follow-up time: 3.5 years). All patients who showed any kind of positive p53 protein expression on initial biopsy were non-responders to chemotherapy. In contrast, 69% (9 out of 13) of those who exhibited no p53 expression on initial biopsy were responders or intermediate responders to chemotherapy. We concluded that p53 expression may be a useful prognostic factor in osteosarcomas. The direct correlation between p53 positive expression and resistance to therapy can help in identifying patients who are in need of a more vigorous or different chemotherapeutical protocol.