Lymphoproliferative disorders What´s essential to remember – Take home message •For students and non-hematologists: •Clinical manifestation – when the disorder is to be suspected •Diagnostic algoritm – how the correct diagnosis is the best to be made •Basic overview of disorders – main groups of diseases and basic information about treatment modalities •For hematology specialists: •Recent optimal treatment algoritms CANCER TYPES INCIDENCE CZECH REPUBLIC 2016 (men; ÚZIS) 3.8% CANCER TYPES INCIDENCE IN CZECH REPUBLIC 2016 (women; ÚZIS) 3,5% 2.10.2020 5 PROGNOSIS AND SURVIVAL OF PATIENTS WITH HEMATOLOGICAL MALIGNANCIES -world data Image result for lymphoma survival 9789283224310 Basic overview of hematological malignancies •Based on WHO classification 2018 •Hematological malignancies come: •from lymphoid cell-line •from myeloid cell-line •from histiocytic cell-line •from monocytoid- • macrofagocytic system • LYMPHOMA CLASSIFICATION HISTORICAL OVERVIEW 2.10.2020 8 •Rappaport (1970) •Kiel (1974) •Working Formulation (1980) •REAL (Revised European American Clasification of Lymphoid Neoplasms) • WHO (5-th revision) 2018 • Symptoms accompanying malignant lymphoproliferative diseases • •We can recognise • •Systemic (General) symptoms •Symptoms of local expansion –Nodal –Extranodal • •GENERAL SYMPTOMS • •WEIGHT LOSS • (≥10% during 3 months; GIT disorders, chronic inflamatory • diseases…) •SUBFEVER/FEVER • (lasting > 3 weeks, dif dg infections, other tumors or • autoimunity disorders) 1. •ITCHING (usually without skin lesions) 1. •NIGHT SWEAT (need to change clothes) 1. •FATIGUE (pathological tiredness) • SYMPTOMS OF LOCAL EXPANSION 1.Peripheral (palpable) lymphadenopathy: „lumps“ 2. 2.Mediastinal lymphadenopathy: irritative dry cough, feeling of pressure, vena cava superior syndrom 3. 3.Abdominal lymphadenopathy: stomach and intestinal dyspepsia, hydronephrosis due to uretheral compression. 4. 4.Splenomegaly: enlarged spleen compressing stomach, feeling of fullness after small meal 5. 5.Bone marrow infiltration: (pan)cytopenia 6. 6.Osteolytic destruction of bones: pain (backbone), fractures EXTRANODAL LOCAL SYMPTOMS •Extranodal involvement in systemic lymphoma •Primary extranodal lymphomas (~ 30% NHL!) • • Related image Diagnostic algoritm Periferal lymphadenopathy Infection must be excluded EBV, HIV, toxoplasma Lymph node biopsy and histological examination Native sample is prefered Non-specific (general) symptoms Imaging examination: Ultrasonogrphy- peripheral lymph node, abdomen CT mediastinum + retroperitoneum PET MR Clinical examination (lumps) P1010068 P1010064 1 1 • Vena cava superior syndrom Swelling of face, enlarged volume of neck Visible collateral veins between vena cava superior and inferior P1010066 P1010046 P1010058 P1010056 P1010052 OVERALL SURVIVAL OF NHL PATIENTS (NIHIL; CLSG) NHL dg 2015 NHL dg 2009 NHL dg 1999 •Histology •Performance status according to ECOG/WHO •Laboratory examination • •Physical examination, imaging (CT, MRI, US±PET) •Bone marrow examination (trephine biopsy) • • Extent of disease = clinical stage PROGNOSIS OF THE PATIENT WITH LYMPHOMA IS BASED ON: Stage I Involvement of 1 lymph nodes (LU) group or 1 extralymfatic organ (EN) (IE) Stage II Involvement 2 or more LN regions on the same side of diaphragma or LOCALISED involvement of 1 EN organ (IIE) including lymph node involvement of 1 or more groups LN on the same side of diaphragma Stage III Involvement of LN or lymphatic organs (spleen, Waldayer circle) on both side of diaphragma, which can be accompanied with LOCALISED involvement of 1 EN organ (IIIE) Stage IV Difuse or diseminated involvement of 1 or more EN organs or tissues with or without LN involvement 1Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31(11):1860-61. 2Rosenberg SA. Report of the committee on the staging of Hodgkin’s disease. Cancer Res 1966; 26: 1310. 3Lister TA, Crowther D, Sutcliffe SB, et al. Report of a commitee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol 1989; 7(11):1630-36. STAGING - ANN ARBOR CLASSIFICATON (modified)1,2,3 image PET 2 FDG-PET (18Fluordeoxyglucose -positrone emission tomography) FDG-PET – what can we really see??? 2.10.2020 28 C:\Documents and Settings\25540\Dokumenty\Obrázky\co_vi.jpg REALITY PET image/scan PET is sensitive but not specific for tumor! Fever of unknown origin – vasculitis proven by FDG-PET Limited stage I and II Advanced stage III a IV vs. WHY IS IMPORTANT TO KNOW STAGE OF THE LYMPHOMA? TREATMENT STRATEGY (I+II vs III+IV stage) IS SIGNIFICANTLY DIFFERENT IN ALL LYMPHOMA SUBTYPES! BASIC INFORMATION ABOUT HISTOLOGICAL CATEGORIES LYMPHOPROLIFERATIONS = malignancies from lymphoid tissue •LYMPHOMAS –Morbus Hodgkin (Hodgkin´s lymphogranuloma) ~30% •Classical (~95%) •Nodular lymphocyte predominant –NonHodgkin´s lymphomas (NHL) ~70% •B-NHL (~90%) •T-NHL (~10%) • • LYMPHATIC LEUKEMIAS B-line: B-CLL, Hairy cell, prolymphocytic leukemia T-line: T-prolymphocytic leukemia, T-LGL, adult T-cell leukemia • MULTIPLE MYELOMA 2.10.2020 33 C:\Documents and Settings\25540\Dokumenty\Obrázky\3160411_1471-2407-11-321-2.png MCL – mantle cell lymphoma BL – Burkitt lymphoma DLBCL- diffuse large B-cell lymphoma FL –follicular lymphoma MALT- mucosa associated lymphoma tissue lymphoma ENKTL –extranodal NK/T lymphoma EATL- enteropathy associated lymphoma PTCL U –peripheral T-cell lymphoma (unspecified) Survival according lymphoma subtype Malignant lymphoproliferative diseases • about 50 units (recent WHO 2008 classification) • from practical point of view two subgroups: C:\Documents and Settings\25540\Dokumenty\Obrázky\83446.gif •Low agressive (indolent) – slow growth, remission possible but usually incurable = start of treatment if symptoms are present • Agressive, high aggressive - rapid progression, BUT several categories potentially curable, start of treatment the earliest possible LOW GRADE LYMPHOPROLIFERATIONS T-cell large granular lymphocytic leukemia (LGL) NK chronic lymphoproliferation Mycosis fungoides/ Sézary syndrom T- cell lymphatic leukemia/lymphoma Primary cutaneous T-cell lymphoma (CD30+) Lymphoplasmacytic lymphoma Hairy-cell leukemia Chronic lymphatic leukemia (CLL) Small lymphocytic lymphoma (SLL/CLL) Follicular lymphoma Marginal zone lymphomas T- line B - line LOW GRADE LYMPHOMAS – basic characteristicsand principles • Overall survival even without treatment in years • to 10 ys • • Radiotherapy indicated and with curative effect in • limited extent (stage I or II) • • • Advanced stages (III/IV) are generally incurable, • chemotherapy-based (CHT) indicated and induces • remission, BUT relapses are the rule • • Curative therapy has to be started immediatelly • • Non-curative treatment (CHT) initiated in symptomatic • patients only FOLLICULAR LYMPHOMA clinical behavior •Slow growing (sometimes vanishing) painless lymphadenopathy with relapsing course after treatment, spontaneous remissions are not exception, with or without general symptoms • •Global median overall survival >18 years (Horning, JCO 2008), • BUT 20% dies during 2 years since diagnosis established • •FL is considered incurable with exception of localised (limited stages I/II) which is relevant for 10-15% patients only • •Cause of death – treatment toxicity and transformation (~25-60%) to more aggressive NHL van Gogh mother •PRIMARY THERAPY (first line) •Localised FL (stage I+II): IF RT 24Gy •Advanced FL (stage III+IV): –/large tumor/: antiCD20+ chemotherapy + antiCD20 maintenance (2ys) –/low tumor/: watch and wait • •THERAPY OF RELAPSE •Chemotherapy ± antiCD20 maintenance •High-dose chemotherapy + autologous stem cell support •Allogeneic bone marrow transplantation •Radioimmunotherapy •Radiotherapy even very low dose (~4Gy!!!) Follicular Lymphoma – Principles of Therapy Anti-CD20 antibody therapies have changed the course of FL •1. Fisher RI, et al. J Clin Oncol 2005; 23:8447–8452. Time (years) ProMACE: prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide * SWOG 9911: CHOP + 131I-tositumomab; SWOG 9800: CHOP + MabThera OS = overall survival 0 2 4 6 8 10 100 CHOP + antibody* ProMACE CHOP p < 0.001 0 20 40 60 80 Anti CD20 monoclonal antibody Rituximab – Mabthera®, Rituxan® •Chimeric humanized IgG1 type •CD20 receptor present on surface • of nearly all B-lymphoid cells •including malignant lymphocytes •Approved for clinical practice (FDA) in 1997 •R is standard component of • treatment of CD20+lymphoma •Favourable efficacy/toxicity ratio • •Mechanism of action –CDC (complement dependent cytolysis) –ADCC (antibody dependent cytotoxicity) –Apoptosis induction –Direct antiproliferative effect C:\Documents and Settings\25540\Dokumenty\Obrázky\ncprheum0424-f1.jpg •Nodal – very similar to FL or SLL •Splenic with/without vilous lymphocytes –Splenomegaly leading symptom –Treatment options: splenectomy • rituximab monotherapy MARGINAL ZONE LYMPHOMAS (MZL) • Extranodal (MALT) FL LN indolent reactive LN LYMPHADENITIS MZL FOLLICULAR LYMPHOMA •MALT – Mucosa associated lymphatic tissuse lymphoma •Etiology: antigen stimulation (H.pylori, Borellia, Chlamydia, HCV…) •Dominating MALT-lymphomas of stomach •Symptoms: „gastric ulceration“ (reccurent or non-healing) MARGINAL ZONE LYMPHOMAS (MZL) extranodal MZL MALT skin MALT gastric MALT- lymphomas (examples) CAVE: gastric MALT or DLBCL are second most frequent tumor of stomach BUT with excelent curability!!! •Limited stage (I and II) •Antibiotics, curative radiotherapy (30Gy) •Generalized stage (III and IV) • treatment like in FL (RCOP/RCHOP) • •IN STAGING IS SPECIFIC: •Multiple biopsy of mucosa (even normally looking) •Helicobacter pylori must be ALWAYS examined MALT- lymphomas treatment principles AGGRESSIVE LYMPHOMAS Prolymphocytic T-cell leukemia Peripheral T-cell lymphoma Angioimunoblastic lymphoma Angiocentric lymphoma Intestinal T-cell lymphoma Anaplastic large T-cell lymphoma Hepatosplenic gd lymphoma Panicullitis like T-cell lymphoma Prolymphocytic B-cell leukemia Multiple myeloma Mantle cell lymphoma Follicular lymphoma (grade III), Diffuse large B-cell lymphoma Primary mediastinal large B-cell lymphoma Burkitt lymphoma T line B line •Some units are curative •Rapid progression with short history •Treatment indicated immediatelly • •An aggressive subtype of lymphoma that typically originates in lymphoid tissues • •The largest subtype of NHL (~ 35%) with about 100,000 new cases per year worldwide • •Clinically and biologically a heterogeneous disease with recent data documenting at least 2 distinct subtypes • •Clinical course is characterized by aggressive, rapid progression and symptoms • •50% long term cure with current standard therapy 46 DIFFUSE LARGE B-CELL LYMPHOMA •Several morphological variants: centroblastic, immunoblastic, anaplastic • •Several subtypes according to WHO 2008 –DLBCL –Primary mediastinal DLBCL –Plasmablastic lymphoma –EBV associated DLBCL in elderly –Primary DLBCL of CNS –T-cell histiocyte rich –Primary cutaneous leg-type –ALK+ anaplastický DLBCL –DLBCL associated with chronic inflamation –Intravascular DLBCL –Primary effusion lymphoma –HHV8 associated DLBCL • 47 DIFFUSE LARGE B-CELL LYMPHOMA 2.10.2020 48 Borderline DLBCL provisional entitty to avoid contamination of „clasical cases of DLBCL or BL high-grade B-lymphoma between BL and DLBCL double hit lymphoma (bcl2+ cmyc) childhood DLBCLwith cmyc BL lacking cmyc Gray zone lymphoma mediastinal lymphoma two morfological and immunophenotype feature B-cell transcriptional programme (BOB1, PAX5, OCT2) activation programme: CD30+ CD15 •CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) was developed empirically over ~ 30 years ago •Doxorubicin & Cyclophosphamide are considered to be essential drugs in high grade lymphomas •R-CHOP is current global standard treatment with significant improvement in PFS and overall survival • 100 80 60 40 20 0 0 5 10 15 CHOP MACOP-B ProMACE-CytaBOM m-BACOD 49 Patients over 60 (LNH98-5) 2002 DLBCL – the global standard care DLBCL GCB Type 3 ~50% ~40% ~10% 1. Alizadeh et al, Nature 2000 2. Davis et al, Exp Med 2001 3. Rosenwald et al, NEJM 2002 4. Hans et al, Blood 2004 5. Ngo et al, Nature 2006 6. Lenz et al, J Clin Oncol 2007 non-GCB (ABC) 50 DLBCL – molecular classification ABC_GCB_R-CHOP Lenz et al, 2008 •GC-DLBCL (germinal center) phenotype –Bcl2, c-myc –Rare mutation in BCR subunits •nonGC (ABC=activated B-cell) phenotype –CARD11, BCL10, MALT1, NF-кB – mutation in BCR receptor subunits (CD79a/CD79b) 51 DLBCL – pathogenesis MANTLE CELL LYMPHOMA •mantle cell lymphoma = lymphoma from „mantle cells“ of lymphatic follicle, CD20+ •Defined as a nosological unit since1992 •6-8 % of all Nonhodgkins´s lymphomas •Typically in older men •Frequent extranodal involvement (>80%cases) –Blood, bone marrow –Gut (multiple lymphomatpus polyposis) • mcl cell Object name is WJG-16-4661-g004.jpg mantle1 CD5+10-19+20+23-79b+sIgDM+sλ+ Diagnosis of MCL can be made by flow from blood and/or bone marrow! Prognosis of MCL (Czech Lymphoma Database) Figure header • Prognosis is poor • New drugs are needed •Chemotherapy has limited efficacy • Targeted therapy • Molecular pathogenesis • t(11;14) is hallmark • cyclinD1 overexpression Cyklin D1 Cyklin D1 E2F RB1 RB1 E2F P P P transition from G1 to S phase of cell cycle Cyklin E > p27 P Degradation p53 ATM ATM mutation Gene instability/ Chromatin interaction/ enzymes modified histones DNA damage MCL- treatment • intensive chemotherapy is recommended R-MaxiCHOP/high dose Arac/ high dose BEAM • transplantation therapy is indicated in younger patients • majority of MCL patients not able to receive intensive treament • new „smart“ drugs (biological agens) focused on BCR signaling are efficace • Ibrutinib, bortezomib, temsirolimus +/- rituximab B-CELL RECEPTOR (BCR) SIGNALING CAL101; idelalisib BCR signaling 2.10.2020 57 Active BCR signaling -Antigen driven -BCR immobile clusters - activation of downstream pathways NF-кB, PI3, MAPkinase - NF-кB activated by BTK -ABC-DLBCL (BTK inhibitor) Tonic BCR signaling - antigen independent, necessary for B-cell survival -BCR freely mobile - namely PI3 pathway - Burkitt lymphoma IBRUTINIB •Ireversibil inhibitor of Bruton´s tyrosinkinase (BTK) •Inhibition of autophosphorylation and phosphorylation by physiological substrate, blocage of phosforylation of PLCγ, ERK (extracelluar signal-regulated kinase),PI3K, NF-κB… •Proliferation inhibition, triggering of apoptosis •Increase resistance to microenvironment signals • C:\Documents and Settings\25540\Dokumenty\Obrázky\ibrutinib.png TEMSIROLIMUS (Torisel®) http://upload.wikimedia.org/wikipedia/commons/e/e4/Temsirolimus.png C:\Documents and Settings\25540\Dokumenty\Obrázky\torisel.jpg •Selective inhibitor mTOR – •protein kinase (mamalian target of rapamycin) •Inhibition mTOR→ cell cycle arrest in G1 and angiogenesis (VEGF) •PI3Kinase/Akt/mTOR pathway –konst. active in MCL • • • – – BURKITT LYMPHOMA •Very rapidly growing; aggressive; high-grade B-cell lymphoma •Rare disease in central Europe –Endemic (Africa, young boys, jaw or facial mass, EBV associated) –Sporadic (any age, abdominal mass) –Epidemic (immunodeficiency associated) – •Different behavior compared to DLBCL •Abdominal symptomatology (intususception, appendicitis-like) •BM and CNS involvement in 30% of cases •Tumor lysis syndrome (!) •CR 80%, long-term survival 50% • – • http://www.ganfyd.org/images/9/93/Burkitt_lymphoma_starry_sky_1.jpg – – BURKITT LYMPHOMA •„Starry sky“ morphology (medium-sized lymphocytes) •WHO recognizes: –Burkitt lymphoma with plasmacytoid differentiation –Atypical Burkitt/Birkitt-like lymphoma –Phenotype: CD10+, bcl6+, bcl2-, CD20+, sIgM+, Ki67≥95% • •t(8;14) ~80% pts •c-myc translocation • •Therapy: intensive chemotherapy •Magrath protocol: R-CODOX-M/R-IVAC –(MTX+ CHOP; high dose AraC + IFO) • – – – PRIMARY CNS LYMPHOMA •Rare type of aggresive lymphoma; about 4% of CNS tumours and about 4-6% of all extranodal lymphoma (1% of all lymphoma) • •Localization: most common in hemispheras (38%), thalamus and basal gangliae (16%), c.calosum (14%) • •Median age 60-65 ys • •Belong to lymphomas with the worst prognosis • (5-year OS 30-50%) • •Histologically: DLBCL in 95% cases 2.10.2020 63 •Symptoms: neurological deficits, epi-paroxysms, amention, lethargy • •Diagnosis: MRI (typical pattern)+ stereotactic biopsy •Corticoids given in antiedematic setting can completely destroy tissue for histological evaluation!!!! • •Treatment: cytostatics must have sufficient level in CSF - high-dose MTX (3g/m2) and AraC (2g/m2) + whole brain radiotherapy (24-36Gy) • • PRIMARY CNS LYMPHOMA – – T-CELL LYMPHOMAS – Nodal •PTCL –NOS peripheral T-cell lymphoma not otherwise specified (25%) •ALCL anaplastic large cell lymphoma (12%) •AITL angioimunoblastic lymphoma (19%) –Extranodal (tissue tropism) •Hepatosplenic γδ lymphoma (1.4%) •Enteropathy associated T-lymphoma (EATL) (5%) •Panniculitis-like T-cell lymphoma (0.9%) –Leukemic •Adult T-cell leukemia, LGL-leukemia, NK-cell leukemia, T-prolymphocytic leukemia T-CELL LYMPHOMA -prognosis 2.10.2020 65 Non-cutaneous T-lymphoma have very poor prognosis • Heterogeneity of units • Too smal populations for clinical trials • Treatment used in B-cell lymphoma is unsuficient •NODULAR LYMPHOCYTE PREDOMINANT –CD20+ –„popcorn“ cells – – HODGKIN´S LYMPHOMAS LymphNode_NodularLymphocytePredominantHodgkinsLymphoma4 clasic m •CLASSICAL M.H. –CD30+, CD15+ –Reed-Sternberg cc. – –Nodular sclerosis –Mixed cellularity –Lymphocyte-rich –Lymphocyte-depleted •SYMPTOMS • •Lymphadenopathy with/without systemic symptoms: • •Fever •Weight loss •Itching •Alcohol-related pain (LN) • •BASIC • •Pathological Hodgkin´s cells (HRS) are derived from B-lymphocytes • •Peaks of incidence around 20 and 60 ys • •Hodgkin´s lymphomas account for 30% of all lymphomas • •Highly curable disease HODGKIN´S LYMPHOMAS •Localised M.H. • 2 x cycle of chemotherapy ABVD • + IF RT 20Gy • •Intermediate M.H. • 2xABVD + 2x BEACOPP escalated • + IF RT 30Gy • •Advanced M.H. • 6 cycles BEACOPP escalated HODGKIN´S LYMPHOMAS – treatment strategy hodgkins-disease-pictures M.Hodgkin - Treatment results (DHG 2001) Effect COPP/ ABVD BEACOP basal BEACOP escalated Complete remission 84 % 88 % 96 % Progression 12 % 8 % 2% 3-ys symptom free survival 72 % 80 % 92 % 3-ys Overall survival 86 % 91 % 92 % CD30 signal pathway D:\Hema\2007\uDec\z13th\Slides\images\nrc2291-f4.jpg •CD30 is expressed – on RS-cells of M.Hodgkin, ALCL, and on primary cutaneous T-lymphomas – – – – – – –Anti CD30 alone is not suficiently efficace! C:\Documents and Settings\25540\Dokumenty\Obrázky\Slide2.jpg Long-term problems related to treatment of Hodgkin´s disease •Increased incidence of secondary malignancies • •Damage of gonadal functions (sterility) • •Long-term adverse events (toxicity) cardiomyopathy, lung fibrosis, myelodysplastic syndrome •Disease damaging (really multiple): • •Bones (pains, fractures) •Kidneys (renal failure, nefrotic syndrome) •Peripheral nerves •Etc….. MULTIPLE MYELOMA - SYMPTOMS Clonal expansion of malignant plasmocyte-derived cells - local infiltration of bone marrow and bones - production of monoclonal Ig Immunofixation and electrophoresis with densitometry (quantification) of monoclonal immunoglobuline • Clinical symptoms of myeloma cells Cytokins inducing osteolysis Osteolytic lesions, or diffuse osteoporosis or both Bone pains Monoclonal Ig: • total molecule •Light chains only! Nephropathy Neuropathy neuropatic pains hypo- i hypercoagulopathy amyloidosis, cold aglutinins Cytopenias B and T immunosupression Fundus paraproteinemicus MM criteria acc. Durie and Salmon, 1975 Big criteria Small criteria 1)Plasmocytoma (histology) 2)Plasmocytes in BM > 30 % 3) M-IgG > 35 g/l, IgA > 20 g/l or light chains in urine > 1g/24h a)10 – 30 % plasmocytes in BM b)M-Ig fewer than under point 3 c)Osteolytic lesions d)Decreased levels of normal Igs: IgM < 0,5 IgA < 1,0 a IgG < 6,0 g/l MULTIPLE MYELOMA •Criteria IMWG 2003 •Monoclonal plasmocytes >10 % biopsy proven plasmocytoma •Monoclonal Ig present in blood and urine •At least dysfunction of one organ • •C – Calcium > 2,8 mmol/l •R - Renal insuficiency (creatinin >176,8 umol/l) •A – Anemia •B – Bone osteolysis • Characteristics of tumor pain Intermitent pain usually back bone Permanent pain Episodic worsening of chronic permanent pain Extremly strong pain during common daily activity: • turning over in bed • during walk · during cough Sch37_02 kopie Bez názvu 5 Symptoms of multiple myeloma 37 36 5BPLUS~1 5A-pluskal CT sternum MR-koro-sternum CT vyšetření:osteolytická ložiska sterna s okrajovou usurací kortikalis MR vyšetření: patrna nádorová aktivita a infiltrace celého sterna obr.3 obr.4 Diferencial diagnostics of back bone pain Lumbago without any radicular iritation 1 month of standard treatment Laboratory and imaging examination ØBack bone pain with radicular iritation ØNight back bone pains ØRapidly worsening pains ØOsteoporosis and back bone pains Patient v remission of multiple myeloma with rapidly worsening of back bone pain irradiating into both legs with muscle atrophy. What´s the cause? X-ray of back bone with no susbstantial pathology explaining the troubles. MRI: Extramedular expansion in L3 and Th8 Nelze FDG-PET: is able to show bone and extrabone myeloma lesions Can monoclonal Ig cause renal failure requiring hemodialysis? Leg oedema in nephrotic syndrome Multiple myeloma - therapy •Conventional chemotherapy – median 3– 4ys •High dose chemotherapy with autologous stem cell transplantation –prolongs median +1,5 y –increases priportion of patients surviving more than 5ys –is a standard procedure for pacients in good condition younger than 65ys •New drugs used in clinical standard care: Thalidomid, bortezomib • Proteasome inhibition •Stabilisation: – CDK inhibitors (p21, P27) ≈ decreasing of proliferation –P53 ≈ apoptosis increasing –Proapoptotic proteins (BAX, BID, BAK) ≈ apoptosis increasing • Increased inhibition of NFкB ≈ apoptosis increasing ≈ proliferation decrease ≈ angiogenesis decrease Beta řetězce bortezomib Proteazom 26S E2 substrát E3 substrát substrát UB Poly - Ubi Multiple myeloma – supportive care •Bisfosfonates •Hemodialsis •Plazmapheresis •Antiinfective therapy, Ig substitution •Anaemia therapy •Radiotherapy •Analgetic therapy • • • Primary AL amyloidosis •Deposits of light chains generally or in selected organs according to „tropism“ of these proteins • •Patients are diagnosed in very advanced stage of disease (heart failure) • •Treatment can remove amyloid deposits, but time is needed (≈ 6 months at least) Changes of tongue DSCN1310