HEMATOLOGIC MALIGNANCIES logo_CELL_verze_02 Hematologic malignancies Origin – hematopoietic cells According to blood lineage - lymphoid malignancies - myeloid malignancies Diseases •Leukemias •Lymphomas a lymphproliferative diseases •Myeloproliferative diseases, myelodysplastic syndromes figS2 figs1 Hematologic malignancies CLONAL disorders resulting from a mutation of DNA within a pluripotent marrow stem cell or very early progenitor cell. CLONAL POPULATION OF CELLS - cells with growth and/or proliferation advantage over against normal bone marrow cells. Mutation of DNA can result in the expression of fusion genes that encode fusion proteins that are oncogenic or in the underexpression of genes that encode molecules critical to control of cell growth or progremmed cell death. Symptoms •Similar •Often non-specific •Bone marrow involvement (leukemia, myeloproliferative neoplasms) •Lymphoid tissue involvement (lymphoma) Leukemia John Hughes Bennett: Two Cases of Disease and Enlargement of the Spleen, in which death took place from presence of purulent matter in the blood, 1845 The young John Hughes Bennett C:\Dokumenty\Michael\Kapitoly do knih a skript\Veterinární krev\Historie fotografie\Bennett-leukemie.JPG Dr. R.L.K. Virchow Rudolf Virchow: Weisses Blut. Frorieps Notizen, 36, s. 152 – 156, 1845 Weisses blut What leukemias are? •Very different diseases •Historical name: accumulation of white blood cells •Not every accumulation of white blood cells is leukemia –Leukemoid reaction –Lymphoma leukemization •Acute or Chronic •Myeloid or Lymphoid Common features of leukemia •White blood cells accumulation –precursor cells (myelo-, lympho-) – blasts – acute leukemia –myeloid lineage cells – CML –mature lymphocytes (CLL) •Leukocytosis (CML, CLL, AL) •Normal WBC or leukopenia (AL) •In almost all cases pathology in differential white blood count •In all cases bone marrow involvement • LEUKEMIAS Do you know differences between acute and chronic leukemias? Briefly: Acute leukemia - there is defect of proliferation, proliferation of young bone marrow cells (blasts) is increased! Chronic leukemia - there is defect of apoptosis (programmed cell death), apoptosis of mature cells is decreased, mature cells are accumulated in the body! CAVE: CL can switch to AL (CML in blast crisis, CLL in Richter´s syndrome) LEUKEMIA INCIDENCE 12,7/100 000 M 9,8/100 000 F Slightly increasing incidence compared with 90´s (except of CML) Europe: 40% CLL, 25% AML, 15% CML, 11% ALL, 2% HCL, 7% other Myelodysplastic syndromes 1 - 2/100 000 (older 10-20/100 000) ALL CML AML CLL cases /100 000 M F age age age age LEUKEMIA INCIDENCE AND PREVALENCE - CLL as example Symptoms affecting patients Frequency infection, fever bleeding thrombosis, DIC lymph nodes enlargement splenomegaly hepatomegaly mediastinal tumor CNS involvemet involvement of another organs 36 % (all) 33 % (APL, AML) 10 % (APL, ET, PV) 57 % (ALL, CLL) 56 % (CML, CLL, PV, MF) 47 % (CML, AML) 14 % (ALL, CLL) 7 % (ALL, AML M5) 9 % (all) Clinical symptoms of malignant diseases of blood and bone marrow CAVE: All symptoms of hematologic diseases are non-specific! Petechie Krvácení Bleeding in acute leukemia Bleeding in acute leukemia AML – gum hyperplasia 280813051546gingivalhyperplasia3 AML – gum hyperplasia PLL – skin involvement ALL – skin involvement Mastocytosis - urticatia pigmentosa Uzliny - článek Uzliny - obrázek CLL - lymph nodes 8671059_f520 CLL - splenomegaly 9,5 - pro prezentaci Myelofibrosis - massive splenomegaly Vak po leukaferéze 1 Lekocytes - leukapheresis bag Leukostáza při hyperleukocytóze Lung infiltration in acute leukemia Time from first symptoms to final diagnosis LEUKEMIAS – PREDISPOSING FACTORS Increased risk of leukemia is in: Genetic syndromes – M. Down, FA, ataxia telangiectasia, inherited germline mutations (ETV6, RUNX1, DDX41…) Drugs (chemotherapy, alkylating agents) Radiation (can cause all leukemias except CLL) Socioeconomic factors (increased incidence of childhood ALL in industrial countries, probably due to later contact of children with alergens or banal childhood infections) Viruses (EBV, HTLV I, HIV) Benzene, toluene, etc. LEUKEMIAS – ETIOLOGY Somatic molecular leasions involving: Cell proliferation Cell division Cell maturation Apoptosis Cell self-renewal LEUKEMIAS – ETIOLOGY The most important somatic molecular changes in leukemia and myeloproliferative neoplasms: BCR-ABL TP53 PML-RARα JAK2 LEUKEMIAS AND MYELOPROLIFERATIVE DISEASES Blood and bone marrow features What can we found in periperal blood (WBC, RBC, platelets)? - acute leukemia - chronic leukemia - myeloproliferative diseases What can we found in bone marrow? - acute leukemia - chronic leukemia - myeloproliferative diseases Vyšetření při podezření na hematologickou malignitu Laboratory diagnostics Peripheral blood count with differential WBC Bone marrow Flow cytometry (analysis of CD antigens) (ALL, CLL, HCL) Cytogenetic analysis (CML, AL, MDS, CLL) Molecular genetic analysis (CML, APL, AL, CLL) Cytology a cytochemistry Histology (necessary in myeloproliferative diseases) Do you know differences between trephine biopsy and sternal puncture? Sternal puncure - we can collect only marrow blood. SP fits for diagnostics of leukemias. Biochemical analysis of blood (elevated LD in myeloproliferative diseases) Coagulation – DIC, thrombophilia, bleeding fibrinogen, aPTT, PT, AT III, DD, EGT Other (Chest X ray, abdominal sonography, ECG, heart sonography, serology – CMV…) - we have to exclude focal infections and to evaluate function of heart, kidneys, liver and lungs (chemotherapy is nephrotoxic, hepatotoxic or cardiotoxic) Laboratory diagnostics CLASSIFICATION OF LEUKEMIA FAB (1982) WHO (1999-) Classification according to morphology, cytogenetic features, flow cytometry, and molecular genetic features Classification according to morphology of malignant cells IMG_0001.jpg CHRONICKÁ LYMFOCYTÁRNÍ LEUKEMIE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) The most common leukemia of Caucasians. CLL is a disorder characterized by the accumulation of small mature-appearing lymphocytes in the blood, marrow, and lymphoid tissues. Laboratory and clinical features: leukocytosis (absolute lymphocytosis), lymphadenopathy, splenomegaly, hepatomegaly, anemia, thrombocytopena, often autoimmune diseases (hemolysis). Prognosis – different (better in CLL mutated genes for IgH or/and in CLL with del 13q14. Median survival of CLL patients is 11+ years. Obrázek 3 - CLL - buňky Obrázek 4 - CLL - průtoková cytometrie CD19 CD5 Diagnostics based on flow cytometry: CD5+19+20dim+23+FMC7-79b-200+sIg+/- CLL staging Treatment in stage Rai III or IV patients only (Binet C) CLL prognosis based on cytogenetics 5b CLL prognosis based on IgHV mutational status 2a Vyšetření IgH (somatické mutace v genu pro IgH) - B-CLL s dobrou prognózou. CLL CLL THERAPY Treatment for advanced stages only: - fludarabine+cyclophosphamide+rituximab - bendamustine+rituximab - chlorambucil + anti CD20 antibody (rituximab, obinutuzumab) - ibrutinib, idelalisib (BCR inhibitors) - venetoclax (Bcl2 inhibitor) - (allogeneic transplant) OS at 3 years 83% vs. 87% p = 0,012 PFS at 3 years 45% vs. 65% p < 0,0001 CLL – FCR regimen treatment outcome Clonal evolution in CLL – TP53 Treatment Before treatment Unfavorable SFB3, NOTCH1, BIRC3 mutations CHRONIC MYELOID LEUKEMIA (CML) CML is a pluripotent stem cell disease that is characterized by extreme blood granulocytosis, basophilia, often thrombocytosis, anemia, and splenomegaly. Stages of untreated CML: chronic phase, accelerated phase (rapid increase of WBC, worsening of thrombocytopenia, new cytogenetic features, resistence to treatment), blast crisis (resembles to acute leukemia) Etiologic role of chromosome discovered in Philadelphia - Ph chromosome Peripheral blood smear shows leukocytosis due to presence of neutrophils in different stages of maturation with two peaks in differential blood count – myelocytes and segmented neutrophils. Basophils are almost invariably increased (yellow arrows) and absolute eosinophil (black arrows) count is increased in the great majority of patients. Bone marrow is hypercellular with an increase in granulocytes and their precursors. The myeloid:erythroid ratio is grater then 10:1, erythroid precursors are very few. All stages of granulocytic maturation are increased with the same pattern like in peripheral blood – two peaks in the percent of myelocytes and segmented neutrophils. 9t(9;22)CMLGRShem ABL BCR FISH - Ph chromosome arises from t(9;22) - chimeric gene BCR-ABL arises from Ph chromosome - BCR-ABL gene produces BCR-ABL tyrosinkinase - BCR-ABL tyrosinkinase induces defect of apoptosis There is almost no BCR-ABL negative CML! Minimal residual disease during treatment - Hematologic monitoring - - Cytogenetic monitoring - - Molecular genetic monitoring (RQ-RT-PCR, digital PCR, NGS) months 10 20 30 40 0,0001 BCR-ABL (%) 0,001 0,01 0,1 1 10 100 Minimal residual disease during therapy Molecular relapse is better manageable compared with cytogenetic or hematologic relapse molecular relapse cytogenetic relapse hematologic relapse CLL THERAPY All patients treated! - imatinib - nilotinib, dasatinib, bosutinib - ponatinib - interferon - allogeneic transplantation Lissauer Asenic trioxide Lissauer: Zwei Fälle von Leucaemie. Berlin. Klin. Wochenschrift, 2, 1865, s. 403 - 404 Imatinib mode of action Léčba CML years 2 4 6 8 25 50 75 100 10 allogeneic transplantation IFN Prognosis of CML patients HU survival (%) imatinib ACUTE MYELOID LEUKEMIA (AML) AML is clonal malignant disease that is characterized by the proliferation of abnormal (leukemic) blasts, principially in the marrow, and impaired production of normal blood cells. Signs and symptoms of AML include pallor, fatigue, weakness, palpitations, bleeding, fever, and dyspnena. In bone marrow, there is more than 20% of blast cells. (less than 20% - myelodysplastic syndrome) Median survival of untreated patients is 6 weeks. 6a00d8342ae08153ef0128764a7a44970c-800wi AML – heterogenous disease AML, NOS, AML wthout maturation AM L, NOS with maturation AML, NOS, acute monoblastic leukaemia Induction 3 + 7 Followed by bone marrow aplasia (2 – 4 weeks) Complete remission (normal BM, blasts bellow 5 % in BM) Partial remission (decrease of blast cells) Progression Consolidation (2 courses), treatment is completed by allogeneic or autologouc BMT/PBSCTin younger patients Reinduction Salvage chemotherapy Bone marrow aplasia after each course (2 - 4 weeks) Palliative or symptomatic treatment in non-responders Treatment of AML Treatment of choice of AML are courses of chemotherapy, the most potent drugs are cytosinarabinoside and anthracyclines. Treatment of AML Novel drugs for AML: Midostaurin Venetoclax Gilteritinib Acute promyelocytic leukemia (APL, AML M3) APL is variant of AML (constitutes about 5-10% of AML in central Europe, about 25% of AML southern Europe, and 50 % of AML in eastern Asia). There are prominent hemorrhagic complications (DIC, melena, hematuria, pulmonary bleeding, CNS bleeding) Prognosis of APL was very poor 30 years ago (almost all patients died). Nowadays, DFS is 80%. Acute promyelocytic leukemia (APL, AML M3) Promyelocytes are granular cells. In granula are coagulopathy-inducing factors (tissue factor…). Majority of APL is characterized by t(15;17). A translocation between chromosome 17 and 15 results in chimeric fusion gene PML-RARα. PML-RARα gene produces PML-RARα abnormal recepror for retinoids. (Retinoids are necessary for normal bone marrow cells differentiation). In cells with t(15;17) normal differentiation is stopped. We can restore differentiation by means of ATRA + ATO or chemo. Chemotherapy or arsenic trioxide + ATRA is treatment of choice for APL! img14 Bleeding diathesis in APL: CP – cancer procoagulant, IL-1β – interleukin 1β, t-PA – tissue plasminogen activator, u-PA – urokinase. Obr Survival of AML patients children and younger adults APL Survival of AML patients F2 normal karyotype t(8;21) inv(16) komplex. karyotype - 7 good risk standard risk poor risk ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) The most common leukemia in childhood. In children - very good prognosis. In adults - poorer prognosis. ALL is a neoplastic disease resulting from somatic mutation in a single lymphoid progenitor cell. B precursor ALL vs. T precurosr ALL BM - more than 20% of lymphoblasts (usually 80 - 100%). ALL, masive infiltration, mitotic figure Chromozomální translokace u ALL Chromozomální translokace u ALL Ph positive ALL ALL – therapy overview Childhood ALL survival adults MYELODYSPLASTIC SYNDROMES Heterogeneous group of malignant diseases with different prognosis – dysplasia of myeloid lineage. In BM - blasts bellow 20 % and dysplastic features (hypogranular cells, cells with atypical shape of nucleus, hypergranular cells, cells with abnormal plasma) The only curative option is BMT/PBSCT in high risk patients. Patients asyptomatic or without donor - only symptomatic treatment or watch and wait strategy. MYELODYSPLASTIC SYNDROMES - dysplastic features Dysgranulation in granulocyte (myelocyte), karyorhexis and Howell-Jolly bodies in late erythroblast, ring nukleus in eosinophil, hypersegmentation in mature neutrophil MDS type Dysplasia Cytopenia Ring sideroblasts Blasts in peripheral blood Blasts in bone marrow Cytogenetics MDS with single lienage dysplasia (MDS-SLD) 1 1 or 2 <15%, < 5% < 1%, no Auer rods <5%, no Auer rods Any except of del(5q) MDS with mixed lineage dysplasia (MDS-MLD) 2 or 3 1 - 3 <15%, < 5% < 1%, no Auer rods <5%, no Auer rods Any except of del(5q) MDS with ring sideroblasts (MDS-RS) MDS-SLD-RS 1 1 or 2 ≥ 15%, ≥ 5%* < 1%, no Auer rods <5%, no Auer rods Any except of del(5q) MDS-MLD-RS 2 or 3 1 - 3 ≥ 15%, ≥ 5%* < 1%, no Auer rods <5%, no Auer rods Any except of del(5q) MDS with isolated del(5q) 1-3 1-2 No or few < 1%, no Auer rods <5%, no Auer rods del(5q) or 1 more except of -7 or del(7q) MDS – classification I MDS – classification II MDS type Dysplasia Cytopenia Ring sideroblasts Blasts in peripheral blood Blasts in bone marrow Cytogenetics MDS with exces of blasts (MDS-EB) MDS-EB-1 0-3 1-3 No or few 2-4%, no Auer rods 5-9%, no Auer rods Any MDS-EB-2 0-3 1-3 No or few 5-19%, or Auer rods 10-19%, or Auer rods Any MDS unclassificable (MDS-U) With 1% of blasts in PB 1-3 1-3 No or few 1%, no Auer rods < 5%, no Auer rods Any With 1 lineage dysplasia and pancytopenia 1 3 No or few < 1%, no Auer rods < 5%, no Auer rods Any With cytogenetic abnormality 0 1-3 < 15% < 1%, no Auer rods < 5%, no Auer rods MDS typical feature Refractory cytopenia in childhood 1-3 1-3 No < 2% < 5% Any Score Prognostic marker 0 0.5 1.0 1.5 2.0 Bone marrow blasts (%) <5 5–10 11–20 21–30 Karyotype Good Intermediate Poor Cytopenia 0/1 2/3 Score IPSS subgroup Median survival (years) 0 Low 5.7 0.5–1.0 Int-1 3.5 1.5–2.0 Int-2 1.2 > 2.5 High 0.4 . MDS - prognosis MDS THERAPY Prognostic group MDS risk score Low High risk •Supportive care, transfusions, prophylaxis of iron overload • •Erythropoietin • •Immnosupressive therapy • •Low-dose chemotherapy • •Epigenetic therapy (5-azacytidine) •Allogeneic SCT, clinical trial MYELOPROLIFERATIVE NEOPLASMS PV PMF ET Proliferation of myeloid lineage (granulocytic, erythroid, megakaryocytic) MYELOPROLIFERATIVE NEOPLASMS MYELOPROLIFERATIVE NEOPLASMS POLYCYTHEMIA Polycythemia is characterized by an increase of the total red cell volume. Primary form (PV, clonal neoplastic disorder) Secondary forms due to appropriate or inappropriate increases in levels of EPO (hemoglobins with high affinity to oxygen, high altitudes, pulomonary and heart diseases, tumours producing EPO) PV is characterised by increases not only of the number of red cells but also of the granulocytes and platelets and splenomegaly. POLYCYTHEMIA VERA Peripheral blood count Histology of bone marrow Total erythrocyte volum Ertythropoietin level JAK2 V617F mutation We have to exclude all secondary polycythemias Secondary polycyhemias are more frequent than PV Complications - bleeding, thrombosis, leukemia, bone marrow fibrosis Diagnosis POLYCYTHEMIA VERA – differential diagnosis PRAVÁ POLYCYTÉMIE 00536918 myeloproliferativedisorders PRAVÁ POLYCYTÉMIE Komplikace: trombózy! Foot%20flaring1 Fibróza, AL, krvácení POLYCYTHEMIA VERA Phlebotomy Antiaggregant therapy of anticoagulation therapy Interferon alpha Hydroxyurea Ruxolitinib (JAK2 inhibitor) Therapy ESSENTIAL THROMBOCYTHEMIA Clonal proliferation of megakaryocytes in bone marrow and incresed peripheral blood platelet count. JAK2 V617F mutation, calreticulin mutation Differential diagnosis: Secondary thrombocytemias (sideropenia, chronic infection, splenectomy, malignancies, bleeding, hemolysis). Myeloproliferative disorders, MDS Complications - bleeding, thrombosis, leukemia, bone marrow fibrosis sejmout0001 ESENCIÁLNÍ TROMBOCYTÉMIE ESSENTIAL THROMBOCYTHEMIA Antiaggregant therapy of anticoagulation therapy Interferon alpha Anagrelide Hydroxyurea Therapy PRIMARY MYELOFIBROSIS Clonal disorder chracterized by transformation of normal bone marrow to fibrotic and non-functional bone marrow. JAK2 V617F, CALR mutation, MPL muation Hyperplastic stage - increased precurors of platelets in BM, increased WBC, RBC and PLT. Late stage – fibrosis (extramedullary hematopoiesis leading to massive splenomegaly). Prognosis – median shorter than in PV or ET. PRIMARY MYELOFIBROSIS Interferon alpha Anagrelide Hydroxyurea JAK2 inhibitors (ruxolitinib) Supportive care Allogeneic transplantation Therapy Lymphoma LYMPHOMA Lymhoid tissue involvement (lymph nodes, other lymphoid tissue) • Mature B cell neoplasms • Mature T cell and natural killer (NK) cell neoplasms • Precursor lymphoid neoplasms • Hodgkin lymphoma • Immunodeficiency-associated lymphoproliferative disorders LYMPHOMA - symptoms Local expansion symptoms Systemic symptoms Weight loss Subfebrilia, fever (>3 weeks) Pruritus Night sweat Fatigue LYMPHOMA - symptoms Local expansion symptoms Lymphadenopathy peripheral Lymphadenopathy mediastinal (cough, feeling of pressure in the chest, upper vena cava syndrome) Lymphadenopathy abdominal (hydronefrosis, abdominal dyscomfort) Splenomegaly (abdominal dyscomfort, quick feeling of satiety) Bone marrow involvment (cytopenia) Osteolytic bone leasions P1010058 LYMPHOMA - symptoms P1010056 LYMPHOMA - symptoms LYMFOMY PŘÍZNAKY P1010064 LYMPHOMA - symptoms P1010052 LYMPHOMA - symptoms P1010046 LYMPHOMA - symptoms 1 LYMPHOMA - symptoms image PET 2 LYMPHOMA - symptoms NON-HODGKIN LYMPHOMA • Mature B cell neoplasms • Mature T cell and natural killer (NK) cell neoplasms -Lymph node involvment -Extranodal lymphoma Indolent NHL slow growth - remission possible, cure unlikely = start of treatment only with symptoms Aggressive NHL potentially curable, treatment start as soon as possible Very aggressive NHL NON-HODGKIN LYMPHOMA Diagnostics Peripheral lymphadenopathy Infection excluded EBV, HIV, toxoplasmosis Lymph node exstirpation and histology Clinical symptoms Peripheral lympho nodes physical examination Imaging methods: Sonography CT scan PET/CT or PET/MR scan MR scan NON-HODGKIN LYMPHOMA Staging CT (neck, upper arms, chest, abdomen and pelvis) -or MRI -or now PET/CT, alternatively PET/MR - Trephine biopsy and bone marrow histology Where appropriate, a specialized examination (gastroscopy, colonoscopy, lumbal puncture…) NON-HODGKIN LYMPHOMA Obsah obrázku mapa, text Popis byl vytvořen automaticky NON-HODGKIN LYMPHOMA Prognostication Stage I and II = limited stage Stage III and IV = advanced stage (several prognostic indexes for adnaced stage – IPI, FLIPI…) NON-HODGKIN LYMPHOMA B-cell NHL subtypes Indolent NHL - folicular lymphoma -Survival without treatment several years in many patients -Radiotherapy for limited stage (I.-II. st.) has curative potential -Systemic treatment leading to remission, but no cure; repeatedly relapsed disease -Systemic treatment in symptomatic patients only The bone marrow is involved in 40-70% cases. In cyto-morphological examination of peripheral blood or bone marrow smears six cytological features of the disease exists. Tumor cells are very small, with almost invisible cytoplasm, with high nucleo/cytoplasmic ratio, nuclear chromatin is smooth and without a nucleolus, the nuclear outline is irregular and angular, and high proportion of lymphocytes have deep and narrow clefts (coffee-bean appearance). Folicular lymphoma prognosis according to histology NEHODGKINOVY LYMFOMY Folicular lymphoma prognostic index (FLIPI) -Hemoglobin below 120 g/L -Age over 60 years -LDH above norm -Stage II B or higher -Involved lympho ode areas over 4 - - Low – FLIPI 0-1 Intermediate – FLIPI 2 High – FLIPI 3 and higher NEHODGKINOVY LYMFOMY First-line therapy •Limited FL (stadia I+II): IF RT 25-35Gy •Advanced FL (stadia III+IV): anti-CD20 antibody + chemotherapy (R-CHOP regimen…) Therapy of relapse •Chemoimmunotherapy with anti-CD20 antibody +/- maintenance with monoclonal antibody •High-dose therapy and autologous bone marrow transplant •Allogeneic bone marrow transplant •Radioimmunotherapy •Radiotherapy (limited forms) Folicular lymphoma therapy NEHODGKINOVY LYMFOMY •MALT – Mucosa Associated Lymphatic Tissuse lymphoma •Ethiologic role of antigen stimulation, H. pylori infection •Majority: MALT lymphomas of stomach •Symptoms: non-healing stomach ulcers Indolent NHL - MALT lymphoma NEHODGKINOVY LYMFOMY Limited clinical stages (I or II) •Antibiotics, radiotherapy (surgery as alternative) • Generalized clinical stages III or IV •Chemoimmunotherapy (as in folicular lymphoma) MALT lymphoma therapy NEHODGKINOVY LYMFOMY •Paliative –Mantle cell lymphoma •Curative –DLBCL –Burkitt lymphoma Aggresive NHL – principles of therapy Burkitt lymphoma NEHODGKINOVY LYMFOMY Diffuse large B-cell lymphoma The most common lymphoma Symptoms -Rapid local growth -Large tumor mass -Continuous generalization -Frequent involvement of the central nervous system and bones Aggresive NHL - DLBCL DLBCL – different morphological forms centroblastic immunoblastic anaplastic Tumour immunoblast is at the bottom of the middle picture NEHODGKINOVY LYMFOMY •Age over 60 years •Reduced physical fitness, ECOG higher than 1 •LDH level over upper limit of the norm •Clinical stage higher than 2 •Extranodal involvement in more than 1 site DLBCL risk factors DLBCL therapy First-line therapy •anti-CD20 antibody + chemotherapy (R-CHOP regimen…) Therapy of relapse •Chemoimmunotherapy with anti-CD20 antibody •High-dose therapy and autologous bone marrow transplant •Allogeneic bone marrox transplant •CAR T-cells NEHODGKINOVY LYMFOMY •Lymphoblastic lymphoma – acute lemphoblastic leukemia based protocols •Burkitt lymphoma – agressive therapeutic regimens Very aggresive NHL HODGKIN DISEASE •Lymphadenopathy with or without systemic symptoms fever, weigt loss, pruritus • •Pathologic Hodgkin or RS cells • •Two peakc of incidence: young adults and elederly • • HODGKIN DISEASE •Good risk goroup: Radiotherapy IF + 2 – 4 cycles of ABVD chemotherapy •Intermediate risk group: BEACOP chemotherapy • •Poor prognosis: BEACOP Nivolumab Brentuximab vedotin (anti CD30) Autologous/allogeneic hematopoietic cell transplantation • HODGKINOVA NEMOC HODGKIN DISEASE Prognosis • •CR rate 95 % •Progression free survival 90 % at 3 years • Multiple myeloma MM Proliferation of clonal malignant plasma cells in bone marrow Complete monoclonal immunoglobulin molecule and/or kappa or lambda monoclonal free light chains produced by plasma cells These changes lead to: Osteolysis, osteoporosis, bone pain Hypercalcemia Hyperproteinemia Renal failure Coagulopathy Neuropathy Cytopenia Incidence 4 / 100 000 MM – immunofixation, electrophoresis, densitometry Paraprotein Numerous pathologic plasma cells can be seen in bone marrow smears. Erythrocytes are forming „rouleaux“ due to presence of monoclonal protein. Cytoplasm of tumours cells contains inclusions of monoclonal protein so call Russel‘s bodies. MM MM Sch37_02 kopie Bez názvu 5 MM 37 MM 36 MM MM Diagnostics: Monoclonal immunoglobulin (or light chains) in peripheral blood and urine Bone marrow histology/cytology Imaging methods: X-ray, MR, PET/CT Serum immunoglobulins Serum calcium level Serum protein Peripheral blood count MM – kidney failure MM - therapy Indication for therapy: Symptomatic patients: cytopenia, bone leasions, hypercalcemia, kidney failure… Drugs: Chemotherapy (vincristine, melfalan) Corticosteroids (dexamethasone) Proteasome inhibitors (bortezomib, ixazomib, carfilzomib) IMIDs (lenalidomide, pomalidomide) Anti-CD38 (daratumumab) High-dose therapy + autologous hematopoietic stem cell transplantation MM – supportive care •Bisfosfonates •Dialysis •Plasmaferesis •Radiotherapy •Pain killers •Prophylaxis of infection •Tranfusions positive mutation