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Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a „Named Patient Program” keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Célkitűzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélők célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeső 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, sőt közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélő 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 túlélők között az immunglobulin-nehézláncot érintő transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezőbb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét mérő nemzetközi stádiumbeosztás (ISS) nem jelezte előre a hosszú túlélést. Gyógyszerelhagyáshoz vezető mellékhatást a hosszú távú túlélő 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 lehetőségről. Orv Hetil. 2021; 162(36): 1451–1458. Summary. 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.

Absztrakt: Az onkoreumatológia a daganatképződés és a reumatológiai kórképek kapcsolatát jelenti. Számos összefüggés van a két orvosi szakterület között. Ezek egy része a reumatológiai kórképben szenvedő betegben jelentkező daganatokat, a másik fele pedig a daganatos betegen fellépő mozgásszervi jelenségeket foglalja magában. Az előbbi csoport keretében a reumatológiai betegségekben jelentkező szekunder tumorokat, a tumorasszociált antigének reumatológiai szerepét, a mozgásszervi betegségek kezelésére használt hagyományos és célzott terápiák esetleges onkogenitását és a korábban vagy jelenleg daganatos, mozgásszervi betegek fizioterápiáját tárgyaljuk. A másik nagy csoport magában foglalja a paraneoplasiás szindrómákat, az onkológiai kezelések (kemoterápia és immunterápia) lehetséges autoimmun-reumatológiai mellékhatásait, a hormondeprivatiós kezelés csonthatásait és a mozgásszervrendszer primer és szekunder daganatait. Orv Hetil. 2020; 161(28): 1151–1165.

Despite the introduction of novel agents, multiple myeloma remains incurable for most patients, necessitating further therapeutic options. Venetoclax, a selective BCL-2 inhibitor, had shown promising results in patients with translocation t(11;14), but questions remain open about its optimal use. We have contacted all Hungarian haematology centers for their experience treating t(11;14) myeloma patients with venetoclax. 58 patients were reported. 37 received venetoclax in the relapsed/refractory setting with few or no other therapeutic options available. 21 patients started venetoclax as salvage after failing to achieve satisfactory response to first line therapy. In the relapsed/refractory setting objective response rate (ORR) was 94%, median progression-free survival (PFS) 10.0 months and median overall survival (OS) 14.6 months. In reinduction patients, ORR was 100%, median PFS and OS were not reached. Importantly, we found no adverse effect of high risk features such as deletion 17p or renal failure, in fact renal failure ameliorated in 42% of the cases, including three patients who became dialysis independent. Our study also reports the highest number of plasma cell leukemia cases successfully treated with venetoclax published in literature, with refractory plasma cell leukemia patients achieving a median PFS of 10.0 and a median OS of 12.2 months.

Multiple myeloma is quite uncommon in the young population. We performed a retrospective review in our database from 2006 to 2015 to examine the clinical features, outcomes and survival of multiple myeloma patients ≤40 years old. Among 312 newly diagnosed patients we found sixteen (5.1%) who were 40 years old or younger. Their characteristics including M-protein type, genetical alterations, clinical symptoms and disease stage were as various as those in the older population. All but two young patients underwent autologous stem cell transplantation after the induction treatment. Their response to treatment did not differ markedly from the older patients. We also compared the survival data of patiens ≤40 years and > 40 years old. The 5-year progression-free survival were 48% and 35%, the 5-year overall survival were 83% and 53% respectively, the latter showing a significant advantage for the younger population. 70% of the young patients received maintenance or consolidation therapy after the initial treatment. Although several effective new therapies have been introduced recently, there is still an unmet need for curative treatment options for young and fit multiple myeloma patients.

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.

Background Despite therapeutic advances, multiple myeloma remains incurable. Venetoclax, a selective bcl-2 inhibitor may be a step toward personalised therapy for t(11;14) patients, but questions remain about its optimal use. Methods We retrospectively evaluated hematologic response, survival and safety after venetoclax treatment in t(11;14) myeloma patients in Hungary. Results Overall, 49 patients from seven clinical centers were reported. We divided patients into two groups based on the clinical setting: 32 relapsed/refractory patients, who received venetoclax after multiple lines of therapy, often in an ultimate effort; and 17 frontline patients, who achieved unsatisfactory response to standard first line therapy and were treated with venetoclax as reinduction before intended ASCT. We observed remarkably good hematological response rates (ORR): 94% in the relapsed/refractory group and 100% in the frontline setting. This translated into a median PFS of 9.6 months and a median OS of 14.6 months in the relapsed group; median PFS and OS were not reached in the reinduction group. Known adverse prognostic factors, such as 17p deletion, kidney failure or 1q21 amplification did not convey significantly worse prognosis in our study. Almost one third of patients had impaired kidney function during venetoclax therapy, including three patients requiring dialysis. Clinically relevant improvement was observed in 42% of these patients; dialysis could be stopped in all three cases. Notably, our study also included six plasma cell leukemia patients, with a remarkable median PFS of 10 months and over one year median OS in relapsed disease. Vulnerable patients with PCL, renal failure or refractory disease reported more adverse events, requiring supportive measures or dose adjustment, but cessation of venetoclax therapy did not become necessary. Conclusion Venetoclax therapy is a promising option with few side effects and very good response rates for t(11;14) patients, both in the frontline and in the relapsed setting

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a "Named Patient Program" keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Célkitűzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélők célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeső 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, sőt közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélő 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 túlélők között az immunglobulin-nehézláncot érintő transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezőbb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét mérő nemzetközi stádiumbeosztás (ISS) nem jelezte előre a hosszú túlélést. Gyógyszerelhagyáshoz vezető mellékhatást a hosszú távú túlélő 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 lehetőségről. Orv Hetil. 2021; 162(36): 1451-1458.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.Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet.We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed.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.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.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.

Oncorheumatology: relationship between malignancies and musculoskeletal diseases Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.

Oncorheumatology is the meeting point of tumour formation and rheumatic diseases. Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. In the first group, secondary malignancies associated with rheumatic diseases, role of tumour-associated antigens in rheumatology, the possible carcinogenicity of conventional and targeted antirheumatic drugs and physical therapy of rheumatic patients with recent or current cancer will be discussed. The second large topic includes paraneoplastic syndromes, autoimmune-rheumatic side effects of oncotherapies (chemotherapy and immunotherapy), effects of hormone-deprivation therapies on bone and primary and secondary malignancies of the musculoskeletal system. Orv Hetil. 2020; 161(28): 1151-1165.

Absztrakt: Bevezetes: A myeloma multiplex (MM) jelenleg is meggyogyithatatlan korkep, de az uj terapias eljarasok, koztuk az immunmodulans szerek (Imid) alkalmazasa jelentősen javitotta a betegseg ...

Background. Myeloma patients reaped immense benefit from the introduction of new classes of drugs over the last decades. This improvement, however, was much less marked in patients with translocation 11;14 [t(11;14)], a group in which immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) - the two most important pillars of current myeloma care - are less effective. This subgroup of patients used to be known for their relatively slow pace of progression often experiencing long plateau phases following autologous stem cell transplantation (ASCT), whereas at the same time t(11;14) is also disproportionately prevalent in difficult to treat clinical entities such as plasma cell leukemia or AL amyloidosis. Venetoclax, a selective bcl-2 inhibitor first approved for CLL was investigated for the treatment of relapsed myeloma patients and although it failed to show benefit for myeloma patients as a whole, t(11;14) patients showed exceptional responses, thus paving the way towards the first genetically targeted treatment in myeloma. As a result, its off label use is on the rise, even though clinicians have to face unanswered questions regarding the right dosage and therapy length, as well as the potential for adverse events (AEs), especially infections. Real world data could help elucidate its optimal use, but is as of yet very limited. Aims and methods. We addressed all Hungarian centers treating myeloma to evaluate the efficacy and safety of venetoclax, collecting data about the treatment duration, AEs, dose modifications and treatment discontinuations, and analysed response rates as well as progression free survival (PFS). Results. 33 patients were reported from 7 Hungarian sites. After the initial analyses, we identified two distinct rationales for venetoclax treatment. 22 patients were relapsed and heavily pretreated with an average of 4.5 prior lines; here venetoclax was chosen as ultimum refugium. In this group, combination partners were bortezomib-dexamethasone (VelDex) in 14 patients, 5 had dexamethasone only, one VRd, one DRd and one Kd. Considering the highly pretreated nature of this group, the overall response rate was a remarkably high 95% with 40.9% partial, 31.8% very good partial, and 22.7% complete responses. Treatment mostly continued until progression. The median PFS and OS calculated from venetoclax initiation were 299 and 437 days. The most common AEs were cytopenias and infections reported in 8 and 6 patients with 1 fatal infection. In the second group, 11 patients received venetoclax after a suboptimal initial response (6 PR, 4 SD, 1 PD) to their first line IMiD+PI combination with the goal of further tumor elimination preceding ASCT. Remarkably, although the length of venetoclax treatment was short - median 2 cycles -, all 11 patients deepened their response to at least VGPR and 7 to CR. 9 patients had ASCT converting 2 further VGPRs into CR, so at the end of the planned protocol 10 of the 11 patients had CR. Venetoclax was combined with VelDex in 9 and VTD in 2 cases, the one year PFS and OS were 91 and 100%, with no venetoclax related AEs reported. An important aspect of our analysis was the question of venetoclax dosing, as the appropriate dose in this indication is not yet clear. Reflecting this uncertainty, as well as funding difficulties with this off-label drug, only one patient received 800 mg dose as seen in the Bellini trial; one received 600 mg daily, with all others taking 400 mg or less. To counteract this lower daily dose available, some centers employed a combination with clarithromycin, a strong CYP3A inhibitor known to increase venetoclax serum levels two- to threefold. Where available, serum venetoclax levels were monitored to ensure serum levels comparable to regular dosing. Another point to emphasize is that 5 patients in the relapsed, and another 2 in the frontline group had deletion 17p, usually resulting in refractoriness to standard treatments. Among these patients however, 5 reached VGPR, 1 PR, and only one progressed on venetoclax treatment. Some responses proved lasting especially in the frontline group. Conclusion. Our results highlight the importance of targeted treatments in multiple myeloma. We experienced lasting responses in quadruple-refractory patients. In the newly diagnosed group where the depth of pre-ASCT response has a big impact on PFS, venetoclax may have a role converting suboptimal responses into CRs by eliminating residual disease. Figure Disclosures Illés: Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. OffLabel Disclosure: venetoclax use in t(11;14) myeloma which is not yet licensed

Multiple myeloma (MM) is an immedicable malignancy of the human plasma cells producing abnormal antibodies (also referred to as paraproteins) leading to kidney problems and hyperviscosity syndrome. In this paper, we report on the N-glycosylation analysis of paraproteins from total human serum as well as the fragment crystallizable region (Fc ) and fragment antigen binding (Fab ) κ/λ light chain fractions of papain digested immunoglobulins from multiple myeloma patients. CE-LIF detection was used for the analysis of the N-glycans after endoglycosidase (PNGase F) mediated sugar release and fluorophore labeling (APTS). While characteristic N-glycosylation pattern differences were found between normal control and untreated, treated and remission stage multiple myeloma patient samples at the global serum level, less distinctive changes were observed at the immunoglobulin level. Principal component analysis adequately differentiated the four groups (control and three patient groups) on the basis of total serum N-glycosylation analysis. 12 N-glycan features showed statistically significant differences (p

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.

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

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.

Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients.To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL.The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1-8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes.Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant.Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL.

Background Rheumatoid arthritis (RA) treatment includes the use of the anti-CD20 monoclonal antibody rituximab (RTX). RTX acts through Fcγ-receptors (FCGR) on effector natural killer cells and macrophages and it can be administered effectively in RA and in lymphomas. Based on the results of in vitro experiments, its efficacy may depend of FCGR gene polymorphisms in both diseases. Aim As genetic background of diseases and therapeutic efficacy (pharmacogenetics) may vary among different geographical regions, we wished to assess possible relationships between FCGR3A polymorphism and the therapeutic outcome of RTX therapy in a Hungarian RA cohort. Patients and methods Altogether, 52 patients, 6 men and 46 women, were included in the study. Peripheral blood samples were used to determine FCGR3A polymorphism by genotyping using real-time PCR method. Results The distribution of FCGR3A genotypes was 8 VV, 34 VF and 10 FF. Disease activity score 28 (DAS28) reductions in patients with VV, VF and FF genotypes were 1.98±0.54 (p=0.008 between DAS28 before and after treatment), 2.07±0.23 (p

Background: Daratumumab is one of the most effective new myeloma drugs recently approved for relapsed/refractory multiple myeloma (MM), first in monotherapy in heavily pretreated patients, later in triplet combinations from first relapse, based on the results of the SIRIUS, POLLUX and CASTOR trials that showed good tolerability and high effectivity of daratumumab both in monotherapy and combined with lenalidomide or bortezomib. However, clinical trials are different from real world use for many reasons including less rigorous patient selection, greater flexibility with dosing and country specific funding restrictions making real world data very important for clinicians. Real world data regarding daratumumab use is currently very limited. In the Hungarian system, funding of daratumumab was initiated in December 2016, and required individual preapproved funding requests. Initially only monotherapy was reimbursed in double-refractory patients, but from 2018 triplet combination in earlier lines could start as well. Aims and Methods: The aim of this study was to evaluate the efficacy and safety of daratumumab in the real world practice. We approached all centers in Hungary where daratumumab was used, in a retrospective analysis. The scope of this study was to analyze response rate, progression free survival (PFS), treatment duration, and adverse events (AEs). Statistical analyses were performed using the SPSS (version 20.0) software package. Results: 8 centers responded with 75 patients altogether. Patients were heavily pretreated, the median number of prior lines was 3 (1-12). All patients had prior bortezomib, and most had lenalidomide (82.6%) and thalidomide (86.6%), all but one had one of the two IMiDs. 62.6% of the patients had prior autologous transplantation, with two having prior allograft, as well. Pre-daratumumab cytogenetic FISH tests of 57 patients were available, here 33/57 had high risk cytogenetics. The majority had high international staging system (ISS) score: 8, 16 and 48 were in the ISS 1, 2 and 3 groups respectively. Treatment usually continued until progression, unacceptable toxicity or death, the mean number of cycles was 6. AEs over grade 3 were uncommon, the most frequent AEs were mild infusion associated reactions (IARs, grade 1-2) and infections (Table 1). There were 7 fatal infections, other fatal AEs were absent. Infusion related toxicities were manageable in all cases. The majority of patients (41) had monotherapy with dexamethasone only, but 17 had bortezomib and another 17 lenalidomide combination. Overall response rate was assessable in 66 patients with 7 complete, 8 very good partial, 24 partial, 5 minor responses. 14 showed stable disease, 8 progressive disease. 9 patients had no formal disease reassessment due to either early death or short follow up. There was no clear connection between the number of prior lines and the quality of the response, however those who had either bortezomib or lenalidomid combinations showed better overall response rate (p=0.045). With 43 events so far the estimated PFS and OS were 151 and 260 days, but it was much better in those who showed at least a partial response (PFS 400 days, OS nor reached; Figure 1). The only other factor that significantly affected the PFS was ISS (p=0.039), we could not demonstrate a significant connection between cytogenetics, the number of prior lines, combination therapy and survival. Conclusion: Our results highlight the differences between patients treated in routine practice and those treated in clinical trials. Here treatment protocols were dictated by funding rules, and therefore similar patients were treated with doublets and triplets. The results of the POLLUX and CASTOR trials were superior in comparison to the SIRIUS study with monotherapy, but our results do not reflect this marked difference, probably due to the almost complete absence of 2nd and 3rd line patients who dominated the Pollux and Castor trials. Importantly these heavily pretreated patients tolerated daratumumab well, IARs over grade 2 were absent. Based on our results, daratumumab is an effective treatment option for relapsed/refractory MM with good safety profile. Disclosures Masszi: Janssen-Cilag: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Illés:Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9-16.

Hodgkin's lymphoma (HL) is a well-curable disease. The treatment usually includes combined multiagent conventional chemotherapy and radiotherapy. One-fifth of the patients need repeated treatments because of relapse or primary progressive disease. Those HL patients, who cannot be cured at least with salvage therapy (including autologous haemopoietic stem cell transplantation (auto-HSCT)), have really unfavourable prognosis.For this heavily pretreated subset of HL patients, novel but less toxic treatment strategies should be considered. Brentuximab-vedotin (BV) is a novel targeted treatment option, which was administered after the failure of two different regimens in patients, who were ineligible for auto-HSCT or after the failure of auto-HSCT. Moreover, there are favourable data with chemotherapeutical regimens supplemented with rituximab not only in relapsed but also in newly diagnosed classical HL patients. Bendamustine, an almost forgotten 50-year-old drug, lives its renaissance in the twenty-first century, which can be administered in refractory HL as well. Combination of the 'new' and 'old' drugs might be also helpful.Our data suggest that rituximab plus bendamustine (supplemented with or without BV) could be a suitable alternative bridging salvage therapy for heavily pretreated HL patients.

The last decade has witnessed a dramatic progress in the treatment of multiple myeloma. Both the chemotherapy protocols and the supportive therapy options have improved significantly since the publication of the previous Hungarian national guideline. An increasing proportion of patients now reach a durable response and cure became a potential option for some. The aim of the authors was to adapt the international guidelines to the specific circumstances of the Hungarian healthcare system in the light of the most recent developments.

The last decade has witnessed a dramatic progress in the treatment of multiple myeloma. Both the chemotherapy protocols and the supportive therapy options have improved significantly since the publication of the previous Hungarian national guideline. An increasing proportion of patients now reach a durable response and cure became a potential option for some. The aim of the authors was to adapt the international guidelines to the specific circumstances of the Hungarian healthcare system in the light of the most recent developments. Orv. Hetil., 2016, 157(4), 123–137.

Background Rheumatoid arthritis (RA) treatment includes the use of the anti-CD20 monoclonal antibody rituximab (RTX). RTX acts through Fcγ-receptors (FCGR) on effector natural killer cells and macrophages and it can be administered effectively in RA and in lymphomas. Based on the results of in vitro experiments, its efficacy may depend of FCGR gene polymorphisms in both diseases. Aim As genetic background of diseases and therapeutic efficacy (pharmacogenetics) may vary among different geographical regions, we wished to assess possible relationships between FCGR3A polymorphism and the therapeutic outcome of RTX therapy in a Hungarian RA cohort. Patients and methods Altogether, 52 patients, 6 men and 46 women, were included in the study. Peripheral blood samples were used to determine FCGR3A polymorphism by genotyping using real-time PCR method. Results The distribution of FCGR3A genotypes was 8 VV, 34 VF and 10 FF. Disease activity score 28 (DAS28) reductions in patients with VV, VF and FF genotypes were 1.98±0.54 (p=0.008 between DAS28 before and after treatment), 2.07±0.23 (p Conclusion Our results suggest that FCGR3A polymorphism may predict more effective disease activity reduction by RTX. Furthermore, carrying the V allele may also be associated with better therapeutic response in Hungarian patients with RA.

Treatment of autoimmune haemolytic anaemia is still a challenge to clinicians. Even today it may be lethal. Half of the cases are secondary due to an underlying disease, and the others are primary or idiopathic cases. According to the specificity and type of autoantibodies there are warm and cold type forms of autoimmune haemolytic anaemia. The hallmark of the diagnosis is to detect the presence of haemolysis by clinical and laboratory signs and detect the underlying autoantibodies. Treatment of autoimmune haemolytic anaemia is still a challenge to clinicians. We still loose patients due to excessive haemolysis or severe infections caused by immunosuppression. First line treatment is corticosteroids. Other immunosuppressive agents like: cyclophosphamide, azathioprine, cyclosporine or the off label rituximab can be used in case of corticosteroid refractoriness. Splenectomy is a considerable option in selective cases. The authors discuss treatment options and highlight difficulties by presenting 4 cases.Az autoimmun haemolyticus anaemia viszonylag ritka betegség, amely sokszor nehezen kezelhető és akár fatális következményekkel járhat. Az esetek fele valamilyen alapbetegséghez társuló szekunder forma, a fennmaradó rész pedig idiopathiás vagy más néven primer autoimmun haemolyticus anaemia. A vörösvértestek idő előtti lebomlásáért felelős antitestek viselkedése alapján meleg, illetve hideg típust különböztethetünk meg. A diagnózis alapja a haemolysis klinikai és laboratóriumi jeleinek fennállása és az autoantitestek jelenléte. A betegség kezelése a mai napig sem teljes mértékben megoldott. Még ma is veszítünk el betegeket az uralhatatlan vagy csak nagy dózisú immunszuppresszív szerek alkalmazásával kezelhető anaemia és a következményes infekció miatt. Az elsőként választandó szer a kortikoszteroid, ennek hatástalansága esetén szóba jön cyclophosphamid, azathioprin, cyclosporin, valamint az off-label anti-CD20 rituximab adása, a splenectomia viszont egyre hátrébb szorul a terápiás algoritmusban. A kezelés során gyakran felmerülő problémákra négy eset kapcsán világítanak rá a szerzők. Orv. Hetil., 2015, 156(11), 449–456.

The B-cell lymphoma, unclassifiable, showing intermediate features typical for both diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (HL) is a novel category of diffuse large B-cell lymphomas (DLBCL/HL), which has been described by the WHO classification in 2008. This rare type of lymphomas, previously called as gray zone lymphoma presents peculiar clinical, morphological and immunophenotypical patterns. In December 2011 a 17-year old male was diagnosed with mixed cellularity subtype of classical HL. His clinical stage was IV/BXS (abdominal bulky) with unfavourable prognosis. Because of the unusually extended disease (nodal-extranodal-bulky) a histological revision was performed. After an incomplete course of ABVD chemotherapy the patient's symptoms disappeared and regression was detected in the size of peripheral lymph nodes. The diagnosis changed into DLBCL/HL, so the treatment was modified to R-CHOP-14 regimen. After the administration of 3 cycles of R-CHOP-14, he achieved a complete metabolic remission (CMR), which was confirmed by a (18)FDG-PET/CT scan. Receiving further 4 cycles of R-CHOP-14 therapy the patient was still in CMR, but a PET negative large mass (70 × 30 mm) still remained visible in the abdominal region. Considering this residuum and the aggressive subtype of lymphoma he was referred for an autologous hemopoietic stem cell transplantation (AHSCT). After 2 cycles of R-DHAP regimen, successful CD34 positive stem cell collection was performed in August 2012. In September 2012, he underwent a R-BEAM conditioning followed by AHSCT. The next (18)FDG-PET/CT still detected CMR 100 days after the AHSCT. The patient was in excellent clinical condition and also in complete remission 15 months after the AHSCT. Upon this case, it should be underlined that the diagnosis may need revision if a patient represents atypical clinical signs and behavior, and the importance of cooperation between clinicians and pathologists is also strongly emphasized.