Screening and monitoring of the BTK C481S 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

Prognostic value of interim and restaging PET/CT in Hodgkin lymphoma: results of the CHEAP (Chemotherapy Effectiveness Assessment by PET/CT) study - long term observation.

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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

Parallel testing of liquid biopsy (ctDNA) and tissue biopsy samples reveals a higher frequency of EZH2 mutations in follicular lymphoma

Background Recent genomic studies revealed enhancer of zeste homolog 2 (EZH2) gain-of-function mutations, representing novel therapeutic targets in follicular lymphoma (FL) in around one quarter of patients. However, these analyses relied on single-site tissue biopsies and did not investigate the spatial heterogeneity and temporal dynamics of these alterations. Objectives We aimed to perform a systematic analysis of EZH2 mutations using paired tissue (tumor biopsies [TB]) and liquid biopsies (LB) collected prior to treatment within the framework of a nationwide multicentric study. Methods Pretreatment LB and TB samples were collected from 123 patients. Among these, 114 had paired TB and LB, with 39 patients characterized with paired diagnostic and relapse samples available. The EZH2 mutation status and allele burden were assessed using an in-house-designed, highly sensitive multiplex droplet digital PCR assay. Results EZH2 mutation frequency was found to be 41.5% in the entire cohort. In patients with paired TB and LB samples, EZH2 mutations were identified in 37.8% of the patients with mutations exclusively found in 5.3% and 7.9% of TB and LB samples, respectively. EZH2 mutation status switch was documented in 35.9% of the patients with paired diagnostic and relapse samples. We also found that EZH2 wild-type clones may infiltrate the bone marrow more frequently compared to the EZH2 mutant ones. Conclusion The in-depth spatio-temporal analysis identified EZH2 mutations in a considerably higher proportion of patients than previously reported. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy

Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL

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

Abstract 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

A Magyar Belgyógyász Társaság Dél-magyarországi Decentrum 43. Továbbképző Tudományos Ülésén elhangzó előadások rövid összefoglalói

1. Előszó 2. Alsó végtagi oedema ritka oka 3. Diabeteses ketoacidosis változások az utolsó öt évben 4. IGF-2-termelő prostatatumor okozta súlyos hypoglykaemia. Esetismertetés 5. Diabeteses beteg tünetmentes sokér-betegsége. Esetismertetés 6. Egy motorbaleset szövődményei – kardiológiai vonatkozások. Esetismertetés 7. Erectilis diszfunkció és alacsony tesztoszteronszint metabolikus szindróma tüneteit mutató 1-es típusú diabetesben 8. „Egyelőre idiopathiás” AA-amyloidosis. Esetismertetés 9. Anti-TNF-α-terápia mellett kialakuló lupus erythematosus 10. Pancreastumor vagy pancreatitis? 11. Videodenzitometria segítségével vizsgált myocardialis perfúzió eltérései diabetes mellitusban 12. A Clostridium difficile-fertőzések alakulása intézményünk fertőzőosztályán 2011-ig 13. A vesebetegségek felismerhetőségének aránya az eGFR tükrében vizsgálva 14. A gestatiós diabetes mellitus miatt gondozott asszonyok utánvizsgálataival szerzett tapasztalataink 15. Az aortamerevségi (stiffness) index prognosztikus jelentősége acromegaliában 16. Akut máj- és veseelégtelenség ritka oka. Esetismertetés 17. Diabeteses enteropathia, gastroparesis és neuropathia, vagy valami más? Esetismertetés 18. QT-variabilitás és vércukorszint: kimutatható-e összefüggés egészséges szénhidrát-anyagcseréjű egyénekben? 19. Renalis szimpatikus rádiófrekvenciás katéteres ablatio terápiarezisztens hypertoniában 20. A kalcium-anyagcsere útvesztői 21. Humán helminthiasisok: Az ember féregélősködők okozta bántalmainak klinikuma a gyakorlatban 22. Terápiás hatékonyság vizsgálata fokális szegmentális glomerulosclerosisos esetekben 23. Vércukormérés és csúcstechnológia 24. Metformin a terhességben. Áldás vagy átok? 25. Thrombocytopenia és immunhiány 26. Az inzulinkezeléssel járó testsúlynövekedés elkerülése intenzív inzulinanalóg-kezelési rendszerrel. Esetismertetés 27. Arteria renalis kardiogén eredetű akut thromboemboliás occlusiójának sikeres thrombolyticus kezelése. Esetismertetés 28. Microvascularis vasomotio és vércukorszint: kimutatható-e összefüggés egészséges szénhidrát-anyagcseréjű egyénekben? 29. Fődiagnózis: cardialis decompensatio. Cardialis decompensatio? Esetbemutatás 30. Tíz év tapasztalatai a gestatiós diabetes szűrésében és gondozásában 31. Az autonóm neuropathia prospektív vizsgálata inzulinpumpával kezelt 1-es típusú diabeteses betegekben 32. Vékonybél-kapszulaendoszkópiával szerzett kezdeti tapasztalataink 33. Transrectalis ultrahang (RUH) szerepe a rectum és perirectalis tér kórképeinek diagnosztikájában. Tapasztalatok saját eseteink kapcsán 34. Korszerű inzulinkezelés detemir bázisanalóggal: saját tapasztalataim és a nemzetközi obszervációs vizsgálat (A1chieve®) tükrében 35. Proteinuria mint cardiovascularis rizik