ABSTRACT BOOK 5 TH INTERNATIONAL SYMPOSIUM HODGKIN LYMPHOMA FEBRUARY 25, Czech Hodgkin Study Group

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1 5 TH INTERNATIONAL SYMPOSIUM HODGKIN LYMPHOMA FEBRUARY 25, 2016 ABSTRACT BOOK Czech Hodgkin Study Group 3 rd Faculty of Medicine, Charles University in Prague, Czech Republic Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic Czech Society of Haematology

2 Hodgkinův lymfom z.s. Spolek lékařů zabývajících se diagnostikou a léčbou HODGKINOVA LYMFOMU Číslo účtu pro příspěvky: /0800

3 SYMPOSIUM SCHEDULE AFTERNOON SESSION (CZECH/SLOVAK) H SESSION III, 14:00 15:50 H Chairs: Kateřina Dědečková, Zdeněk Král KATEŘINA DĚDEČKOVÁ New Target Volume Definition in Lymphoma Radiotherapy and Proton Radioterapy for Mediastinal Lymphomas. Nové definice cílových objemů v radioterapii lymfomů a protonová radioterapie u lymfomů s postižením mediastina H REGISTRATION H MORNING SESSION (ENGLISH) H SESSION I, 8:30 10:10 H Chairs: Tomáš Kozák, Roman Kodet TOMÁŠ KOZÁK Welcome H HARALD STEIN Molecular Diagnostics in Lymphoma Using New Highly Efficient Genomics Technologies H ROMAN KODET Modern Trends in Diagnostics of Malignant Lymphomas in the Czech Republic H LUKÁŠ PLANK Primary Mediastinal Lymphomas in the Routine Biopsy Practice of the Consultation Centre of ML Biopsy Diagnosis in the Slovak Republic H VÍT PROCHÁZKA Prognostic Factors in Hodgkin Lymphoma H COFFEE BREAK H SESSION II, 10:40 12:30 H Chairs: Heidi Mociková, Marek Trněný OTAKAR BĚLOHLÁVEK Volumetry and SUV Measurement in Hodgkin Lymphoma Patients H CARSTEN KOBE Differences in Evaluation of PET and Its Impact on Treatment in Hodgkin Lymphoma H MASSIMO FEDERICO Latest results of the EORTC/ LYSA/FIL H10 Study H MICHAEL FUCHS Milestones in the Treatment of Hodgkin Lymphoma: What s Next? H LUNCH/POSTER PRESENTATION H HEIDI MOCIKOVÁ Treatment of Relapsed/Refractory Hodgkin Lymphoma, AETHERA study. Léčba relabovaného/refrakterního Hodgkinova lymfomu, studie AETHERA H ZDENĚK KRÁL Brentuximab vedotine In the Treatment of Relapsed/Refractory Hodgkin Lymphoma. Brentuximab vedotin v léčbě relabovaného/refrakterního Hodgkinova lymfomu H SAMUEL VOKURKA Brentuximab Vedotin in Patients With Refractory/Relapsed Hodgkin s Lymphoma as Bridging Prior to Allogeneic Stem Cell Transplantation. Brentuximab vedotin u pacientů s refrakterním/relabujícím Hodgkinovým lymfomem jako meziléčba (bridging) před alogenní transplantací krvetvorných buněk H COFFEE BREAK H SESSION IV, 16:20 18:00 H Chairs: Jana Marková, Vít Procházka TRNĚNÝ MAREK Antibody Targeted Therapy in Hodgkin Lymphoma. Cílená léčba protilátkami u Hodgkinova lymfomu H VERONIKA VÁLKOVÁ Treatment of Patients With Relapsed Hodgkin Lymphoma After Allogeneic Stem Cell Transplantation. Léčba pacientů s relapsem Hodgkinova lymfomu po alogenní transplantaci H JANA MARKOVÁ Rare Syndromes in Hodgkin Lymphoma diagnostic difficulties. Vzácné syndromy u Hodgkinova lymfomu problémy s diagnostikou H MICHAELA ČEPELOVÁ Late Toxicity in Pediatric Patients Treated for Hodgkin Lymphoma Focus on Cardiovascular Toxicity and Second Cancers. Pozdní toxicita u dětí léčených pro Hodgkinův lymfom se zaměřením na kardiovaskulární toxicitu a sekundární nádory H KRISTÝNA FRÜHAUFOVÁ Current Options of Gonadal Protection and Preservation of embryonic cells in Patients With Hodgkin Lymphoma. Současné možnosti ochrany gonád a uchování zárodečných buněk u pacientek s Hodgkinovým lymfomem H HEIDI MOCIKOVÁ Summary and Adjourn H

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5 ORAL PRESENTATIONS

6 1 Molecular Diagnostics in Lymphoma Using New Highly Efficient Genomics Technologies Harald Stein Berlin Reference Center for Lymphoma and Hematopathology at the Pathodiagnostik Berlin, Germany Histopathology is a powerful method for the diagnosis of cancer. However, it was soon learnt that the diagnostic power of histopathology is limited in the field of lymphoid and myeloid diseases. Therefore there were numerous attempts to increase the diagnostic power by new methods. First progress began with the introduction of the enzyme cytology. These assays proved to be very powerful in myeloid diseases but not in lymphomas. The improvement of the diagnostic of lymphomas took place when immunohistochemical methods were developed by which cell type-, differentiation- and functional specific protein molecules were made detectable in routinely processed tissue sections with the usage of antibodies generated by the monoclonal antibody technology. The great advantage of this method is that not only the mentioned molecules are made visible but also the cells which harbour these molecules. This enabled the formulation of a world-wide accepted cell type based classification of malignant lymphomas, i.e. the WHO lymphoma classification 2001 and 2008 and thus revolutionized the diagnostic of these neoplasms. Genetic and molecular findings have also significantly contributed to the definition of certain lymphoma entities (e.g. follicular l, mantel cell l, anaplastic large cell l.) Now, there is an enormous expectation regarding next generation sequencing (NGS). It is widely believed that NGS will lead to a second revolution in the diagnostic of lymphomas and alter the lymphoma classification. This presentation will show where NGS has already generated pivotal findings which will affect the diagnostics of lymphoid neoplasms.

7 2 Modern Trends in Diagnostics Of Malignant Lymphomas in The Czech Republic Roman Kodet, Vít Campr, Markéta Kalinová, Petra Manďáková, Marcela Mrhalová, Jan Soukup Department of Pathology and Molecular Mediciny, 2 nd Faculty of Medicine, Charles University and Faculty Hospital Motol, Prague, Czech Republic The contemporary diagnostics of lymphomas has a great support in the WHO classification of heamatopoietic neoplasms. WHO classification has an enormous impact on an improvement, consistency and interpretation of individual nosologic entities. It would seem, therefore, that there are little problems left with lymphoma diagnostics. The answer to such a thought is that this is only partially true, however. In typical cases the identification of individual entities is relatively straightforward provided the laboratory is equipped with a reasonable panel of antibodies and immunohistochemical procedures. However, in real life the diagnosis of a significant proportion of lymphomas may pose obstacles and even traps. First, even a simple sampling and tissue handling may pose a problem. Insufficient or crushed specimens are good examples for which there is a need to repeat diagnostic surgery or biopsy. This may be a problem in patients with life threatening symptomatology and also in elderly patients or patients suffering polymorbidity. Second, the diagnostic problem may arise in indentification of a lymphoma in the differential spectrum of non-lymphoma categories. There exist a score of diseases which may cause a considerable problem even to an experienced pathologist. This may be the case for example with Kichuchi-Fujimoto lymphadenitis or with rare diseases such as autoimmune lymphoproliferative syndrome Canale-Smith. Third, even the lymphomas are sometimes difficult to recognize if they occur at a less usual site, age or clinical settings or have an unusual phenotype / genotype. We shall present examples of each of the above categories to outline the complexity of the diagnostic approach as well as the problems which a diagnostic team should solve. Diagnostic approach must be combined with the help of clinical data and appropriate laboratory approach e.g. using flow cytometry or special procedures of in situ hybridization and PCR diagnostics. The complex approach using a well defined and processed material is a way how to refer a relevant diagnosis to start an adequate treatment. It is a practice in this country to provide primary diagnostics of lymphoma or lymphoma-like diseases for second oppinion and though the instruments of diagnostics and precise classification of nosologic entities has improved such a practice should continue to support a maximally precise interpretation of findings. Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization (University Hospital Motol, Prague, Czech Republic)

8 3 Primary Mediastinal Lymphomas in The Routine Biopsy Practice of The Consultation Centre of ML Biopsy Diagnosis in The Slovak Republic Lukáš Plank Department of Pathology, Comenius University Jessenius Medical Faculty and University Hospital in Martin, Slovakia and Martin s Biopsy Center, Ltd., Martin, Slovakia Introduction: With exclusion of a lymphoblastic lymphoma and secondary involvement of the mediastinal organs by other disseminated malignant lymphomas (incl. those of the diffuse large B-cell lymphomas /DLBCL/ - M9680/36), the most common primary mediastinal lymphomas include classical Hodgkin lymphomas (CHL - especially the nodular sclerosing type /M9663/3/) and primary mediastinal large B-cell lymphomas (PMBL M9679/36). A rare but the most complex entity of the mediastinal lymphoma category is represented by B-cell lymphomas, unclassifiable, with features intermediate between CHL and DLBCL (BCLU 9596/3). We have reviewed a 12 years biopsy diagnostic series of patients with primary mediastinal lymphomas in an attempt to evaluate our diagnostic experiences. Material and Methods: We have summarized patients data of Slovak National Consultation Centre of ML Biopsy Diagnosis in the period 01/ /2015 registered in its files with the topographic codes of mediastinal lymphomas (incl. those of thymus, mediastinum and intrathoracic lymph nodes) in association with diagnostic M-codes 9679/36, 9680/36, 9596/36, and 9663/3 resp. The biopsies were sent in the time of actual diagnosis to our center either within the mutual agreement and cooperation of the Slovak pathologists and/or on demand of oncologists working in the lymphoma centers in Slovakia. All the cases were in the corresponding time diagnosed acc. to the WHO malignant lymphoma classification 2001 and 2008 resp. using standardized histological techniques (HE, PAS, Gomori impregnation and Giemsa staining) as well a panel of actually in the real times available immmunohistochemical methods (e.g. detection of CD45, CD20, CD79a, PAX5, CD3, CD5, CD30, CD15, CD23, LMP-EBV, bcl2, bcl6, CD10, MUM1, Ki-67, ALK and myc protein, etc.), in association with available clinical data and other eventual biopsies of the patients (incl. staging bone marrow biopsies and restaging biopsies). Results: Within the 12 years period, the biopsies of 243 patiens were encountered in the files with the PMBL, CHLNS and BCLU diagnosis, 113 (46.5%) of male and 130 (53.5%) of female gender. At the time of diagnoses they were in age ranging from 7-83 years, however the majority of them was represented by patients between years. Altogether 165 (73 = 44.2% male and 92 = 55.8% female) patients in the age years were registered with the PMBL diagnosis. The CHL of NS type was diagnosed in 65 (31 = 47.7% male and 34 = 52.3% female) patients within the age 7 65 years. The BCLU category was registered in 13 (9 = 69.2% male and 4 = 31.8% female) patients in the age years. Discussion and conclusions: In spite of recent ccumulation of knowledge on importance of some new markers of PMBL (e.g. transcriptional factors, MAL and nuclear c-rel/p65 protein) and re-definitions of BCLU category, the biopsy diagnostic criterias of all evaluated mediastinal lymphoma diagnoses based on the multiparametric approach acc. to the WHO 2001 and 2008 classifications resp. were relativelly consistent during the followed period. However, the overlapping morphological, phenotypical and clinical features between CHL and DLBCL, especially of PMBL type, underline the necessity of a closed clinico-pathological discussion and cooperation. In our presentation we will focus on the strong and weak points/moments of this cooperation and on the challenges for the future.

9 4 Prognostic Factors in Hodgkin Lymphoma Vít Procházka, Tomáš Papajík Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Czech Republic Hodgkin lymphoma, the classic type (chl), is the most common lymphoid malignancy affecting patients below the age of 30. There is wide international variation in the incidence of HL; however, the incidence rates in the US and Central Europe are comparable with 2.7 new cases per 100,000 population per year. Despite the relatively high curability of chl, there still remains a proportion of about 20% of patients who relapse after the front line therapy and about 15% of them die within five years after diagnosis. Risk-adapted treatment strategies with dose-intensive chemotherapy protocols (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine; BEACOPP) have brought some survival benefit to advanced-stage chl patients. However, there may be a proportion of patients who are over-treated. The International Prognostic Factors Project s score (IPS), based on simple clinical and laboratory parameters, used to be the gold standard in risk stratification for many years. Lately, it became obsolete and is now rarely used for adapting treatment intensity. Since personalized medicine strongly emphasizes an individual treatment approach to every patient, there is a need for novel predictive tools that closely reflect the biological characteristics of the tumor. Last years have brought an improved understanding of the HL genetics, microenvironment and tumorhost immunity relationship. However, only few reliable biological markers are available to predict the outcome after dose-intensive therapy and none of them can be used in relapsed patients. We will summarize current knowledge about prognostic assessment in chl patients with focus on imaging techniques (PET) and microenvironment studies.

10 5 Volumometry and SUV Measurement in Hodgkin Lymphoma Patients Otakar Bělohlávek PET Centre, Na Homolce Hospital, Prague, Czech Republic Hybrid positron emission tomography / computed tomography (PET/CT) using radioactive derivative of glucose (FDG) became a standard of diagnostics in oncology, including lymphoma. Besides initial staging, restaging and reveal of cancer recurrence, it might be exploited for the assessment of anticancer treatment. During the treatment and at its end, FDG-PET/CT finding might become either completely negative or clearly progressive; but very often some graphical pathology persists and it is not easy to decide, whether it represents residual disease or benign posttreatment changes. This problem is of special consideration in lymphoma patients, because less/more aggressive systemic therapy might be chosen and radiotherapy might be added, with respect to the effect of actual treatment. In the past, morphologic approach based on measurement of the size of pathologic foci using CT was widely exploited. Response evaluation criteria in solid tumours (RECIST) were set for CT. This approach is too rough to reliably decide the effect of the treatment residual enlarged foci might be fibrotic without neoplastic cells, and vice versa, small foci might still represent viable neoplasia. Introduction of FDG-PET into clinical practice brought the possibility to assess glycolytic activity of tissues. Hodgkin lymphoma cells as well as frequent types of non-hodgkin lymphomas typically exhibit intense glucose metabolism and increased FDG uptake measurable by PET. The changes in FDG uptake by lymphoma during the treatment can be visually compared with liver and/or blood background activity. Visual 5-point scale was adopted at the meeting in Deauville (2009) and its utility to predict disease free survival was later verified in lymphoma. Image analysis of PET offers various quantitative parameters: absolute glucose metabolic turnover, indexes of relative tumour uptake in comparison to reference tissue (liver, blood pool), standardized uptake value (SUV) that represents measured tissue activity normalized to administered activity and to body weight or to lean body mass. SUV is measured in regions of interest and expressed as an average or maximal voxel value. The assessment of changes of SUV is the cornerstone for PET response criteria for solid tumours (PERCIST). Using computer assistance, there is also possibility to summarize SUV from all pathologic lesions and calculate total lesion glycolysis (TLG) or metabolic tumour volume (MTV) within the body. The change in these parameters during the course of therapy represents prognostic factor reliably identifying patients with early progression. Recent scientific works address this topic. The key issue of using (semi)quantitative parameters for therapy response assessment is the reproducibility of PET investigations. The same metabolic condition of the patient is essential (glycaemia, insulinaemia, hydration, and thermic status), the same PET scanner, the same data acquisition and processing parameters, exact measurements of uptake time and net administered activity. The error of 10 % might be achievable in optimal conditions, but in clinical practice it is usually higher. This fact must be taken into account while clinically interpreting (semi)quantitative parameters.

11 6 Differences In Evaluation of PET and Its Impact on Treatment in HL Carsten Kobe 1, Georg Kuhnert 1, Heinz Haverkamp 2, Michael Fuchs 2, 3, Peter Borchmann 2, 3, Alexander Drzezga 1, Andreas Engert 2,3, Markus Dietlein 1 1 Department of Nuclear Medicine, University Hospital of Cologne, Germany 2 German Hodgkin Study Group, University Hospital of Cologne, Germany 3 Department of Internal Medicine I, University Hospital of Cologne, Germany Aim: The aim was to analyze the degree of agreement between the central review panel and the local PET interpretation within the HD15 trial and its impact on subsequent treatment and progression free survival. Methods: The analysis set consisted of 739 patients with residues 2.5 cm after 6 or 8 cycles of BEACOPPesc from the HD15 trial performed by the German Hodgkin Study Group. The recommendation for or against further radiotherapy was based on the central [18F]FDG-PET interpretation. Central PET interpretation was compared to the local PET interpretation and concordance was measured using Cohen s Kappa coefficient. Prognostic impact of the analysis of concordance between local and central PET interpretations was evaluated using progression free survival (PFS); groups were compared with the log rank test. Results: The central panel rated 548 of 739 patients (74%) as PET negative. Of these, 513 were also rated as PET negative in the local PET interpretation. PET positivity was seen by central reviewers in the remaining 191 patients (26%), in concordance with local reviewers in 155 cases. Even though substantial agreement was found (Cohen s Kappa 0.81), the interpretation of the central PET review panel led to a different therapeutic recommendation in 71/739 (10%) patients. PFS was equally high in groups in which the therapeutic regime had been changed on the basis of the central panel decision. Conclusion: High concordance is found between local and central reviewers with regard to PET interpretation in residual tissue after intense chemotherapy. The existence of the central PET review panel allows the identification of additional patients as PET negative where radiotherapy can be safely omitted (35 of 548 pts. = 4.7%).

12 7 Early FDG-PET Adapted Treatment in Patients With Stages I/II Hodgkin lymphoma (HL): Latest Results of The Randomized Intergroup EORTC/LYSA/FIL H10 trial Massimo Federico, EORTC/LYSA/FIL Intergroup H10 team Oncologia Medica, Università di Modena e Reggio Emilia Policlinico, Modena, Italy Background. Combined-modality treatment is considered worldwide the standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an FDG-PET scan after 2 cycles of ABVD could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial to evaluate: i) whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan; ii) the efficacy of intensification of chemotherapy in patients with a positive early PETscan after two cycles of ABVD. Methods. Patients with stage I-II disease were randomized upfront and the standard combined modality treatment consisted of ABVD followed by radiotherapy, irrespective of the early PET result. In the experimental arm, the early PET negative patients with early favorable (F) and unfavorable (U) disease continued with 2 and 4 additional cycles of ABVD, respectively. The early positive patients switched from ABVD to 2 cycles of BEACOPPesc and radiotherapy. Primary endpoint was progression-free survival (PFS). Results. From October 2006 till June 2011, 1950 patients, age yrs with previously untreated stage I/II supradiaphragmatic, classical HL, were included in the trial. Out of 1950 randomized patients, 1925 had an early PET and 361 (18.8%) were positive. In August 2010, the preplanned interim futility analysis on the early PET negative group revealed that the experimental no-inrt group had more progressions than the standard CMT group in both F and U patients. It was unlikely to show non-inferiority for the experimental no-rt arm if accrual would continue. Therefore, the early PET negative experimental arm was prematurely stopped. At a median follow-up of 4.5 years, the final analysis of the early PET negative group confirmed the conclusions of the published interim analysis, i.e. we could not show the non-inferiority of the no-rt arm as compared to the standard CMT. In the group of patients with early positive PET scan, significantly fewer progressions or relapses occurred in the BEACOPPesc than in the ABVD arm. The estimated 5-year PFS rate was 90.6% vs. 77.4% with a difference of 13.2% (95% CI, 5% to 21%) and a HR=0.42 (95%CI, 0.23 to 0.74), in favor of the BEACOPPesc arm (p-value=0.002<0.037). The OS rates at 5 years were 96.0% vs. 89.3% (HR=0.45, 95%CI, 0.19 to 1.07) in the BEACOPPesc and ABVD arm respectively. Except for hematological toxicities, no excess severe toxicities were observed in the BEACOPPesc arm. Conclusions. In early PET negative patients we could not show non-inferiority for the no-rt arm compared to standard CMT. Instead, in patients with early PET positivity after two cycles of ABVD, intensification with two cycles of BEACOPPesc produced a significantly better 5-year PFS than ABVD.

13 8 Milestones in The Treatment of Hodgkin Lymphoma: What s Next? Michael Fuchs, German Hodgkin Study Group (GHSG) Department of Internal Medicine I, University Hospital of Cologne, Germany Forty years ago, Hodgkin lymphoma used to be an incurable malignant disease, but its treatment has improved considerably, and today it is actually associated with the best chance of recovery of all cancers in adults. This development is based on a few milestones, including substantial improvements in radiotherapy and the development of polychemotherapy. Today, after the initial diagnosis of Hodgkin lymphoma, patients receive a combination of chemotherapy and radiotherapy. The German Hodgkin Study Group (GHSG) has been conducting clinical trials and scientific research projects on Hodgkin lymphoma for more than 30 years now, and over 20,000 patients have been treated within the scope of its trials over time. One of the central pillars in modern Hodgkin lymphoma therapy is a strict quality control system by means of an interdisciplinary review panel that combines the fields of pathology, radiotherapy and nuclear medicine. Based on large-scale prospective, randomized multicenter trials, the GHSG has shown that, for example, 90% of early-stage ( early favorable ) patients can be cured with 2 cycles of chemotherapy (ABVD) and 20 Gy small radiation field therapy. The prognosis for advancedstage patients has clearly improved as well, due to the introduction of the escalated BEACOPP regimen, with a current overall survival rate of 95% at 5 years. Due to new treatment modalities that have been introduced, such as the antibody-drug conjugate Brentuximab vedotin, which targets the CD30-antigen, even Hodgkin lymphoma patients with multiple relapses can be treated effectively now. Other new substances are currently being developed.

14 9 New Target Volume Definition in Lymphoma Radiotherapy and Proton Radioterapy for Mediastinal Lymphomas Nové definice cílových objemů v radioterapii lymfomů a protonová radioterapie u lymfomů s postižením mediastina Kateřina Dědečková 1, 2 1 Proton Therapy Center, Prague, Czech Republic 2 Institute of Radiation Oncology, Na Bulovce Hospital and 1 st Faculty of Medicine, Charles University in Prague, Czech Republic Introduction: Radiotherapy (RT) is an important modality in the treatment of lymphomas, especially in combination with chemotherapy. There is an effort to diminish risk of postradiation toxicity via decreasing radiation load (reduction or radiotherapy omission, utilization of modern photon or proton techniques). Methods: Reduction of target volume size Previously used target volume definition =involved field RT (IF-RT) covered relatively big volume of irradiated tissue. In fact, RT IF included irradiation of initially macroscopically involved lymph nodes and subclinically supposed involved nodes within initially affected regions. New concept involved node RT (IN-RT), designed by Girinski et al in 2006, involves irradiation of only initially affected lymph nodes. New recommendation for routine clinical practice based on IN-RT concept is called involved site RT (IS-RT). This definition is less rigorous to the extent of irradiation targeted to only particular lymph nodes. In clinical practice, there is not always knowledge about the accurate extent of disease before start of treatment (Hoskins et al, 2012). The application of IS-RT is recommended by the International Lymphoma Radiation Oncology Group (ILROG) for routine clinical use. ILROG is the group of radiation oncology experts that gathers international authorities in the field of lymphoma RT. New RT techniques As for photon techniques in Czech Republic, there is frequently used 3D conformal technique (3D-CRT). From more advanced photon techniques, intensity modulated RT (IMRT), volumetric arc RT (VMAT) and helical tomotherapy is available. The major advantage of these techniques is reduction of non-targeting tissue volume exposed to high doses of radiation. The major disadvantage of these advanced photon techniques are low-dose bath (big volume of tissue exposed to middle and low doses of unintended irradiation). This situation can be associated with increased risk of secondary malignancies induction and late functional impairment of healthy tissue. From the local control point of view, the steep dose gradient could be dangerous due to the risk of partial target volume underdosage. The new technique of mediastinal irradiation in deep inspiration breath hold (DIBH), which can be use in combination with photon or proton technique, means active control of patient s breathing, which is then irradiated in mediastinal position of maximal inspiration. This technique compared to more often used free breathing technique is associated with better lung tissue sparing, sparing of heart, coronary arteries and due to the fixation of mediastinal position during RT decreases risk of target missing or under dosage. Proton RT (pencil beam scanning technique) uses another source of ionizing radiation than photon RT. This technique ensures better dose distribution for purpose of medical irradiation compared to photons. Proton RT is used in Hodgkin (HL) and non-hodgkin lymphomas (NHL) (Hoppe et al. 2014, Winkfield et al.2015). Proton RT significantly decreases dose to cardiac structures, lungs, spinal cord and integral dose. It is well tolerated treatment that ensures excellent local control. It decreases risk of acute, late and very late toxicity development. Proton RT ensures possibility of reirradiation, in chemoresistant lymphomas often possibility of dose escalation in specific situations. Results: From 4/2013 to 12/2015, 49 patients (pts) with lymphoma were irradiated in Proton Therapy Center (36 HL, 13 NHL). 43 of them underwent proton RT of supradiaphragmatical involvement including mediastinum, 6 pts of them were irradiated to another region affected by lymphoma. From 3/2015, IS-RT has been used, from 4/2015, mediastinal RT in DIBH has been applied. No patient has showed development of radiation toxicity of grade 3 or 4. From the evaluable patients with follow-up more than 3 months (22 pts) no patient has showed local relapse in irradiated region. Conclusion: New approaches in lymphoma RT with target volume reduction and new techniques of dose delivery into target volume offer significant reduction of treatment related toxicity. IS-RT should be a new standard for target volume definition in lymphomas. Proton RT with its potential to decrease unintended healthy tissue irradiation should be consider in patients with necessity of mediastinal RT or reirradiation.

15 10 Treatment Of Relapsed/Refractory Hodgkin Lymphoma, AETHERA Study Léčba relabovaného/refrakterního Hodgkinova lymfomu, studie AETHERA Heidi Móciková Department of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and 3 rd Faculty of Medicine, Charles University in Prague, Czech Republic Hodgkin lymphoma (HL) can be cured in a vast majority of patients by the first-line treatment, however, relapses occur in 10 % of patients in early stages and up to 30% of patients in intermediate or advanced stages. Most frequently reported prognostic factors in relapse of HL are: B symptoms, bulky disease >5cm, advanced clinical stage IV in relapse, early relapse up to 12 months, poor performance status, PET positivity after salvage chemotherapy before autologous stem cell transplantation (ASCT) and insufficient response to salvage treatment- less than partial remission. Current goal of salvage chemotherapy before ASCT is to achieve a complete metabolic response PET negativity either after the first or the second salvage treatment. Numerous salvage chemotherapies are used in relapsed/refractory HL: DHAP, ICE, IGEV, GVD, etc. and the reported overall response rate (ORR) ranges between 60% and 85%. A new drug-brentuximab vedotin (BV) alone achieves ORR of 69%. The best response rate before ASCT is achieved by combination of BV with bendamustine (ORR 96%, CRR 83%) according to phase I/II study. Combinations of BV with other chemotherapies or new drugs are currently investigated in ongoing trials. Relapses after high-dose chemotherapy BEAM and ASCT occur in approximately 50% of patients. A phase 3, randomized, placebo-controlled AETHERA trial evaluated whether post-asct consolidation treatment with BV(1.8mg/kg i.v. q3wk up to 16 cycles) could prevent disease progression in HL patients at high risk for relapse. Consolidation with BV significantly improved 3-year progression-free survival (PFS) when compared with placebo: the 3-year PFS rate was 61% for the BV arm and 43% for the placebo arm, (hazard ratio [HR]=0.58, P=0.001). Median PFS was not reached in the BV arm and was 15.8 months in the placebo arm (HR=0.52, 95% CI ). Peripheral sensory neuropathy (56%) and neutropenia (35%) were the most common adverse events. Tandem ASCT represents another promising approach how to prevent a relapse post ASCT in a high risk group of relapsed/refractory HL patients. Relapses after ASCT can be effectively treated with BV (ORR 75%, CRR 34%) and younger patients achieving a remission can proceed to allogeneic stem cell transplantation. Anti-PD-1 antibodies (e.g. Nivolumab or Pembrolizumab) are currently investigated in phase I trials with promising results in relapsed/refractory HL: Nivolumab achieves ORR of 87% (CRR 17%) and the ORR of Pembrolizumab is 66% (CRR 21%). Conclusion. PET/CT driven salvage chemotherapy before ASCT and implementation of Brentuximab vedotin into the treatment and consolidation of relapsed/refractory HL represent a significant progress in the management of these patients.

16 11 Brentuximab Vedotine in The Treatment of Relapsed/Refractory Hodgkin Lymphoma Brentuximab vedotin v léčbě relabovaného/refrakterního Hodgkinova lymfomu Zdeněk Král 1, Jozef Michalka 1, Heidi Móciková 2, Jana Marková 2, Alica Sýkorová 3, David Belada 3, Alexandra Jungová 4, Samuel Vokurka 4, M. Lukášová 5, Vít Procházka 5, Juraj Ďuraš 6, Roman Hájek 6 1 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Czech Republic 2 Department of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and 3 rd Faculty of Medicine, Charles University in Prague, Czech Republic 3 Fourth Department of Internal Medicine - Hematology, Faculty of Medicine and University Hospital, Charles University, Hradec Králové, Czech Republic 4 Department of Hemato-Oncology, University Hospital in Plzen, Pilsen, Czech Republic 5 Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic 6 Department of Hemato-Oncology, University of Ostrava, Ostrava, Czech Republic Introduction: Approximately, 20 30% of patients with classical Hodgkin s lymphoma (HL) require further treatment due to relapse or disease resistance. The treatment of patients with refractory/relapsed Hodgkin s lymphoma (HL) still remains challenging. Brentuximab Vedotin (BV) has demonstrated promising efficacy in refractory/relapsed Hodgkin s lymphoma. Patients and Methods: We performed retrospective, multicenter analysis of efficacy BV in 17 heavily pretreated patients with refractory/relapsed BV naive HL in the Czech Republic. Patients received infusions of BV at a dose 1.8mg/kg of body weight every 3 weeks, dose reduction was documented only in 3 cases (2 x neuropathy and 1 x irritation of the pankreas). Therapeutic response to BV (median of 6 cycles) was evaluated in 17 patients. Results: Seven patients (41.2%) achieved a complete response, one (5.9%) a partial response, and nine (52.9%) patients showed disease progression after BV treatment. The response rate to the BV was 47.1%. Of the patients who achieved remission, one relapsed after 13 months. Currently seven (41.2%) of the 17 analyzed patients are alive in a complete remission (follow-up 1-16 months), 6 (35.3%) patients are treated for disease progression or relapse, and 4 (23.5%) patients died of progressive HL. Conclusion: Analysis results confirm that BV as a single agent is effective in heavily pretreated patients with refractory/relapsed classical HL.

17 12 Brentuximab Vedotin in Patients With Refractory/Relapsed Hodgkin s Lymphoma As Bridging Prior To Allogeneic Stem Cell Transplantation Brentuximab vedotin u pacientů s refrakterním/relabujícím Hodgkinovým lymfomem jako meziléčba (bridging) před alogenní transplantací krvetvorných buněk Samuel Vokurka, Alexandra Jungová, Pavel Jindra, Martin Pachner, Michal Karas, Marcela Hrabětová Department of Hemato-Oncology, University Hospital in Plzen, Pilsen, Czech Republic Introduction: The CD30 antigen is strongly expressed on RS cells of Hodgkin lymphoma (HL). Brentuximab vedotin (BV) is a conjugate of an anti-cd30 antibody with monomethyl auristatin antimitotic antineoplastic molecule. The drug is indicated in a dose of 1.8 mg/kg every 3 weeks to treat adult patients with relapsed or refractory CD30+ HL after autologous stem cell transplantation (HSCT), or after at least two prior therapies where autologous HSCT or combined chemotherapy does not represent a therapeutic option. The response rate is about 75%, median time to objective response takes 6 weeks (2 doses) and to complete remission 12 weeks (4 doses), median PFS is 5.6 months and 20.5 months in patients achieving CR, 25% of patients stay in remission for 4 years (Younes A, J Clin Oncol 2012). BV has also been given as a pretreatment (bridging) prior to allogeneic HSCT and two retrospective analyzes in 18 and 9 patients showed no negative impact on transplantation results (Chen R, Blood 2012; Garciaz S, Hematol Oncol 2014). Methods: A retrospective analysis of case studies of five patients treated at our center using BV (Adcetris 1.8 mg/kg every 3 weeks) indicated as a pretreatment (bridging) prior to allogeneic HSCT. Reimbursement of the treatment was approved individually by Health insurance companies No. 111, 201, 205 and 207. The drug was administered as a slow infusion taking 30-60minutes, premedication with 100 mg hydrocortisone i.v. was administered, the first dose of BV was administered during short-course hospitalization. Case No.1: 43-y, female, st.ii.a, IPS risk 0, BV launched 18 months since the diagnosis at the 3rd HL progression, after previous treatment with 4x ABVD, 2x DHAP, 2x autologous HSCT (BEAM, BAM), 6 cycles of BV were administered without complications, a temporary PR was achieved with incipient 4th progression at the time of allogeneic HSCT, now the patient stays in CR lasting 24 months since the start of BV. Case No.2: 33-y, female, st.iii.a, IPS risk 0, BV launched 19 months since diagnosis at the 4th HL progression, after previous treatment 4x ABVD, 2x DHAP, 2x autologous HSCT (BEAM, BAM), 1x CEVD, 3 cycles of BV were administered and complicated with allergic reaction, a temporary PR was achieved with incipient 5th progression at the time of allogeneic HSCT, now the patient stays in CR lasting for 22 since the start of BV. Case No.3: 36-y, male, st.iii.a, IPS risk 1, BV launched 29 months since diagnosis at the 3rd PR, after previous treatment 6x ABVD, 2x DHAP, 2x autologous HSCT (BEAM, BAM), 4 cycles of BV were administered without complications, CR was achieved, now the patient stays in CR lasting for 16 months since the start of BV and allogeneic HSCT was cancelled due to complications in donor. Case No. 4: 48-y, male, st.iv.b with lungs and bone marrow involvement, IPS risk 3, BV launched 38 months since diagnosis at the 3rd PR, after previous treatment 6x ABVD, 2x autologous HSCT (BEAM, BAM), 8 cycles of BV were administered without complications, CR was achieved, now the patient stays in CR lasting for 12 months since the start of BV and allogeneic HSCT was cancelled at the request of the patient. Case No.5: 36-y, male, st.ii.b bulky mediastinum and lungs infiltration, IPS risk 2, BV was launched 21 months since diagnosis at the 1st PR, after previous treatment 6x ABVD, 2xDHAP, autologous HSCT (BEAM), radiotherapy, autologous HSCT (BAM), 2 cycles of BV were administered and two more are to be given prior to allogeneic HSCT in 21/2015. Conclusions: very unfavourable prognosis HL cases with several and intensive treatment courses administered to ensure at least some control over the resistant or very early relapsing lymphomas are presented. BV administration allowed to bridge the period of an allogeneic stem cells donor search. BV has led to a distinct (mostly temporary) minimization of the disease. Administration of BV was well tolerated except for one allergic reaction. Allogeneic HSCT brought further significant effect in two patients, two patients are alive in CR without any transplantation and one patient is waiting for it.

18 13 Immunotherapy for Hodgkin s Lymphoma Imunoterapie u Hodgkinova lymfomu Marek Trněný First Medical Department Clinical Department of Haematooncology, First Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Czech Republic Hodgkin s tumor cells have origin in GCB lymphocytes and their survival depends on tumor microenvironment which is formed by themselves. The RS and Hodgkin s cells finally represent less than 1% of cells in the tumor. Successful allogeneic stem cell transplant with graft versus lymphoma effect proves the role of immune mechanisms in the eradication of HL 1,2. The introduction of brentuximab vedotin (BV) demonstrated the role of targeted therapy through CD30 antigen and its impact of tumor shrinkage and remission induction 3, although the effect of naked anticd30 antibody was negligible4,5. BV is now the standard part of treatment strategy especially for relapsed/refractory HL. Due to the important role of microenvironment and immune interaction the new approaches are now tested. The review is going to discuss the effect of several approaches to modulate of immune interaction. The first one is focused on immune-checkpoint axis, the second one on the use of bispecific antibodies and the third one on the use of genetically engineered autologous T cell lymphocytes with chimeric antigen receptors (CARs). 1. Immune-checkpoint axis. The inhibitory signals through PD1-PDL1 (programmed cell death protein 1 and programmed cell death 1 ligand 1) axis and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) effect play important role in regulation of immune response and prevention of immune system overreaction and autoimmune reaction. The HL cells as well as nontumour cells from the microenvironment overexpress these inhibitory proteins that suppress T-cell-effector functions, which finally leads to immune escape of the lymphoma. The inhibition of these inhibitory mechanisms could lead into restoration of immune effect on tumor (HL) cells6,7. The nivolumab and pembrolizumab represent the PD1-PDL1 axis inhibitors and ipilimumab CTLA-4 inhibitor. Nivolumab led into 87% objective response rate (ORR) (out of 23 pts) with CR in 17% and PR in 70% 8. Half of the responders (10 out of 20) remain progression free with median follow up longer than 1,5 year, there were 4 progressions, 5 pts proceed to stem cell transplant. There was one case of successful nivolumab retreatment 9. Patients who failed BV and were treated by pembrolizumab achieve ORR in 65% (out of 31 pts) with CR in 16%, PR in 48% and SD in 23%. With median follow up almost 10 month there were 45% pts still on the treatment and progression was observed in 39% pts 10,11. Combination of BV with ipilimumab is tested in phase I study and preliminary data is showing very promising efficacy with 8 responses (out of 12 pts) which consists of 5 CRs and 3 PRs. Two additional pts have SD Bispecific antibodies represent very interesting approach to increase engagement of T-cells and NK activity against tumor cells. Blinatumumab (anti CD19 anti CD3 antibody construct) represents very potent approach in acute lymphoblastic lymphoma treatment. Already 15 years ago two bispecific antibodies anticd16/cd30 13 and anticd64/cd30 14 were tested but further development was stopped due to manufacturing issues. Novel anticd16/cd30 antibody (AFM13) was tested in phase I study with 11.5% of PR (out of 26pts) and 50% of SD CAR T-cell approach is tested in many clinical studies focused mainly on CLL, ALL and Non-Hodgkin s lymphomas. Construct targeting CD30 antigen has been developed and clinical testing is on the way with first efficacy report of 9 (7 HL and 2 ALCL) pts treated with this approach. Altogether CR and PR were reached in 2 pts, SD in 4 pts16. Combination of CAR T-cells and checkpoint inhibitors or lenalidomide are going to be tested. Conclusion: Immunotherapy of HL represents very interesting and rapidly evolving field. The use of immune-checkpoint inhibitors is already tested in the pivotal trials based on very promising phase I studies data. The other approaches (bispecific antibodies, CAR T-cells) are of great interest as well. Moreover combinations with other drugs such as brentuximab vedotin are tested as well.

19 14 Treatment of Patients With Relapsed Hodgkin Lymphoma After Allogeneic Stem Cell Transplantation Léčba pacientů s relapsem Hodgkinova lymfomu po alogenní transplantaci Veronika Válková Institute of Haematology and Blood Transfusion, Prague, Czech Republic Introduction: Despite the excellent prognosis of majority of patients with Hodgkin lymphoma (HL), 25 to 30% of them are not cured with first-line modern chemo-radiotherapy. Autologous stem cell transplantation (ASCT) as a part of second-line therapy may rescue approximately 50% of relapsed and minority of refractory patients. Disease recurrence or progression after ASCT is associated with a very poor prognosis with the median survival months in different series. Various new therapeutic options are currently available for those patients. Despite an extraordinary efficacy, these drugs are probably limited in long-term disease controle. Allogeneic stem cell transplantation (allo-sct) remains the only strategy with a curative potential for relapsed and refractory patients. Nevertheless, among patients after allo- SCT, long-term progression-free survival (PFS) does not exceed 25-35% in most series. Several factors may significantly affect the outcome of allo-sct. One of the most important is the disease status before allo-sct. In recent years, great interest has been focused on transplantations from haploidentical family donors with ecouraging preliminary results. However, disease relapse after allo-sct still represents a major issue that needs to be addressed. Different strategies are used in relapse management including pontentiation of GVL effect by withdrawal of immunosuppression or donor lymphocyte infusions (DLI), eventually combined with chemo or radiotherapy. Recent data suggest that also second allo-sct may lead to 20-30% PFS at 3 years in HL patients. The implementation of novel agents, such as brentuximab vedotin (BV), nivolumab or bendamustine offers completely new possibilities. Promising data were reported using BV or bendamustin in HL patients relapsed after allo-sct with overall response-rate more then 50%. Another option is the combination of these drugs with DLI. A successful treatment with nivolumab in patient with HL refractory to multiple therapy lines including allo-sct and BV was also reported. Conclusions: The integration of novel drugs specifically targeting genetic or epigenetic mechanisms of tumor cells or microenvironment, and allo-sct may significantly change poor prognosis of refractory patients. Achievement of remission using new agents may offer allo-sct to a larger number of patients. The combination of new drugs with DLI can enhance GVL effect in patients relapsed after allo-sct. Second allo-sct can result in long term remission in substantial fraction of patients relapsed after first allo-sct. Haploidentical transplants have opened the possibility of an allo-sct to virtually all patients with extremely ecouraging preliminary results.

20 15 Rare Syndromes in Hodgkin Lymphoma Diagnostic Difficulties Vzácné syndromy u Hodgkinova lymfomu problémy s diagnostikou Jana Marková, Heidi Móciková, Ľubica Gahérová Department of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and 3 rd Faculty of Medicine, Charles University in Prague, Czech Republic Impaired immune system in patients with Hodgkin lymphoma (HL) can induce autoantibody mediated damage of tissues and organs. Here we report 3 cases of rare syndromes that led to difficulties in establishing the diagnosis of HL. Case report 1 Systemic lupus erythematosus (SLE) was initially diagnosed in a 43-year-old male patient with trigeminal neuralgia, lumbosacral pain, night sweats, fever, mild splenomegaly, weight loss, depression and positive anti-nuclear antibodies. The patient underwent two laparotomies: the first biopsy of abdominal lymph node raised a suspicion from HL, however, SLE was not excluded. Tissue from the second biopsy was completely necrotic and patient refused the third biopsy. Treatment of SLE was not effective. Clinical findings (progressive abdominal lymphadenopathy, involvement of the spleen according to PET/CT and B symptoms) and reassessment of the first biopsy by the pathologist led us to review the initial diagnosis of SLE and the diagnosis of classical HL was established. Treatment of HL was initiated 2 years since his first signs of HL. He was treated with 8 cycles of BEACOPP escalated and radiotherapy of 30 Gy and achieved a complete remission (CR). Relapse of chl NS occuring after 5 years was successfully treated with salvage chemotherapy, high dose chemotherapy and autologous stem cell transplantation. Currently he is alive in a second CR lasting 8 years. Case report 2 A 36-year-old female patient suffered from cough for 5 years and eosiophilia in her peripheral blood count. Chest X-ray revealed pulmonary infiltrates. Bronchoscopy and video-assisted thoracoscopy showed unspecified inflammation with incipient interstitial pulmonary fibrosis. Open lung biopsy and biopsy of the cervical lymph node was performed 5 years after the first symptoms occured and confirmed HL-nodular sclerosis. The patient is in a CR lasting 13 years after 8 cycles of BEACOPP eacalated without radiotherapy. Case report 3 A 34-year-old female patient suffered from pruritus, palm eczema, erythema with macular lesions of the whole skin, psoriasis of feet. Abdominal pain and diarrhoea occured 3 years since the onset of the first skin lesions. Colonoscopy confirmed Crohn s disease. The patient was treated for Crohn s disease and psoriasis. Bulky mass of cervical lymph nodes occured two years after the diagnosis of Crohn s disease. Biopsy of cervical lymph node confirmed HL- nodular sclerosis. The patient was treated with 2 cycles of BEACOPP escalated and 2 cycles of ABVD and involved field radiotherapy of 30 Gy. All signs of eczema, erythema, psoriasis and Crohn s disease disappeared during the treatment of HL and the patient is alive in a CR lasting 5years. All above mentioned syndromes occured a long time before the diagnosis of HL has been established. Some of rare syndromes can be life - threatening (liver failure, nephrotic syndrome, etc.) and they may be even more serious than HL. The extent of examinations before the diagnosis of HL in these patients is enormous and it induces stress for patients and decreases their quality of life.