DIAGNOSTIC APPROACH AND TREATMENT OF IMMUNE THROMBOCYTOPENIA IN ADULTS

Cilj ovog preglednog rada jest prikazati najnovija saznanja povezana s definicijom imune trombocitopenije u odraslih (ITP), pato¬fiziologijom bolesti, dijagnostičkim i terapijskim postupnikom. ITP je karakterizirana brojem trombocita manjim od 100x109/L te kroničnim tijekom u odsustvu neke druge bolesti koja bi mogla dovesti do smanjenja broja trombocita. Patogeneza ove bolesti temelji se na dva ključna mehanizma: destrukciji kompleksa trombocit-protutijelo i inhibiciji sazrijevanja prekursora trombocita. Dijagnoza ITP-a temelji se na isključenju drugih mogućih uzroka trombocitopenije. Odluka o početku liječenja donosi se individu¬alno, prema broju trombocita (manji od 30x109/L) te rizičnim faktorima krvarenja. Okosnica prve linije terapije su kortikosteroidi. U slučaju izostanka uspjeha liječenja kortikosteroidima preporuča se primjena intravenskih imunoglobulina s brzim, ali često i kratkotrajnim odgovorom. U drugoj liniji terapije su kirurški i farmakološki pristupi. Kirurški pristup, splenektomija, karakteriziran je vrlo visokom stopom dugotrajnog odgovora. Farmakološki pristup danas znači ili primjenu agonista trombopoetina (TPO) ili rituksimaba. Agonisti TPO pokazali su se kao lijekovi s visokom stopom odgovora, no potreba za kontinuiranim davanjem i cijena donekle ograničavaju njihovu upotrebu. Iako se rituksimab često koristi u drugoj liniji liječenja, za sada ne postoje randomizirana klinička istraživanja koja bi poduprla njegovu primjenu. U bolesnika s refraktornim ITP-om liječenje je potrebno samo u bolesni¬ka s brojem trombocita manjim od 30x109/L te krvarenjem. Terapija je primjena agonista TPO, polikemoterapija, alemtuzumab te transplantacija perifernih matičnih stanica.The aim of this review is to provide the Croatian medical public with novel insights into the definition, pathogenesis, diagnostic algorithms and treatment approaches to immune thrombocytopenia (ITP) in adults. Recently, primary ITP has been uniformly de¬fined as an autoimmune disorder characterized by an isolated platelet count lower than 100x109/L without preexisting disease or conditions, which could lead to thrombocytopenia. The recognition of primary and secondary ITP is important because they require different treatment strategies. In secondary ITP, therapeutic approach oriented towards the underlying disorder. Unlike childhood onset ITP, which is a self-limited condition with high rates of spontaneous remissions, adulthood onset ITP usually has chronic course. Previously, the pathogenesis of ITP was considered to be immune mediated destruction of platelets in liver and spleen, while recent findings have shown a novel pathophysiological pathway based on the inhibition of thrombopoiesis, leading to novel treatment approaches. The diagnosis of ITP is based on exclusion of the possible underlying causes of thrombocytope¬nia and consists of simple diagnostic procedures. The decision to treat ITP should be based individually: platelets count (lower than 30x109/L), various bleeding risk factors and patient’s preference. The use of corticosteroids is the mainstay of first line ther¬apy. Two most commonly used corticosteroids are prednisone and dexamethasone. Prednisone is administered continuously, while dexamethasone is applied in cycles. Due to the lack of randomized clinical trials, it is not possible to recommend certain class of corticosteroid therapy. Another two agents used as first line therapy in case of corticosteroid refractoriness or the need of rapid platelet elevation, are intravenous immunoglobulins and anti-D immunoglobulin (anti-D is not approved in Europe). They are characterized by rapid onset of platelet recovery and low long-term remission rates. Until recently, splenectomy, with adequate infectious and thromboprophylaxis, was the therapy of choice in patients who did not respond to corticosteroids due to high long-term remission rates and low relapse rates. This procedure can be offered to a younger patient without significant comorbidities after the first year of ITP duration. With advances in the understanding of ITP pathogenesis, a new class of drug has been established: thrombopoietin agonists (TPO). Eltrombopag and romiplostim, the TPO agonists currently approved for the management of ITP in patients who failed the first line therapy and are not suitable for splenectomy, are only two agents that have shown benefits in large clinical randomized trials. They are characterized by a high response rate and appropriate safety profile, but the need for continuous use, a high relapse rate after therapy withdrawal, and price limit their use in everyday practice. TPO agonists represent an appropriate treatment choice in patients who have relapse after splenectomy. Another agent, often used in everyday clinical practice, is rituximab with high response and relapse rates. Its use is based on small studies, and due to the lack of clinical randomized controlled trials, rituximab is not approved by the lead¬ing medical agencies for this indication. As shown in this review article, our understanding and therapy for ITP has improved, but further research is needed to implement evidence-based therapy in clinical practice

Suvremeni pristup ne-Hodgkinovu limfomu plaštene zone: pregled literature [Current approach to non-Hodgkin mantle cell lymphoma: literature review]

Mantle cell lymphoma (MCL) represents the fourth most common type of non-Hodgkin lymphomas. It is characterized by aggressive course and frequent relapses. The main aim of this review is to evaluate current treatment approach towards this type of lymphoma. In younger patients the chemotherapy including high doses of cytarabine is the gold standard. In case of complete or partial remission, the consolidation with autologous stem cell transplantation is indicated as consolidation approach. In older patients CHOP-R regimen is not the treatment of choice. These patients should be treated with bendamustine in combination with rituximab. In case of complete or partial remission, further therapy with rituximab maintenance as consolidation represents an option. The vast majority of patients with MCL will ultimately relapse which poses a challenge in treatment approach. The approach in relapsed MCL can be divided in two types: chemotherapy or biologic therapy. In young fit patients chemotherapy based on bendamustine and cytarabine is a reasonable option. In patients with comorbidities or poor performance status biologic agents are reasonable options. Ibrutinib, Bruton kinase inhibitor, is characterized by highest overall response rate and the longest duration of response and should be offered to these patients. With the development of novel potent inhibitor of B cell receptor signaling pathway, these agents may become the gold standard in future and introduce the treatment of MCL in „chemo-free“era

Bendamustin: stari lijek u novoj eri za bolesnike s ne-Hodgkinovim limfomima i kroničnom limfocitnom leukemijom

The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation.Cilj ovoga preglednog rada je procijeniti aktivnost bendamustina te njegovih kombinacija u ne-Hodgkinovim limfomima (NHL) i kroničnoj limfocitnoj leukemiji (KLL). Bendamustin je sada indiciran u Republici Hrvatskoj za liječenje rituksimab-rezistentnog NHL-a i u bolesnika s KLL-om koji nisu kandidati za konvencionalnu terapiju. No, kombinacija bendamustina s rituksimabom (B-R) u prvoj liniji terapije indolentnog NHL-a i limfoma plaštene zone pokazala se boljom od konvencionalne kemoterapije pa bi B-R trebao postati zlatni standard u prvoj liniji liječenja ovih limfoma. Protokol B-R ­također ima aktivnost u relapsnom indolentnom NHL-u te predstavlja opciju za bolesnike koji su progredirali nakon konvencionalne kemoterapije. U rituksimab-rezistentnom NHL-u nedavna studija GADOLIN koja je proučavala dodatak ­obinutuzumaba bendamustinu pokazala je jasnu superiornost prema bendamustinu i promijenila zlatni standard u ovoj ­populaciji zahtjevnoj za liječenje. U KLL-u usprkos inferiornosti B-R prema FCR-u u studiji CLL10 B-R je bio obilježen boljim profilom toksičnosti te se može ponuditi pojedinim bolesnicima na temelju individualizirane odluke. U relapsnom okružju KLL-a dodatak ibrutiniba protokolu B-R pokazao je superiornost prema B-R s mogućom promjenom paradigme liječenja ovih bolesnika. Zaključno, bendamustin sam ili u kombinacijama pokazao je visoku aktivnost s povoljnim toksičnim profilom u liječenju indolentnih NHL-a i KLL bez mutacije del(17p)

SALVAGE CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION MAY BE CURATIVE IN 50% OF RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: A SINGLE-CENTER EXPERIENCE

Cilj ovog rada bio je prikazati rezultate liječenja bolesnika s relapsnim ili refraktornim klasičnim Hodgkinovim limfomom visokodoznom kemoterapijom praćenom autolognom transplantacijom matičnih stanica u jednoj ustanovi. U retrospektivno istraživanje uključen je 101 bolesnik liječen u razdoblju od 1995. do 2014. godine. Svi su bolesnici primili mijeloablativni protokol BEAM. Ukupna stopa odgovora bila je 92,1 %, medijan praćenja je iznosio 42 mjeseca. Petogodišnje ukupno preživljenje je iznosilo 56 %, a preživljenje bez progresije bolesti 51 %. U svakom ishodu postignut je plato bez daljnjih događaja pokazajući liječidbenu mogućnost ovog pristupa za oko 50 % bolesnika. Prognostički čimbenici povezani s kraćim ukupnim preživljenjem bili su prisutnost B simptoma i anemije u relapsu, odnosno nepostizanje kompletne remisije na visokodoznu terapiju. Bolesnici, koji nisu postignuli drugu kompletnu remisiju, imali su kraće ukupno preživljenje s postignutim platoom u oko 40 % bolesnika što pokazuje mogućnost autologne transplantacije da donekle umanji kemorefraktornu bolest kao negativan prognostički čimbenik. Neuspjeh postizanja druge kompletne remisije bio je jedini čimbenik povezan s kraćim preživljenjem bez progresije bolesti. Bolesnici koji nisu postignuli kompletnu remisiju na autolognu transplantaciju ili su imali drugi relaps bolesti imali su lošije petogodišnje ukupno preživljenje u iznosu od 31% i 16 %. Prema našim rezultatima te, sukladno literaturnom pregledu, pokazali smo da je visokodozna terapija praćena autolognom transplantacijom matičnih stanica optimalan pristup ovim bolesnicima.The main aim of this study was to present outcomes and prognostic factors in relapsed and refractory classical Hodgkin lymphoma undergoing salvage chemotherapy followed by stem cell transplantation. This retrospective study included 101 adult patients being treated at a single center in the period between 1995-2014. The most commonly used salvage chemotherapy was miniBEAM. All patients received BEAM myeloablative protocol followed by stem cell reinfusion. The ORR was 92.1%. After a median of follow-up of 42 months, 5-year OS rate was 56% with 5-year PFS rate being 51%. In each survival curve, a plateau was achieved implying the curative possibility of autologous stem cell transplantation. Adverse prognostic factors associated with worse OS were presence of B symptoms and anemia at relapse and chemoresistance to salvage chemotherapy, defi ned as inability to achieve 2nd complete remission. However, in survival curve a plateau was reached indicating that 40% of chemorefractory patients can be cured with this approach. Only prognostic factor associated with inferior PFS was chemoresistance to salvage therapy. Outcomes for patients not responding to or relapsing after stem cell transplantation were less advantageous with 31% and 16% 5-years OS rates, stressing the need for better clinical approach in this subpopulation. Based on our results and according to the literature review, we demonstrate that salvage therapy followed by autologous stem cell transplantation represents a treatment of choice in transplant-eligible patients suffering from relapsed or refractory Hodgkin lymphoma

Održavanje rituksimabom u uznapredovalom folikularnom limfomu: kontroverzije

Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologic malignancies in the last decade. The main aim of this review is to present data on the use of rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance strategies in the first and second line treatment. Th is approach has improved the outcome in FL patients with better progression-free survival in all patients and better overall survival in relapsed setting. Regardless of good results, this strategy has generated controversies in medical community in the range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatment and toxicities to its unknown role in the era of novel agents. The existing data suggest that rituximab maintenance should be a rational therapeutic option for all patients with FL responding to first line therapy and transplant-ineligible patients responding to reinduction.Rituksimab je kimerično antiCD20 protutijelo koje se koristi u liječenju CD20 pozitivnih ne-Hodgkinovih limfoma te je promijenilo paradigmu liječenja ovih hematoloških neoplazma u prošlom desetljeću. Glavni cilj ovoga preglednog rada je predstaviti njegovu primjenu u folikularnom limfomu (FL) s naglaskom na terapiju održavanja. Ova strategija doprinijela je boljem preživljenju bez progresije bolesti u prvoj i drugoj liniji terapije, odnosno boljem ukupnom preživljenju u bolesnika s relapsom FL-a. No, usprkos dobrim rezultatima, održavanje rituksimabom je doprinijelo kontroverzi u medicinskoj zajednici. Navedene nedoumice potječu od nedostatka poboljšanja ukupnog preživljenja u prvoj liniji terapije, moguće toksičnosti do nepoznate uloge u eri novih lijekova za liječenje FL-a. Prema postojećim podacima zaključujemo da terapiju održavanja rituksimabom treba ponuditi bolesnicima s FL-om koji su odgovorili na prvu liniju terapije te bolesnicima s relapsom FL-a koji su odgovorili na reindukciju, a nisu kandidati za liječenje autolognom transplantacijom matičnih stanica

AUTOLOGOUS STEM CELL TRANSPLANTATION IN REFRACTORY OR RELAPSED DIFFUSE LARGE B CELL LYMPHOMA – A SINGLE CENTRE EXPERIENCE

Autologna transplantacija perifernih matičnih stanica zlatni je standard u liječenju refraktornog ili relapsnoga kemosenzitivnog difuznog B-velikostaničnog limfoma u pogodnih bolesnika. Cilj je ovog rada prikazati ishode autologne transplantacije perifernih matičnih stanica u bolesnika s refraktornim ili relapsnim ne-Hodgkinovim limfomom difuznoga B-velikostaničnog tipa. Retrospektivno smo analizirali podatke 62-je bolesnika liječenih autolognom transplantacijom u našem centru u razdoblju od 2000. do 2013. godine. Većina bolesnika (71%) liječena je kemoterapijom miniBEAM, a svi su primili mijeloablativnu kemoterapiju BEAM s reinfuzijom vlastitih matičnih stanica. Ukupna stopa odgovora (kom­pletna i parcijalna remisija) nakon autologne transplantacije iznosila je 75,8%. Medijan ukupnog preživljenja iznosio je 37,2 mjeseca. Medijan preživljenja bez događaja vezanih uz bolest iznosio je 16,9 mjeseci. Čimbenici statistički značajno povezani s ukupnim preživljenjem bili su aktivnost bolesti prije visokodozne spasonosne terapije, odgovor na spasonosnu terapiju. Internacionalni prognostički indeks, stadij bolesti, odgovor na autolognu transplantaciju perifernih matičnih sta­nica te radioterapija nakon autologne transplantacije. Liječenje rituksimabom nije bilo statistički značajno povezano s ishodom. U ovoj skupini bolesnika autologna je transplantacija perifernih matičnih stanica bila učinkovita u postizanju remisije i preživljenja, što je dobar i očekivan ishod navedenog postupka. Naglašavamo da je i u skupini bolesnika s kemorezistentnom bolešću autologna transplantacija bila učinkovita u 32,5% bolesnika.Autologous stem cell transplantation represents the gold standard in chemosensitive diffuse B large cell lymphoma in relapse or in refractory setting. The aim of this study was to present the outcome of peripheral autologous stem cell transplantation in patients with refractory or relapsed diffuse large B cell lymphoma. We retrospectively analysed the data of 62 patients, who underwent this procedure for the period 2000–2013. The majority of patients (71%) were treated with miniBEAM salvage chemotherapy and all received BEAM myeloablative protocol followed by the stem cell reinfusion. The overall response rate for autologous transplantation was 75.8%. Median overall survival was 37.2 months. Median event-free survival was 16.9 months. Factors associated with overall survival were state of disease prior to salvage chemotherapy, chemosensitivity of disease, International prognostic index, disease activity at the relapse, response to autologous transplantation and post-transplantation radiotherapy. The use of rituximab was not significantly correlated to the outcome. In this patient group autologous stem cell transplantation was found to be effective in achieving remission and survival showing the adequate role of this procedure in this clinical setting. We stress out that autologous stem cell transplantation was effective in 32.5% patients with chemorefractory disease after salvage therapy

CURRENT APPROACH TO NON-HODGKIN MANTLE CELL LYMPHOMA: LITERATURE REVIEW

Limfom plaštene zone (engl. Mantle cell lymphoma – MCL) četvrti je najučestaliji ne-Hodgkinov limfom. ­Karakteriziran je agresivnim tokom s multiplim relapsima. Cilj je rada literaturnim pregledom opisati suvremeni pristup liječenju ovog limfoma. U mlađih bolesnika zlatni je standard intenzivna kemoterapija visokim dozama citarabina. Pri kompletnoj ili parcijalnoj remisiji kao konsolidacija je indicirana autologna transplantacija perifernih matičnih stanica. U starijih bolesnika kemoterapija CHOP-R-om nije prikladno rješenje. Ove bolesnike treba liječiti benda­mustinom u kom­binaciji s rituksimabom. Pri kompletnoj ili parcijalnoj remisiji opcija je konsolidacija odgovora održavanjem rituksimabom. Većina će bolesnika s MCL-om relabirati pa je njihovo liječenje izazov i teškoća u daljnjim postupcima. Liječenje relapsnog MCL-a može se podijeliti u dvije skupine: kemoterapija i biološki lijekovi. U bolesnika s dobrim općim statusom prikladna može biti kemoterapija temeljena na bendamustinu i citarabinu. U bolesnika s komor­biditetima moguća je opcija biološka terapija. Od biološke terapije treba istaknuti ibrutinib, inhibitor Brutonove kinaze, zbog najveće stope odgovora i trajanja učinka liječenja. S razvojem novih potentnih inhibitora B-staničnoga receptorskog puta aktivnih u MCL-u uskoro bi biološki lijekovi mogli postati zlatnim standardom i uvesti liječenje MCL-a u eru bez kemoterapije.Mantle cell lymphoma (MCL) represents the fourth most common type of non-Hodgkin lymphomas. It is characterized by aggressive course and frequent relapses. The main aim of this review is to evaluate current treatment approach towards this type of lymphoma. In younger patients the chemotherapy including high doses of cytarabine is the gold standard. In case of complete or partial remission, the consolidation with autologous stem cell transplantation is indicated as consolidation approach. In older patients CHOP-R regimen is not the treatment of choice. These patients should be treated with bendamustine in combination with rituximab. In case of complete or partial remission, further therapy with rituximab maintenance as consolidation represents an option. The vast majority of patients with MCL will ultimately relapse which poses a challenge in treatment approach. The approach in relapsed MCL can be divided in two types: chemotherapy or biologic therapy. In young fit patients chemotherapy based on bendamustine and cytarabine is a reasonable option. In patients with comorbidities or poor performance status biologic agents are reasonable options. Ibrutinib, Bruton kinase inhibitor, is characterized by highest overall response rate and the longest duration of response and should be offered to these patients. With the development of novel potent inhibitor of B cell receptor signaling pathway, these agents may become the gold standard in future and introduce the treatment of MCL in „chemo-free“era

Bendamustine: an Old Drug in the New Era for Patients with Non-Hodgkin Lymphomas and Chronic Lymphocytic Leukemia

The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation

Smjernice za liječenje kronične limfocitne leukemije – veljača 2019.

Nove smjernice (KroHem v1.2019) su rezultat prethodnih smjernica, relevantnih kliničkih studija faze 3 i sukladne su s najvažnijim međunarodnim smjernicama za liječenje KLL (NCCN, ESMO)