Malignant Lymphomas Janikova A et al 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 to be made • •Basic overview of disorders – nosological units, treatment , prognosis • • •For hematology specialists: •Recent optimal treatment algoritms CANCER INCIDENCE CZECH REPUBLIC 2016 (men; ÚZIS) 3.8% CANCER INCIDENCE IN CZECH REPUBLIC 2016 (women; ÚZIS) 3,5% 9789283224310 Overview of hematological malignancies •WHO classification of Haematopoietic and Lymphoid system (last update 2018) • -separated system from ICD (MKN) • •Hematological malignancies are derived: •from lymphoid cell-line •from myeloid cell-line •from histiocytic cell-line •from monocytoid- macrofagocytic • system • SURVIVAL OF PATIENTS WITH HEMATOLOGICAL MALIGNANCIES -world data Image result for lymphoma survival LYMPHOPROLIFERATIONS = malignancies from lymphoid tissue •WHO 2018 > 60 nosological units •LYMPHOMAS –Hodgkin lymphoma (Hodgkin´s lymphogranuloma) ~30% •Classical (~95%) •Nodular lymphocyte predominant (~ 5%) –NonHodgkin´s lymphomas (NHL) ~70% •B-NHL (~90%) •T-NHL (~10%) •LYMPHOCYTIC LEUKEMIAS –B-line: B-CLL, Hairy cell, prolymphocytic leukemia –T-line: T-prolymphocytic leukemia, T-LGL, adult T-cell leukemia •MULTIPLE MYELOMA • 29.3.2020 8 ETHNICAL DIFFERENCES IN LYMPHOID NEOPLASM DISTRIBUTION CLINICAL SYMPTOMS OF MALIGNANT HEMATOLOGICAL DISEASES • •We can recognise: • •Systemic (General) symptoms •Symptoms of local expansion –Nodal –Extranodal • •GENERAL SYMPTOMS •(the most frequent) • •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 (with or without skin lesions) 1. •NIGHT SWEAT (need to change clothes/pyjama during sleeping) 1. •FATIGUE (pathological tiredness interfering with usual daily activity) • SYMPTOMS OF LOCAL EXPANSION •NODAL: •Peripheral (palpable) lymphadenopathy: –„lumps“ •Mediastinal lymphadenopathy: –irritative dry cough, feeling of pressure, vena cava superior syndrom •Abdominal lymphadenopathy: –stomach and intestinal dyspepsia, hydronephrosis due to uretheral compression. •Splenomegaly: –enlarged spleen compressing stomach, feeling of fullness after small meal • •EXTRANODAL: •Bone marrow infiltration: (pan)cytopenia •Osteolytic destruction of bones: pain (backbone), pathol. fractures •Organ specific symptoms: ~30% primary extranodal lymphomas –mimicking relevant carcinoma (different therapy approach!) 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 •Histology subtype •Performance status (according to ECOG/WHO) •Laboratory examination •Extent of disease = clinical stage • • •Imaging (CT±PET ev. MRI±PET) –CT usually „gold standard“ •Bone marrow examination (trephine biopsy) –Not necessary in some lymphomas PROGNOSIS OF PATIENT WITH MALIGNANT LYMPHOMA IS BASED ON: image PET 2 STAGING: FDG-PET (18Fluordeoxyglucose -positrone emission tomography) FDG-PET – BUT, what can we really see??? Be cautious with the interpretation of PET scan! 29.3.2020 24 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 descovered by FDG-PET 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) Limited stages: I and II Advanced stages: III a IV vs. WHY IS IMPORTANT TO KNOW STAGE (~EXTENT) OF THE LYMPHOMA? •TREATMENT STRATEGY DEPENDS ON THE STAGE IN THE MOST LYMPHOMA SUBTYPES! • •EXTENT OF DISEASE DYNAMICS IS USED FOR RESPONSE EVALUATION IF-RT- based / IF-RT containing therapy Systemic therapy (immuno-, chemo-, or immunochemotherapy) MALIGNANT LYMPHOMAS - GENERAL SURVIVAL C:\Documents and Settings\25540\Dokumenty\Obrázky\83446.gif Low agressive (indolent) •slow growth •usually incurable (relapses) •start of treatment in symptoms Aggressive/ high aggressive •rapid progression •BUT several categories potentially curable •start of treatment the earliest possible •Clinical behavior (aggressive vs. indolent) is an important factor for therapy decision •Irrespective of the lymphoma subtype 29.3.2020 29 C:\Documents and Settings\25540\Dokumenty\Obrázky\3160411_1471-2407-11-321-2.png B-NHL (~90% of NHLs): MCL – mantle cell lymphoma BL – Burkitt lymphoma DLBCL- diffuse large B-cell lymphoma FL –follicular lymphoma MALT- mucosa associated lymphoma tissue lymphoma T-NHL (~10% of NHLs): ENKTL –extranodal NK/T lymphoma EATL- enteropathy associated lymphoma PTCL U –peripheral T-cell lymphoma (unspecified) OVERALL SURVIVAL OF SELECTED NONHODGKIN LYMPHOMA SUBTYPES MALIGNANT LYMPHOMAS (overview of clinically important subtypes) 29.3.2020 30 •HODGKIN LYMPHOMAS (~30% of lymphomas) CLASSICAL (~95% of Hodgkin lymphoma) NODULAR LYMPHOCYTE PREDOMINANT •NON-HODGKIN LYMPHOMAS (~70% of lymphomas) B-CELL LYMPHOMAS (~90% of NHLs) DLBCL (DIFFUSE LARGE B-CELL LYMPHOMA; 40% NHLs) BURKITT LYMPHOMA (1% of NHLs) FOLLICULAR LYMPHOMA (20% of NHLs) MZL (MARGINAL ZONE LYMPHOMA; 10%of NHLs) MCL (MANTLE CELL LYMPHOMA; ~7% of NHLs) PCNSL (PRIMARY CNS LYMPHOMA; ~1%) T-CELL LYMPHOMAS (~10% of NHLs) ALCL (ANAPLASTIC LARGE CELL LYMPHOMA) PTCL-NOS (PERIPHERAL T-CELL LYMPHOMA, NOS) AITL (ANGIOIMMUNOBLASTIC LYMPHOMA) •NODULAR LYMPHOCYTE PREDOMINANT •CD20+ •„popcorn“ cells – – HODGKIN LYMPHOMAS clasic m •CLASSICAL HODGKIN •CD30+, CD15+ •Reed-Sternberg cc. • •Nodular sclerosis •Mixed cellularity •Lymphocyte-rich •Lymphocyte-depleted LymphNode_NodularLymphocytePredominantHodgkinsLymphoma4 RS cells ~ derived from thymic B-lymphocytes Peaks of incidence: 20-30yrs (75%), 60-80yrs (25%) Symptoms similar like in NHLs with one exception: Alcohol-related pain (10-15% pts) •Localised disease: 2x cycle ABVD+ IF RT 20Gy •Intermediate disease: 2x ABVD+ 2x BEACOPP escalated+ IF RT 30Gy •Advanced disease: 6x BEACOPP escalated •HODGKIN LYMPHOMA: highly curable disease (80-85%) • •IF RT: involved field radiotherapy •BEACOPP ESCALATED –bleomycin, etoposid, adriamycin, – cyklofosfamid, vinkristin, prokarbazin, – prednison •ABVD –adriamycin, bleomycin, vinblastin, – dacarbazin • • HODGKIN LYMPHOMAS – TREATMENT B-NONHODGKIN LYMPHOMA •90% of NHLs •Expression of CD19+, CD20+ •Anti-CD20 based therapy • •B-cell receptor (BCR) signaling pathway –ibrutinib –idelalisib • •Microenvironment –lenalidomid •Aggressive B-NHL –DLBCL – Burkitt • •Indolent B-NHL –Follicular lympoma –Marginal zone lymphoma –Mantle cell lymphoma 29.3.2020 33 Anti CD20 monoclonal antibody Rituximab – Mabthera®, Rituxan® •Chimeric humanized IgG1 •CD20 receptor on surface • of nearly all B-lymphoid cells •including malignant lymphocytes •R is standard component of • treatment of B-lymphomas •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 BCR (B-CELL RECEPTOR) SIGNALING 29.3.2020 35 Active BCR signaling -Antigen driven -BCR immobile clusters - activation of NF-кB, PI3, MAPk -NF-кB activated by BTK -ABC-DLBCL Tonic BCR signaling -Antigen independent -essential for B-cell survival -BCR freely mobile - namely PI3 pathway - Burkitt lymphoma •An aggressive subtype of NHL (~ 35-40% of NHLs) •Median age at diagnosis around 60yrs •Clinically and biologically heterogeneous disease •Recently identified at least 2 distinct subtypes („GCB“ vs. „ABC“) •Clinical course usually with aggressive, rapid progression •50% long term cure with current standard therapy (R-CHOP) •CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) developed empirically ~ 40 years ago, R-CHOP is current global standard •Doxorubicin & Cyclophosphamide essential drugs in high grade lymphomas • • 36 DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) Patients over 60 (LNH98-5) 2002 100 80 60 40 20 0 0 5 10 15 CHOP MACOP-B ProMACE-CytaBOM m-BACOD 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) 37 DLBCL – MOLECULAR CLASSIFICATION ABC_GCB_R-CHOP Lenz et al, 2008 GCB (germinal center) phenotype: Bcl2, c-myc Rare mutation in BCR subunits ABC( = activated B-cell) phenotype CARD11, BCL10, MALT1, NF-кB mutation in BCR subunits •Morphological variants: –centroblastic, immunoblastic, anaplastic • •DLBCL subtypes according to WHO 2008 –DLBCL, NOS –Primary mediastinal DLBCL –Plasmablastic lymphoma –EBV associated DLBCL in elderly –Primary DLBCL of CNS –T-cell histiocyte rich –Primary cutaneous leg-type –ALK+ anaplastic DLBCL –DLBCL associated with chronic inflamation –Intravascular DLBCL –Primary effusion lymphoma –HHV8 associated DLBCL –DLBCL myc+bcl2+ • 38 DIFFUSE LARGE B-CELL LYMPHOMA Borderline DLBCL: DLBCL/BL Gray zone lymphoma: DLBCL/Hodgkin – – PRIMARY CNS LYMPHOMA •Rare type of aggressive lymphoma –about 4% of CNS tumours –about 1% of all lymphoma •Localization: –common in hemispheras (38%) –Thalamus/basal gangliae (16%) –c.calosum (14%) • •Median age 60-65 ys • •PCNSL (5-year OS 30-50%) • •Histologically: DLBCL in 95% cases 29.3.2020 40 • Symptoms: neurological deficits, epi-paroxysms, amention, lethargy • • Diagnosis: MRI (typical pattern) + stereotactic biopsy • !Corticosteroids! give in antiedematic setting NOT BEFORE BIOPSY, corticoids can completely destroy lymphoma tissue for histological evaluation!!!! • • Treatment: cytostatics with ability to cross blood-brain barrier and have sufficient level in CSF - high-dose MTX (~3g/m2) and high-dose AraC (~2g/m2) + whole brain radiotherapy (36-46 Gy) • • PRIMARY CNS LYMPHOMA – – 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 related) –Sporadic (any age, usually abdominal mass) –Epidemic (immunodeficiency associated) – •Different behavior (and therapy) compared to DLBCL •„Starry sky“ morphology (medium-sized lymphocytes) –Phenotype: CD10+, bcl6+, bcl2-, CD20+, sIgM+, Ki67≥95%, –t(8;14) in 80% cases, c-myc translocation • •Abdominal symptomatology (intususception, appendicitis-like) •BM and CNS involvement in 30% of cases •Tumor lysis syndrome (spotaneous!) –hyperuricaemia, extremelly elevated LDH •Therapy: highly intensive chemo: CR 80%, long-term survival 50% • – • BASIC CHARACTERISTICS OF LOW AGGRESSIVE B-NHLs (FL, MZL, SLL,..) • Overall survival even without treatment in years to 10 ys • • Radiotherapy (IF RT) can have a curative effect in stage I or II • • • Advanced stages (III/IV) are chemosensitive but generally • incurable because of reccurent disease • •Chemotherapy-based (CHT) therapy is indicated in symptomatic cases or in large mass • • • Transformation into more aggressive and resistant lymphoma • in 10-60% patients during course of disease 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, • BUT up to 20% dies during 2 years since diagnosis • •FL is considered incurable with exception of localised (limited stages I/II ~ 10-20% FL patients) • •Cause of death – treatment toxicity and transformation (~25-60%) to more aggressive NHL •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 (and other indolent B-NHLs): 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 •Indolent B-NHLs •Nodal – very similar to FL •Splenic with/without vilous lymphocytes –Splenomegaly leading symptom –Treatment options: splenectomy • rituximab monotherapy MARGINAL ZONE LYMPHOMAS (MZLs) • Extranodal (MALT) FL LN indolent reactive LN LYMPHADENITIS MZL FOLLICULAR LYMPHOMA •Subtype of MZL •Etiology: antigen stimulation (H.pylori, Borellia, Chlamydia, HCV…) •MALT-lymphoma of stomach –symptoms: „gastric ulceration“ (reccurent or non-healing) –Helicibacter pylori •MALT lymphoma of conjunctiva –chlamydia •MALT lymphoma of skin –Borelia infection MALT: MUCOSA ASSOCIATED LYMPHATIC TISSUE LYMPHOMA extranodal MZL •Limited stage (I and II) –Antibiotics, curative radiotherapy (30Gy) • •Generalized stage (III and IV) –treatment like in FL (RCOP/RCHOP) • •REMARKS: •Multiple biopsy of mucosa (even normally looking) •Helicobacter pylori must be ALWAYS examined MALT lymphomas: treatment principles MANTLE CELL LYMPHOMA •Mantle cell lymphoma = lymphoma from „mantle cells“ of lymphatic follicle •6-8 % of all Nonhodgkins´s lymphomas •B-NHL (CD20+) •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 generally poor • New drugs are needed •Chemotherapy has limited efficacy • Targeted therapy antiCD20 •New drugs (ibrutinib) • 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 if possible 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 • •rituximab in induction and in maintenance improved MCL prognosis • new „smart“ drugs (biological agens) focused on BCR signaling are promissing •Ibrutinib, bortezomib, temsirolimus +/- rituximab – – T-CELL LYMPHOMAS – Nodal •PTCL, NOS: peripheral T-cell lymphoma not otherwise specified (25-36%) •ALCL: anaplastic large cell lymphoma (12-29%) •AITL: angioimunoblastic lymphoma (7-19%) –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 29.3.2020 54 Non-cutaneous T-lymphoma have very poor prognosis • Heterogeneity of units/ smal populations for clinical trials • Treatment used in B-cell lymphoma (CHOP) is insufficient • CHOEP (CHOP+ etoposide) better than CHOP • CD30+ T-cell lymphoma can be treated with brentuximab vedotin •CD30 is expressed: – on RS-cells of M.Hodgkin – on ALCLs –on primary cutaneous T-lymphomas –on some PTCL NOS and AITL – – – – – – –Anti CD30 alone is not suficiently efficace! CD30 signal pathway D:\Hema\2007\uDec\z13th\Slides\images\nrc2291-f4.jpg C:\Documents and Settings\25540\Dokumenty\Obrázky\Slide2.jpg Long-term problems related to treatment of Hodgkin´s disease •Typically ~10yrs or more since end of therapy •Chemotherapy/radiotherapy •Increased general incidence of secondary malignancies –More then 10-times • •Damage of gonadal functions (sterility) • •Long-term adverse events (toxicity) –cardiomyopathy –lung fibrosis –myelodysplastic syndrome