Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma.

Primary cutaneous follicle center lymphoma (PCFCL) has an excellent prognosis using local treatment, whereas nodal follicular lymphoma (nFL), occasionally presenting with cutaneous spread, often requires systemic therapy. Distinction of the 2 diseases based on histopathology alone might be challenging. Copy number alterations (CNAs) have scarcely been explored on a genome-wide scale in PCFCL; however, they might serve as potential biomarkers during differential diagnosis and risk stratification. Low-coverage whole-genome sequencing is a robust, high-throughput method for genome-wide copy number profiling. In this study, we analyzed 28 PCFCL samples from 20 patients and compared the copy number profiles with a cohort of diagnostic samples of 64 nFL patients. Although the copy number profile of PCFCL was similar to that of nFL, PCFCL lacked amplifications of 18q, with the frequency peaking at 18q21.33 in nFL cases involving the BCL2 locus (PCFCL: 5.0% vs nFL: 31.3%, P = .018, Fisher exact test). Development of distant cutaneous spread was significantly associated with higher genomic instability including the proportion of genome altered (0.02 vs 0.13, P = .033) and number of CNAs (2 vs 9 P = .017), as well as the enrichment of 2p22.2-p15 amplification involving REL and XPO1 (6.3% vs 60.0%, P = .005), 3q23-q24 amplification (0.0% vs 50.0%, P = .004), 6q16.1-q23.3 deletion (6.3% vs 50.0%, P = .018), and 9p21.3 deletion covering CDKN2A and CDKN2B loci (0.0% vs 40.0%, P = .014, all Fisher exact test) in PCFCL. Analysis of sequential tumor samples in 2 cases harboring an unfavorable clinical course pointed to the acquisition of 2p amplification in the earliest common progenitor underlining its pivotal role in malignant transformation. By performing genome-wide copy number profiling on the largest patient cohort to date, we identified distinctive CNA alterations conceivably facilitating the differential diagnosis of PCFCL and secondary cutaneous involvement of nFL and potentially aiding the risk stratification of patients with PCFCL in the future.

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.

Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma.

Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 in 33% of 157 PMBCL patients. Subsequent gene expression profiling (n = 120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217 led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure.

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.

Long-time progression-free survival in relapsed, refractory multiple myeloma with the oral ixazomib-lenalidomide-dexamethasone regime / Hosszú távú progressziómentes túlélés relabált, refrakter myeloma multiplex tisztán orális ixazomib-lenalidomid-dexametazon kezelésével.

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetoen gyógyíthatatlan betegség, ezért nagy klinikai jelentoségük van az eredményes mento kezeléseknek. A szájon át adható elso proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekbol álló kombináció, mely hazánkban 2015 áprilisától kezdodoen a "Named Patient Program" keretén belül vált elérhetové relabált, refrakter myeloma multiplexes betegek kezelésére. Célkituzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélok célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeso beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan-Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sot közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélo betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélok között az immunglobulin-nehézláncot érinto transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezobb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét méro nemzetközi stádiumbeosztás (ISS) nem jelezte elore a hosszú túlélést. Gyógyszerelhagyáshoz vezeto mellékhatást a hosszú távú túlélo csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID-19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetoségrol. Orv Hetil. 2021; 162(36): 1451-1458. INTRODUCTION: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. OBJECTIVE: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. METHOD: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. RESULTS: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. DISCUSSION: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. CONCLUSION: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID-19 pandemic. Orv Hetil. 2021; 162(36): 1451-1458.

Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers.

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.

Hodgkin's lymphoma-related vanishing bile duct syndrome / Hodgkin-lymphomához társult eltunoepeút-szindróma.

Összefoglaló. Az eltunoepeút-szindróma ritka, rossz prognózisú kórkép. Az epeutak progresszív destrukciójával, az intrahepaticus epeutak eltunésével jár, epepangáshoz, biliaris cirrhosishoz, végül májelégtelenséghez vezet. A háttérben álló kiváltó okok között infekciók, ischaemia, gyógyszermellékhatások, illetve daganatos megbetegedések szerepelhetnek. A malignitások közül a leggyakrabban a Hodgkin-lymphomához társult formájával találkozhatunk. Cikkünkben egy fiatal, Hodgkin-lymphomás betegünk esetét szeretnénk bemutatni, akinél az icterus hátterében eltunoepeút-szindróma igazolódott, melyet egyéb okok kizárását követoen szövettani mintavétellel igazoltunk. A két ciklus ABVD-protokoll szerinti kezelést követo PET/CT az alapbetegség tekintetében komplett metabolikus remissziót igazolt. A klinikai javuláshoz azonban hosszú hónapokra volt szükség. Végül az epeúteltunés esetünkben reverzibilis folyamatnak bizonyult, az alapbetegség tekintetében a komplett metabolikus remisszió elérésével az epeút-károsodás megállítható volt. Orv Hetil. 2021; 162(22): 884-888. Summary. destruction and loss of the intrahepatic bile ducts leading to cholestatis, biliar chirrosis and finally liver failure. It has been described in different pathologic conditions including infections, ischemia, adverse drug reactions and malignancies. The Hodgkin's lymphoma-associated type occurs most frequently among the forms of the disease of malignant origin. In this report, we introduce the case of a 32-year-old male patient with Hodgkin's lymphoma, diagnosed with vanishing bile duct syndrome upon liver biopsy as a root cause behind his icterus. The PET/CT has proven complete metabolic remission after 2 cycles of ABVD chemoterapy. Clinical improvement, however, occurred only after several months. Finally the loss of bile ducts proved to be a reversible process, the complete metabolic remission of Hodgkin's lymphoma resulted in the regeneration of the bile ducts. Orv Hetil. 2021; 162(22): 884-888.

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.

Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSL) are aggressive non-Hodgkin lymphomas affecting the central nervous system (CNS). Although immunophenotyping studies suggested an uniform activated B-cell (ABC) origin, more recently a spectrum of ABC and germinal center B-cell (GC) cases has been proposed, with the molecular subtypes of PCNSL still being a matter of debate. With the emergence of novel therapies demonstrating different efficacy between the ABC and GC patient groups, precise assignment of molecular subtype is becoming indispensable. To determine the molecular subtype of 77 PCNSL and 17 secondary CNS lymphoma patients, we used the NanoString Lymphoma Subtyping Test (LST), a gene expression-based assay representing a more accurate technique of subtyping compared with standard immunohistochemical (IHC) algorithms. Mutational landscapes of 14 target genes were determined using ultra-deep next-generation sequencing. Using the LST-assay, a significantly lower proportion (80% vs 95%) of PCNSL cases displayed ABC phenotype compared with the IHC-based characterization. The most frequently mutated genes included MYD88, PIM1, and KMT2D. In summary, we successfully applied the LST-assay for molecular classification of PCNSL, reporting higher proportion of cases with GC phenotype compared with IHC analyses, leading to a more precise patient stratification potentially applicable in the diagnostic algorithm of PCNSL.

Real-world data on the efficacy and safety of daratumumab treatment in Hungarian relapsed/refractory multiple myeloma patients.

Daratumumab is a human anti-CD38 monoclonal antibody used in the treatment of refractory and relapsed multiple myeloma. We investigated the efficacy and safety of daratumumab therapy in a real-world setting. Ninety-nine Hungarian patients were included; 48 received monotherapy, while lenalidomide and bortezomib combinations were administered in 29 and 19 cases, respectively. Overall response rate was assessable in 88 patients, with 12 complete, 10 very good partial, 34 partial, and seven minor responses. At a median duration of follow-up of 18.6 months, median progression-free survival (PFS) among all patients was 17.0 months. These values were inferior in the bortezomib combination and monotherapy groups. Patients with early-stage disease (ISS1) had better survival results than those with stage 2 or 3 myeloma (p = 0.009). Heavily pretreated patients had inferior PFS compared to those with 1-3 therapies (p = 0.035). Patients with impaired renal function had PFS results comparable with those having no kidney involvement. There were 10 fatal infections, and the most frequent adverse events were mild infusion-associated reactions and hematologic toxicities. Our results confirm that daratumumab is an effective treatment option for relapsed/refractory MM with an acceptable safety profile in patients with normal and impaired renal function.

Real World Efficacy and Safety Results of Ixazomib Lenalidomide and Dexamethasone Combination in Relapsed/Refractory Multiple Myeloma: Data Collected from the Hungarian Ixazomib Named Patient Program.

Ixazomib-Revlimid-Dexamethasone is an all-oral treatment protocol for multiple myeloma with a manageable tolerability profile which was available through a named patient program for Hungarian patients from December 2015 to April 2017. We analyzed the clinical characteristics and survival of 77 patients treated at 7 centers within this program. The majority of patients responded, we found complete response in 9, very good partial response in 8, partial response in 32, minor response or stable disease in 13 and progressive disease in 11 patients. Progression free survival was 11.4 months. There was a trend of longer progression free survival in those with 1 vs. >1 prior treatment, with equally good effectivity in standard risk and high risk cytogenetic groups. The adverse events were usually mild, none leading to permanent drug interruptions. There were 5 fatalities: 3 infections and 2 pulmonary embolisms. Our real word data support the use of Ixazomib-Revlimid-Dexamethasone as a highly effective and well tolerated oral treatment protocol for relapsed myeloma.

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.

Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein.

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.

Efficacy and Tolerability of a 2-Year Rituximab Maintenance Therapy in Patients with Advanced Follicular Lymphoma after Induction of Response with Rituximab-Containing First Line-Regimens (HUSOM Study).

Follicular lymphoma is a lymphoid malignancy commonly showing slow progression which makes the treatment of the disease challenging. Rituximab monotherapy and rituximab added to standard chemotherapy has been proven to increase survival among patients with advanced stage of the disease. However, the benefit of a rituximab maintenance therapy after induction was still unclear at the time of the initiation of this study. HUSOM was a phase III open-label, single-arm, multi-centre study aimed to assess the efficacy and the safety of the 12 cycles of rituximab (375 mg/m2 every 8 weeks) maintenance therapy in patients had already presented partial or complete response to R-CVP or R-CHOP. Efficacy endpoints such as event-free survival and overall survival were estimated. Adverse events were recorded during the entire course of the study. A total number of 124 patients were enrolled by 15 Hungarian study sites. Out of these, 86 patients received 12 cycles of rituximab and 69 patients completed the 3-year follow-up phase as well. The probabilities of the event free survival and progression at 4.3 years were estimated to be 70.3% and 74.4%, respectively. The overall and the disease free survival at 4 years were estimated to be 90.7% and 87.9%, respectively. A total number of 85 adverse events were reported during the study out of which 5 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those reported by controlled clinical trials (EORTC 20981, PRIMA) conducted in parallel with the HUSOM study.

[Incidence and treatment of extranodal natural killer/T-cell lymphoma nasal type. Hungarian experiences]. / Nasalis típusú extranodalis natural killer T-sejtes lymphoma hazai elofordulása és kezelésével szerzett tapasztalatok.

INTRODUCTION: Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL) represents a rare subtype of T-cell lymphomas with aggressive clinical behavior according to WHO 2016 classification. AIM: ENKTL has distinctive geographic distribution with higher incidence in Asia and Latin America (10% of all non-Hodgkin lymphoma cases), than in Europe and North America (<1%). ENKTL tipically origins from nasopharynx and upper aerodigestive tract. Anthracycline-based chemotherapy regimens are largely ineffective in the treatment of ENKTL. METHOD: Our aims were to evaluate the incidence and treatment strategies of ENKTL patients in Hungarian Haematological Centres between 2003 and 2015. Altogether 20 patients with ENKTL were treated in the 4 haematological hospitals (male:female ratio 12:8, with median 49.5 years of age). RESULTS: Ten patients had localized (stage I-II) disease at the time of the diagnosis. Seventeen patients were treated with chemotherapy (11/CHOP, CHOP-like, 2/HyperCVAD, 1/ProMACECytaBom, 1/SMILE, 2/others), which was completed with involved-field radiation therapy (IFRT) (40-46 Gy) in 6 cases were used. After first-line therapy 9 patients achieved complete remission (CR), 3 patients had partial remission (PR), 3 patients had progressive disease (PD), and 2 patients had stable disease (SD). Median follow-up was 32 (3-113) months. Five patients received second-line therapy for progressive or recurrent disease [2/DHAP, 1/VIM, 1/HyperCVAD, 1/ProMACECytaBom]. None of the patients achieved CR after second-line therapy. Two patients have undergone autologous hematopoietic stem cell transplantation (HSCT) after the first CR. CONCLUSION: ENKTL treatment is more effective with nonanthracycline-containing regimens. L-asparaginase containing chemotherapy and concurrent or sequential chemo-radiotherapy improves survival and CR rates. Orv Hetil. 2017; 158(41): 1635-1641.

[Standard CHOP immuno-chemotherapy for primary mediastinal lymphomas]. / A primer mediastinalis lymphomák standard R-CHOP immun-kemoterápiás kezelése.

INTRODUCTION: Primary mediastinal lymphoma (PMBCL) is an aggressive diffuse large B-cell lymphoma entity. It is a rare disease with specific clinical symptoms. The tumor is predominantly localized in the mediastinum but grows rapidly and infiltrates the surrounding tissues and organs. Two thirds of the patients are young females. Previous studies showed that third generation treatments are more effective than former standard cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) regimens. AIM: Authors' goal was to assess whether adding the anti-CD20 monoclonal antibody, rituximab to the standard CHOP regimen improves the efficacy of the treatment compared to their previous results with CHOP and third generation chemotherapy regimens. METHODS: Between October, 2002 and December, 2004 they have started the rituximab-CHOP (R-CHOP) treatment of 20 newly diagnosed, previously untreated PMBCL patients. Results were compared to the data of 24 patients receiving CHOP (n = 9) or procarbazin-prednisolone-doxorubicin-cyclophosphamide-etoposide-cytosin-arabinoside-bleomycin-vincristin-methotrexate (ProMACE-CytaBOM) (n = 15) treatment in the past. RESULTS: During an average follow-up of 64.6 months, the 5-year overall survival (OS) rate was significantly higher in the R-CHOP group compared to the CHOP treatment (79.4% vs. 33.3%; p = 0.026). However, due to the low number of cases, significant statistical difference could not be demonstrated in the 5-year event-free survival (EFS: 70.0% vs. 33.3%; p>0.05), disease-free survival (DFS: 70.0% vs. 33.3%; p>0.05) and relapse-free survival rate (RFS: 93.0% vs. 100%; p> 0.05), despite of the remarkable numeric difference. When comparing the 5-year survival rates of R-CHOP and ProMACE-CytaBOM treatments, the results were very similar without any significant statistical difference between the two types of treatment (OS: 79.4% vs. 80%; EFS: 70.0% vs. 60.0%; DFS: 70.0% vs. 60.0%; RFS: 93.0% vs. 82.0%; p> 0.05 in all cases). With adding rituximab to CHOP treatment, which was previously considered an insufficient treatment on its own, authors have obtained as good results in treating PMBCL as with third generation regimens. Patients have received the R-CHOP treatments without major side effects and mainly as out-patients. CONCLUSIONS: Standard R-CHOP treatment could therefore replace the more toxic third generation regimens in PMBCL as well. The data are comparable with those reported in the international literature.

[Prognostic value of FDG-PET in Hodgkin lymphoma for posttreatment evaluation. Long-term follow-up results]. / Az FDG-PET prognosztikai értéke Hodgkin-lymphomás betegek követésében - hosszú távú eredményeink.

UNLABELLED: In the past few decades Hodgkin lymphoma (HL) has become a highly curable malignant disease, as a result of using modern polychemotherapy and irradiation. Differentiation of active tumor from fibrosis or necrosis within residual radiographic masses represents a problem of interpretation. AIMS: The aim of this retrospective study is to assess the value of FDG-PET for prediction of remission or relapse in HL. PATIENTS AND METHODS: Data of 128 patients, who had residual masses on CT after completion of their planned treatment, have been analyzed. FDG-PET was performed between January 1995 and February 2005. RESULTS: The median duration of the follow-up from PET was 75.5 months (range: 20-180 months). 89 (70%) patients had negative and 39 (30%) patients had positive FDG-PET results. The numbers of true-positive, true-negative, false-positive and false-negative subjects were 29, 83, 10 and 6, respectively. Sensitivity of post-treatment FDG-PET was 83%, specificity 93%, positive predictive value 74%, negative predictive value 93%, and accuracy 88%. The difference between the event free survival of PET positive and negative cases is highly significant (p = 0.0000), according to the Mantel-Cox test. CONCLUSION: Our results, in accordance with literature, clearly indicate that patients with negative FDG-PET results are unlikely to progress or relapse during a long follow-up. However, false positive uptake is a problem. We have investigated the effect of age, histological subtype, clinical stage and the type of treatment on the accuracy, but on the basis of these facts we could not find any significant difference. However, the date of the investigation influenced the results: before 2000 the number of false results was significantly higher than after that time, which shows the importance of investigators' experience.

[Results of immuno-chemotherapeutic treatment of patients with diffuse large B-cell lymphoma]. / Diffúz nagy B-sejtes lymphomák immunokemoterápiás kezelésével elért eredményeink.

Treatment with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been considered as the standard therapy for diffuse large B-cell lymphoma (DLBCL) for more than 20 years. CHOP treatment in combination with targeted immunotherapy, rituximab (R-CHOP), resulted in significant improvements in the treatment of this group of patients. In this study, efficacy of R-CHOP and R-CHOP-like treatments was analysed. Results were compared to the data of historical patients only receiving CHOP treatment or CHOP-like treatment. Between September 2002 and April 2005, 140 newly diagnosed, untreated DLBCL patients started to receive R-CHOP treatment in a single centre. The eligibility criteria included advanced stage (clinical stages III-IV), or large tumour size (>7 cm) and/or symptom B or extranodal manifestation in the case of clinical stages I-II. The results were compared to the data of 130 patients only receiving CHOP treatment in the past. In the patients receiving R-CHOP, the therapeutic outcomes were superior for all parameters. During an average follow-up period of 44 or 52 months, the overall remission rate was 73.6% in the R-CHOP group in comparison with 47.7% in the CHOP group. The 5-year overall survival was 68.6% vs. 41.0% (RR: 0.4293, CI: 0.2963-0.6221; p < 0.0001), the event-free survival was 59.8% vs. 33.5% (RR: 0.5038, CI: 0.3606-0.7038; p < 0.0001) and the progression-free survival was 64.4% vs. 37.6% (RR: 0.4915, CI: 0.3442-0.7019; p < 0.0001). Since prognostic parameters were more favourable in the R-CHOP group, patient groups were also compared using the International Prognostic Index score. Again, significant differences were revealed by the subgroup analyses. The 5-year overall survival was 74.4% vs. 47.9% (RR: 0.4475, CI: 0.2418-0.8285; p = 0.0084) and 52.0% vs. 28.8% (RR: 0.4989, CI: 0.3098-0.8035; p = 0.003) in the group with good prognosis and in the group with poor prognosis, respectively. In the group with very good prognosis, the statistical difference between the two groups in terms of the 5-year survival parameters remained undetectable as a result of the already very high therapeutic effect and low case number (OS and EFS: CHOP: 100% and 62.5% vs. R-CHOP: 90.9% and 87.0%; p = 0.3873 and p = 0.1702). Combining the standard CHOP treatment with rituximab resulted in a significant improvement of the therapeutic outcomes irrespective of the prognostic grouping. The data are comparable with those reported in the international literature.

[Hodgkin's lymphoma in adolescents: where to treat it--in an adult or pediatric institution?]. / Hodgkin-lymphoma adolescens korban. Hol érdemes kezelni: felnôtt- vagy gyermekintézményben?

UNLABELLED: Adolescent patients with Hodgkin's lymphoma (HL) are treated either in pediatric, or in adult oncological wards. AIM: The aim of our work was to compare the treatment modalities and the survival rates in adolescents with HL treated in adult (A) or pediatric (P) institutes. METHODS: From January 1990 to December 2004, 138 patients (14-21 years) with HL were treated in two adult institutes (A) and 107 in the 10 centres of the Hungarian Pediatric Oncology Network (P). RESULTS: Male:female ratio was 1:1.15 (A) and 1:1.38 (P). The mean age was 18.6 (A) and 15.7 (P) years. There was no difference between the distribution of the stages in the two patient groups. The distribution of histological subtypes (A and P): nodular sclerosing 47% and 59%, mixed cellularity 45% and 25%, lymphocyte rich 1.5% and 10%, lymphocyte depleted 4% and 1%, nodular lymphocyte predominant 1.5% and 3% and unknown 1% and 2%. The majority of the patients were treated with ABVD (A) and OPPA/OEPA +/- COPP (P). One hundred and fifteen (A) and 97 (P) adolescents received irradiation therapy. 80% (A) and 91% (A) of the patients got radiotherapy. In group A 14%, in group P 13% of the patients had relapse. In group A 16 patients died and in group P 7. There was no significant difference in the overall survival (OS) rates at 5 and 10 years in the two patient groups. The event-free survival (EFS) was 76.5 +/- 4% and 72.5 +/- 4% at 5 and 10 years in group A, and 85.3 +/- 4% at both times in group P ( p = 0.0452). CONCLUSION: Survival rates in HL are quite high, 80-90% of the patients can be cured. Event-free survival was higher in pediatric than in adult institutes. In case of patients younger than 18 years, the survival rates were much better in pediatric institutes, so these patients should be treated in pediatric institutes or with protocols used by the pediatricians.

Detection and quantification of MBR/JH2 t(14;18) BCL-2 gene rearrangement in follicular lymphoma using a combined real-time polymerase chain reaction assay.

We report our experience with a new real-time polymerase chain reaction (PCR) assay applicable for simultaneous quantification and characterization of MBR/JH translocation in follicular lymphomas. This technique, which combines amplification with the FRET probe with SYBR Green I melting curve analysis, allows efficient detection of tumor cells in bone marrow or peripheral blood and their comparison with the original neoplastic clone.