WOUNDS IN HEMATOLOGY PATIENTS

Kod hematološkog bolesnika rane mogu biti dio kliničke slike u trenutku postavljanja dijagnoze, posljedica infekcije, nuspojave terapije ili napredovanja tumorske bolesti s kožnim infiltratima. liječenje rana kod hematoloških bolesnika zahtijeva multidisciplinaran pristup hematologa, kirurga, dermatologa, mikrobiologa i ostalog medicinskog osoblja koje je uključeno u svakodnevnu brigu o bolesniku. Kako se radi o onkološkim imunosuprimiranim bolesnicima, iznimno je važno pridržavati se mjera asepse te spriječiti infekcije rana zbog kojih bi se zakomplicirao ionako dugotrajan oporavak i zaliječenje. Važno je na vrijeme prepoznati ranu s malignom infiltracijom jer je pravodobna kemoterapija u takvom slučaju kurativna mjera.Hematology patients can have wounds as part of the initial presentation of the disease, as a result of infection or therapy. Wound therapy is very important and requires multidisciplinary approach of the hematologist, surgeon, dermatologist, and all other medical staff involved in the patient’s care. It is very important to provide aseptic care and prevent infections that could complicate the patient’s recovery and cure. It is very important to recognize the wound with malignant infiltration because an appropriate chemotherapy can be curative

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

Serum Immunoglobulins in non-Hodgkin’s Lymphoma Patients

Serum proteins and immunoglobulin (Ig) findings in 119 non-Hodgkin’s lymphoma (NHL) patients were analysed. Out of them 96 (81%) patients had B non-Hodgkin lymphoma (B-NHL), and 23 (19%) T-NHL. Indolent type of NHL was more frequent (77 patients, 65%), then aggressive type of NHL (42 patients, 35%). Most patients had normal serum protein concentration, the increased protein concentration was seen in 17% of patients while decreased concentration was noticed in 7% of patients. Hypoalbuminaemia was more frequent (43%) then hyperalbuminaemia (1%). In contrast to albumin, low levels of other protein fractions (alpha1-, alpha2-, and beta-globulin) were rather rare (0.6%, 4%, and 3% of patients, respectively) and high levels were frequent (23%, 37%, and 8%, respectively). Polyclonal hyperimmunoglobulinaemia was more frequent finding than hypoimmunoglobulinaemia. In 29% patients higher IgG level and in 25% patients higher IgA level were found. IgM hypoimmunoglobulinaemia (22%) was more frequent than IgG (11%) and IgA (8%) hypoimmunoglobulinaemia. M-spike in serum protein electrophoresis was found in 11 (7%) patients. The statistically significant association was not found between serum Ig concentration and lymphoma malignancy grade as well as between serum Ig concentration and immunologic origin of lymphoma. T-NHL patients have more often IgA concentration level above or under normal values than B-NHL patients (p<0.05)

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL

Praćenje bolesnika s klasičnim Hodgkinovim limfomom nakon liječenja – suvremena saznanja i nedoumice. Pregled literature [Follow-up of patients with classical Hodgin lymphoma after treatment - novel evidence and dilemmas. Literature review]

In this review we present current evidence for the follow-up of patients treated for classical Hodgkin lymphoma (HL). Nowadays introduction of novel therapies enabled successful treatment in most patients with classical HL in first remission with 5-year overall survival rate estimation of 80%. We have performed extensive literature search on the methodological approach to detection of relapse. Evidence regarding imaging clinical methods in detecting relapse on serial computed tomography and/or positron emission tomography scans is scarce. These imaging modalities are associated with considerable economic cost, unnecessary exposure to radiation and patients' stress. Furthermore, the detection of asymptomatic relapse does not seem to be associated with improved outcome in this patient group. Available data on this subject indicate that standard imaging methods, such as ultrasound, and judicious clinical examination in detecting of relapse should be the basis of HL patient follow-up. Late toxicity due to various modalities of treatment represents serious morbidity in HL. They vary from secondary solid cancers and hematologic neoplasms, associated with poor outcome, to benign disorders (fertility issues, thyroid dysfunction, cardiovascular and lung disorders). Current data on the incidence, prevalence and etiological factors do not yet provide evidence on appropriate screening methods. Most recommendations in various guidelines are associated with low level of evidence (grade IV). We, therefore, propose individually-tailored screening methods for each patient based on the modality of treatment received

FOLLOW-UP OF PATIENTS WITH CLASSICAL HODGIN LYMPHOMA AFTER TREATMENT – NOVEL EVIDENCE AND DILEMMAS. LITERATURE REVIEW

Cilj je ovoga preglednog rada prikazati suvremeno stajalište struke, ali i prijepore u svezi s medicinskom skrbi za bolesnike s klasičnim Hodgkinovim limfomom u prvoj remisiji. Većina bolesnika s klasičnim Hodgkinovim limfomom izliječena je prvom linijom terapije i u nastavku je važan medicinski pristup radi otkrivanja mogućeg relapsa. Pregledom literature nismo našli jednoznačne smjernice za rutinsko praćenje bolesnika slikovnim metodama, tj. kompjutoriziranom tomografijom ili pozitronskom emisijskom tomografijom. Prema dokazima u literaturi, otkriće asimptomatskog relapsa nije povezano s poboljšanim ishodom liječenja. Za sada se može smatrati da su standardne kliničke i radiološke metode ­dostatne za praćenje ovih bolesnika. Kasne toksičnosti uzrokovane mnogim lijekovima i zračenjem znatno pridonose morbiditetu bolesnika. To uključuje pojavu sekundarnih solidnih malignoma (ponajprije karcinoma pluća i dojke) i hematoloških ­neoplazma koštane srži te pojavu benignih toksičnosti kao što su poremećaji funkcije štitnjače, fertiliteta i kardiovaskularnih bolesti. Usprkos obilju literature i smjernica za praćenje ovih bolesnika nakon završetka liječenja, za sada ne postoje rezultati prospektivnih istraživanja koji bi pružili temelj zasnovan na dokazima za nove smjernice i preporuke. Smatramo da otkrivanje kasne toksičnosti treba biti prilagođeno pojedinačnom bolesniku, sukladno specifičnom liječenju i kasnijem utjecaju te toksičnosti na mogući morbiditet u ovih bolesnika.In this review we present current evidence for the follow-up of patients treated for classical Hodgkin lymphoma (HL). Nowadays introduction of novel therapies enabled successful treatment in most patients with classical HL in first remission with 5-year overall survival rate estimation of 80%. We have performed extensive literature search on the ­methodological approach to detection of relapse. Evidence regarding imaging clinical methods in detecting relapse on ­serial computed tomography and/or positron emission tomography scans is scarce. These imaging modalities are associated with considerable economic cost, unnecessary exposure to radiation and patients’ stress. Furthermore, the detection of ­asymptomatic relapse does not seem to be associated with improved outcome in this patient group. Available data on this subject indicate that standard imaging methods, such as ultrasound, and judicious clinical examination in detecting of ­relapse should be the basis of HL patient follow-up. Late toxicity due to various modalities of treatment represents serious morbidity in HL. They vary from secondary solid cancers and hematologic neoplasms, associated with poor outcome, to benign disorders (fertility issues, thyroid dysfunction, cardiovascular and lung disorders). Current data on the incidence, prevalence and etiological factors do not yet provide evidence on appropriate screening methods. Most recommendations in various guidelines are associated with low level of evidence (grade IV). We, therefore, propose individually-tailored screening methods for each patient based on the modality of treatment received

Myeloid Sarcoma Involving the Breast

Myeloid sarcoma is a tumor mass with extramedullary growth pattern, composed of myeloblasts or immature myeloid cells. The development of myeloid sarcoma may precede or concur with acute or chronic myeloid leukemia (AML or CML) or other myeloproliferative diseases or myelodysplastic syndromes (MDS). Isolated myeloid sarcoma of the breast is very rare. A case is presented of a 25-year-old, previously healthy woman that presented to our department for a palpable node, 5x2 cm in size, in the upper medial quadrant of her left breast. Fine needle aspiration (FNA) produced a sample consisting of medium sized blasts. Additional work-up revealed anemia, thrombocytopenia and leukocytosis, along with atypical blasts detected in peripheral blood and bone marrow smear. Based on the morphology, cytochemical characteristics and immature cell immunophenotype, it was considered a case of acute myeloid leukemia without maturation. In spite of intensive chemotherapy, the patient died within a year of diagnosis. In cases of isolated breast myeloid sarcoma, the diagnosis can be missed if the possibility of myeloid sarcoma is not remembered on differential diagnosis of a breast neoplasm

T-Lymphoblastic Lymphoma with an Unusual t(8;14)(q24;q11) – Case Report

Cytogenetic abnormalities seen at presentation of acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/ LBL) are associated with distinct clinical and hematologic disease entities. T-ALL/LBL are morphologically indistinguishable from those of B-ALL/LBL. An abnormal kariotype is found in 50–70% of cases of T-ALL/LBL. We present a 35-year old male patient with T-ALL/LBL and t(8;14)(q24;q11.2). Our patient presented with B-symptoms, bulky mediastinal disease and CNS infiltration. Bone marrow was morphologically normal and cytogenetically without clonal aberrations. Cytological findings of the supraclavicular lymph node showed numerous CD3 positive (100%) and CD2 positive (88%) lymphoblasts, negative for CD34 and CD10. Flow cytometry of lymph node revealed T cell phenotype of im- mature cells: CD45+CD2+CD5+CD7+CD4+CD8+CD3cyt +CD3TdT+CD10-CD34-HLAD/DR-. Cytogenetic analysis of lymph node showed translocation t(1;4)(p32;p12), t(8;14)(q24;q11.2). Southern blot analysis of extracted DNA from the supraclavicular lymph node demonstrated clonal rearrangement of the T cell antigen receptor (TCR/J) gene (region Vb+Jb2). Based on these findings, diagnosis of T lymphoblastic non Hodgkin lymphoma was established. Cerebrospinal fluid analysis showed CNS infiltration with 49% lymphoblasts positive for CD4 and CD8. The disease progressed rapidly with poor response to therapy. T-ALL/LBL with an unusual t(8;14)(q24;q11.2) is a very rare hematologic disorder with rapid disease progression and poor response to conventional therapy because of frequent central nervous system involvement and early relapses

SKIN SIDE - EFFECTS OF HYDROXYUREA THERAPY

Kod hematološkog bolesnika, kožne promjene mogu biti dio kliničke slike u trenutku postavljanja dijagnoze ili napredovanja bolesti koji se oćituju kožnim iniltratima, posljedica infekcije ili nuspojave terapije. hidroksiureja je peroralni citostatik uz kojeg se mogu pojavljivati dermatološke nuspojave čak i i nekoliko godina od početka liječenja. Prikazujemo bolesnicu s ulkusima potkoljenica nastalima u tijeku terapije hidroksiurejom. Važno je na vrijeme prepoznati kožne promjene vezane uz hidroksiureju jer je ukidanje navedenog citostatika u takvom slučaju kurativno.Hematology patients can have wounds as part of the initial presentation of the disease, as a result of infection, side effects of therapy, or disease progression with skin iniltration. hydroxyurea is an oral cytotoxic drug with known cutaneous side effects that can appear years after treatment initiation. here we present a case of a female patient who developed crural ulcerations during hydroxyurea treatment. It is very important to recognize the wound related to hydroxyurea treatment because drug discontinuation is usually curative