Smjernice za dijagnostiku i liječenje kronične limfocitne leukemije – Krohem B-CLL 2017.

Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials constantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine.Nedavni događaji u dijagnostici i liječenju kronične limfocitne leukemije (B-KLL) doveli su do promjene pristupa u kliničkoj praksi. Nova liječenja su odobrena na temelju rezultata randomiziranih multicentričnih pokusa za prvu liniju terapije i za liječenje relapsa/refraktorne bolesti, a rezultati brojnih kliničkih pokusa u tijeku trajno doprinose daljnjem unaprjeđenju terapijskih strategija. Uz to prisutan je bitan porast razumijevanja genskih promjena bolesti zbog velikog napretka tehnologije nove generacije sekvencioniranja. Definiramo trenutni stav Hrvatske suradne skupine za hematološke bolesti o dijagnostici i liječenju B-KLL u sadašnjoj tranziciji iz kemo-imunoterapijske paradigme u novu koja se temelji na novoj dijagnostičkoj slojevitosti i izvrsnim terapijskim rezultatima inhibitora B-staničnih receptora (BRI) i Bcl-2 antagonista. To se područje brzo razvija kako velik broj kliničkih ispitivanja koja su u tijeku neprestance doprinosi i pruža nova znanja. Vjerujemo da će istraživanje novih terapija uz genomsku dijagnostiku pružiti nove mogućnosti koje će na kraju dovesti do vremenski ograničenog liječenja bez kemoterapije i do učinkovitije kliničke skrbi B-KLL na temelju individualizirane i precizne medicine

DIAGNOSIS AND THERAPY FOR PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA Guidelines of Croatian Cooperative Group for hematologic disorders – KROHEM

Esencijalna trombocitopenija (ET) klonski je mijeloproliferativni zloćudni tumor. Hrvatska kooperativna grupa za hematološke bolesti, KROHEM, predlaže smjernice dijagnostičkog i terapijskog pristupa. Dijagnoza ET temelji se na kriterijima dijagnostike i podjele mijeloidnih zloćudnih tumora Svjetske zdravstvene organizacije (SZO). Razina terapijskih preporuka polazi od pokazatelja predloženih od elektronskog izvora medicinskih informacija, UpToDate®. Za dijagnozu ET potrebno je dokazati trajan porast broja trombocita (>450×109/L), uz tipičnu histološku sliku megakariocitopoeze u koštanoj srži te isključiti postojanje sekundarne trombocitoze ili drugih kroničnih mijeloproliferativnih zloćudnih tumora. Liječenje se temelji na pokazateljima rizika od bolesti koji je određen brojen trombocita, dobi bolesnika te prisutnošću rizika ili znakova tromboze i krvarenja. Bolesnike niskog rizika (dob 60 godina) prva linija terapije je hidroksiureja, a anagrelid se primjenjuje u bolesnika s nepotpunim odgovorom na hidroksiureju. U trudnica, kada je potrebno liječenje, preporučuje se alfa-interferon.Essential thrombocythemia (ET) is a clonal myeloproliferative neoplasm. Croatian Cooperative Group for hematologic disorders, KROHEM proposes the diagnostic and treatment guidelines for ET. Diagnosis of ET is based on the criteria and classification of World Health Organization (WHO). The level of treatment recommendation is based on the UpToDate® (web based medical community database) criteria. For ET diagnosis it is mandatory to show sustained increased number of platelets with typical histomorphological changes of megakaryopoiesis in bone marrow. Secondaly thrombocytosis and other chronic myeloproliferative neoplasms have to be excluded. Therapy is based on risk factors for ET. The risk factors are number of platelets, patient’s age, and the risk levels for thrombosis and bleeding. Patients with low risk (age <60 years and platelets <1000×109/L) arw not candidates for therapy. In younger group of patients with platelets between 1000 and 1500×109/L or more than 1500×109/L treatment with anagrelide or hydroxyurea is recommended respectively. In high risk patients hydroxyurea is the first line treatment. Anagrelide is indicated in these patients in the absence of treatment response. Alpha-interferon is recommended for pregnant women with ET and high platelet counts

Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia. Krohem B-Cll 2017

Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials constantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine

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)

IL12RB2 Gene is Associated with the age of Type 1 Diabetes Onset in Croatian Family Trios

BACKGROUND: Common complex diseases are influenced by both genetic and environmental factors. Many genetic factors overlap between various autoimmune diseases. The aim of the present study is to determine whether four genetic variants known to be risk variants for several autoimmune diseases could be associated with an increased susceptibility to type 1 diabetes mellitus. METHODS AND FINDINGS: We genotyped four genetic variants (rs2358817, rs1049550, rs6679356, rs9865818) within VTCN1, ANXA11, IL12RB2 and LPP genes respectively, in 265 T1DM family trios in Croatian population. We did not detect association of these polymorphisms with T1DM. However, quantitative transmission disequilibrium test (QTDT, orthogonal model) revealed a significant association between the age of onset of T1DM and IL12RB2 rs6679356 variant. An earlier onset of T1DM was associated with the rs6679356 minor dominant allele C (p = 0.005). The association remained significant even after the Bonferroni correction for multiple testing and permutation. CONCLUSIONS: Variants originally associated with juvenile idiopathic arthritis (VTCN1 gene), sarcoidosis (ANXA11 gene), primary biliary cirrhosis (IL12RB2 gene) and celiac disease (LPP gene) were not associated with type 1 diabetes in our dataset. Nevertheless, association of IL12RB2 rs6679356 polymorphism with the age of T1DM onset suggests that this gene plays a role in defining the time of disease onset

Podnošljivost kombinacija obinutuzumaba i viših doza klorambucila u prvoj liniji liječenja kronične limfocitne leukemije

Podnošljivost kombinacija obinutuzumaba i viših doza klorambucila u prvoj liniji liječenja kronične limfocitne leukemij

Podnošljivost kombinacija obinutuzumaba i viših doza klorambucila u prvoj liniji liječenja kronične limfocitne leukemije

Podnošljivost kombinacija obinutuzumaba i viših doza klorambucila u prvoj liniji liječenja kronične limfocitne leukemij

Transmission disequilibrium analysis for <i>IL12RB, ANXA11, VTCN1</i> and <i>LPP</i> gene SNPs in 265 family trios (T:U – copies of the minor allele transmitted (T) and untransmitted (U) from heterozygous parents to affected offspring<i>).</i>

*<p>Nominal p values are shown uncorrected for multiple testing. The Bonferroni-corrected significance threshold is p = 0.0125.</p

Quantitative transmission disequilibrium analysis (Abecasis’s orthogonal test) in 262 family trios with age of T1DM onset as a quantitative variable.

*<p>Nominal p values are shown uncorrected for multiple testing. The Bonferroni-corrected significance threshold was p = 0.0125.</p>**<p>Empirical p-values were obtained using 10000 Monte Carlo permutations. Empirical significance threshold of 0.05 corresponded to a p-value of <0.0128.</p

Diagnosis and Therapy for Patients with Philadelphia positive chronic myeloid leukemia – Guidelines of Croatian cooperative group for hematologic disorders (Krohem)

Cilj: Prijedlog Hrvatske kooperativne grupe za hematološke bolesti (Krohem) smjernica dijagnostičkog i terapijskog pristupa za Philadelphia pozitivnu kroničnu mijeloičnu leukemiju. Metode: Dijagnoza KML-a temelji se na kriterijima dijagnostike i podjele mijeloidnih zloćudnih tumora Svjetske zdravstvene organizacije (SZO). Razina terapijskih preporuka polazi od pokazatelja koje predlaže elektronički izvor medicinskih informacija UpToDate®. Rezultati: Za dijagnozu KML-a potrebno je dokazati prisustvo Philadelphia kromosoma tehnikama klasične citogenetike ili BCR-ABL prijepis FISH-om ili molekularnim tehnikama. Liječenje se temelji na primjeni inhibitora tirozin kinaze. Dasatinib i nilotinib pokazuju bolji antileukemijski učinak od imatiniba. Zbog raspoloživosti lijekova u Hrvatskoj, u ovom trenutku imatinib se i dalje primjenjuje u prvoj liniji terapije. U bolesnika s nepovoljnim odgovorom, ovisno o prethodnom liječenju, u drugoj liniji primjenjuju se bilo dasatinib ili nilotinib. U uznapredovanoj fazi bolesti, ubrzanoj fazi ili blastičnoj krizi, terapija izbora je alogena transplantacija. Prije transplantacije predlaže se liječenje inhibitorima tirozin kinaze, kako bi se smanjila leukemijska masa bolesti. Bolesnici s mutacijom abl proteina T315I otporni su na liječenje inhibitorima tirozin kinaze i zahtijevaju što je moguće brže liječenje alogenom transplantacijom. Rasprava i zaključak: Terapija izbora u Ph+ KML-u u kroničnoj fazi su inhibitori tirozin kinaze. U bolesnika s optimalnim terapijskim odgovorom postiže se dugotrajna kontrola bolesti i dobra kvaliteta života. U uznapredovanoj fazi bolesti i mutacije T315I, terapija izbora je alogena transplantacija.Aim: Guidelines for diagnosis and therapy of Philadelphia positive chronic myeloid leukemia are proposed by Croatian cooperative group for hematological diseases – Krohem. Methods: Diagnosis and classification of CML is based on the criteria proposed by WHO. The level of treatment recommendation is based on the UpToDate® (web based medical community database) criteria. Results: For CML diagnosis it is mandatory to prove the Philadelphia chromosome with G-banding technique or to prove BCR-ABL transcript by FISH method or molecular analysis. Tyrosine kinase inhibitors (TKI) are treatment of choice for CML. A significantly better antileukemic activity is associated with dasatinib or nilotinib therapy compared to imatinib. But these drugs are not available for first line therapy in Croatia. Because of that imatinib is still the first line therapy. For second line therapy patients should receive dasatinib or nilotinib depending on the previous therapy. In accelerated phase or blastic crisis allogeneic stem cell transplantation is the treatment of choice. Before transplant, tyrosine kinase inhibitors should be given to decrease the leukemic mass. Patients with T315I mutation are resistant to TKI and should be also allografted. Discussion and conclusion: TKI are the treatment of choice for Ph+ CML in chronic phase. Patients with optimal response are long-term survivors with a good quality of life. In advanced phase of CML or in patients with T315I mutation stem cell transplantation is the treatment of choice