1 (Malignant) Lymphoma. 2 Malignant lymphoproliferation Def: clonal disease of lymphocyte in various...

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(Malignant) Lymphoma

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Malignant lymphoproliferationDef: clonal disease of lymphocyte in

various stage of onthogenesis

WHO 1999:

Precursor Peripheral

HLNHLALL (B,T) LBL

HL: Hodgkin´s lymphoma, NHL: nonhodgkin´s lymphoma, ALL: acute lymphoblastic leukemia, LBL: lymphoblastic lymphoma

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Thomas HodgkinThomas Hodgkin18321832

„„On Some Morbid On Some Morbid AppearancesAppearancesof the Exorband Glands of the Exorband Glands and Spleen“and Spleen“

.

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Hodgkin´s lymphoma - HL

Bimodal incidence: between 20.-30. and 60.-70. years of age

Pathology: Reed´s-Stenberg´s (RS cells), resp. Hodgkin´s cells

Etiology: unclear, role of EBV not established yet in 80% of RS cells the EBV genom present

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HL - histologic subtypes WHO classification

1. Nodular sclerosis: HL 50-80%

2. Mixed cellularity: HL 20-30%

3. Classic HL lymphocyte rich

4. Classic HL, lymphocyte depletion

5. Nodular HL lymphocyte predominant (paragranuloma)

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HL - histologic subtypes WHO classification

1. Nodular sclerosis: HL 50-80%

2. Mixed cellularity: HL 20-30%

3. Classic HL lymphocyte rich

4. Classic HL, lymphocyte depletion

5. Nodular HL lymphocyte predominant (paragranuloma)

RS- cells

H- cells

Reed- Stenberg cells

Hodgkin´s cells

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Hodgkin´s lymphoma (HL), clinical presentation

Lymphadenopathy +• constitutional symptoms may be present: subfebriles or fever unexplained, weight loss, night swets, breathlessness (dyspnoe), chest pain, sometimes weakness, itching (pruritus), alcohol pain, etc.

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• Rare: paraneoplastic syndromes (AIHA, ITP, demyelinisation syndrome, aother neurologic syndromes, nephrotic syndrome.

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• Rare: paraneoplastic syndromes (AIHA, ITP, demyelinisation syndrome, aother neurologic syndromes, nephrotic syndrome.

• Extremly rare: CNS symptoms due to direct HL

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Assessing adenopathy: Physical examination

Location

Single lymphnode, region

Advanced involvement

Generalized adenopathy

Symetry

Size

Sensitivity

Consistence (texture)

Reaction of the surrounding area

Lymphadenopathy vs. pseudolymphadenopathy

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Lymphatic organsLymphatic organs

Waldeyer´s ring

Lymphnodes

Thymus

Spleen

Bone marrow

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LymphadenopathyLymphadenopathy

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Causes of lyphadenopathyInfections

EBV (IM), CMV, IH, postvaccinal lymphadenitis, adenovirus, VZV, HIV, HTLV-I

Staphylococcus, Streptococcus spec.,TB, atypical mycobacteria, syphilis, cat scratch disease, Chlamydias (lymf. venereum)

Toxoplasmosis, histoplasmosis, coccidiomycosis,

Scrub typhus, filariosis, etc.

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Autoimmune disorders

RA, SLE, dermatomyositis, MCTD, Sjögren´s

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Autoimmune disorders

RA, SLE, dermatomyositis, MCTD, Sjögren´s

Malignant causes

Hematologic: Hodgkin´s, NHL, chronic lymphocytic leukemia (CLL), Waldenström´s disease, some acute leukemias (ALL), systemic mastocytosis.

Metastic cancers: breast, lung, renal, stomach, melanoma etc.

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Frequent causes of adenopathy according to the location

Inguinal (or axillar) adenopathy 1cm: usually benign

Cervical adenopathy: infections, carcinomas (consistency), lymphomas. Sialoadenitis (pseudolymphadenopathy)

Mediastinal adenopathy: lymphomas (mediastinum anterior), sarcoidosis, metastatic cancer

Isolated axillar adenopathy: infection, breast Ca, lymphoma

Isolated inguinal adenopathy (significant): infection (also veneral), lymphoma, metastatic Ca (consistency)

Generalized adenopathy: infection (EBV, HIV, etc.), malignant lymphomas, CLL

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Hodgkin´s lymphoma: making the diagnosis

• Proper history• Physical examination: lymphadenopathy (rubber texture) + - pleural effusion +- splenomegalyLaboratory: ESR elev., may be anemia, lymphopenia, eosinophilia.Biochemistry: may be elevated: LDH, beta2 microglobulin, CRP

Chest X-ray: a mass (bulk) in anterior mediastinum, may be pleural or pericardial effusions

CT scan, PET scan, ultrasonography,Bone marrow examination

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Hodgkin´s lymphoma: making the diagnosis

• Proper history• Physical examination: lymphadenopathy (rubber texture) + - pleural effusion +- splenomegalyLaboratory: ESR elev., may be anemia, lymphopenia, eosinophilia.Biochemistry: may be elevated: LDH, beta2 microglobulin, CRP

Chest X-ray: a mass (bulk) in anterior mediastinum, may be pleural or pericardial effusions

CT scan, PET scan, ultrasonography,Bone marrow examination

HISTOLOGY (LYMPHNODE)

STAGING

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Staging of HL (= staging in NHL)

Ann Arbor system

I: single nodal site or limited single extranodal organ involvement

II. Two or more nodal sites on one side of the diaphragma

III: involvement of both sides of diaphragma. Also spleen or one extranodal limited involvement may be present: IIIS(E)

IV: Diffuse involvement or one or more extranodal sites (organs)

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Staging of HL (= staging in NHL)

Ann Arbor system

I: single nodal site or limited single extranodal organ involvement

II. Two or more nodal sites on one side of the diaphragma

III: involvement of both sides of diaphragma. Also spleen or one extranodal limited involvement may be present: IIIS(E)

IV: Diffuse involvement of one or more extranodal sites (organs)

B symptoms: unexplained fever or subfebriles, weight loss ≥ 10%, swettings (night)

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Treatment of HL

a) Early stage: chemotherapy (ABVD) + radiotherapy involved field (IF)

b) Intermediate stage: chemotherapy ABVD or BEACOPP + radiotherapy IF

c) Late stage: chemotherapy BEACOPP („escalated BEACOPP“)

ABVD: Adriamycin, Blemocyin, Vinblastin, Dakarbazin

BEACOPP: Bleomycin, etoposid, Adriamycin, Cyklofosfamid, Vincristin, Prokarbazin, Prednison

Prognosis: 70 - 90 % cured

Complications: secondary malignancies

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NHL vs. HL

• incidence increasing (with age)

• 30% primarily extranodal

• CNS involvement frequent

• histological and biological variability

• variable prognosis

• stable incidence bimodal

• 99% primary nodal

• CNS involvement very rare

• 5 histol. subtyptypes

•70 - 90% cured

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DeVita et al, eds. Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008; Non-Hodgkin’s Lymphoma Cyberfamily Web site. http://www.nhlcyberfamily.org/types.htm. Accessed November 15, 2009.

What Is NHL?

Neoplastic transformation of normal lymphoid cells residing primarily in lymphoid tissue– Bone marrow (BM)– Lymph nodes– Spleen – Thymus

Encompasses >30 different histologies originating from 3 cell types– B cells – T cells – Natural killer (NK) cells

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Nehodgkin´s lymphomas - ageNehodgkin´s lymphomas - ageincidence v letech 1973 - 1975 incidence v letech 1973 - 1975 ve srovnání s roky 1994 - 1996ve srovnání s roky 1994 - 1996

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Nehodgkin´s lymphomasNehodgkin´s lymphomasIncidence and mortality between 1982 -2001Incidence and mortality between 1982 -2001

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NHL: etiology Not known in general

• Germinal mutations (AT, Wiskot Aldrich, NBS)

• Infection (EBV (+ malárie), H.I.V., HSV-8, HCV, H.pylori, Bor. burgdorferi)

• Chemicals (org. rozpouštědla, barvy na vlasy, chemoterapie)

• Imunosupression (transplantace orgánů)

• Autoimune diseases (SLE, Sjög.sy.)

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NHL: staging

• Ann Arbor system as in HL

• early stage: I, II

• late (advanced) stage: III, IV

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NHL Incidence in the US (2009)

In the US, approximately 65,980 people will be diagnosed with NHL1

Predominates in the 40-70 year-old age group2

– Most common neoplasm in the 20-40 year-old age group

About 452,723 people are currently living with NHL, and an estimated 19,500 people will die of their disease1

– 9th most common cause of cancer death in men– 6th most common cause of cancer death in women

1. Leukemia and Lymphoma Society Web site. http://www.leukemia-lymphoma.org/all_page.adp?item_id= 8965#_moreinfo. Accessed October 16, 2009; 2. Data on file, Celgene.

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Global NHL Incidence (2007)

An estimated 196,298 cases of NHL were diagnosed in men worldwide in 20071*

Approximately 111,126 deaths due to NHL in men occurred worldwide1*

Globally, incidence of NHL has been increasing2

– 150% growth over the past 30 years– Increasing by 4% annually since 1970s– Mortality rate is also rising by ~2% rise per year (exceeded only

by lung cancer in women and malignant melanoma)

*Incidence rates were only reported for top 10 cancer sites in each sex; no data for specific incidence rates in women available.1. American Cancer Society Web site. http://www.cancer.org/downloads/STT/Global_Facts_and_Figures_2007_rev2.pdf. Accessed October 16, 2009; 2. American Cancer Society Web site. http://www.cancer.org/docroot/PRO/content/PRO_1_1_Cancer_Statistics_2009_Presentation.asp. Accessed October 16, 2009.

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Lymphoma Classification

Revised European-American Lymphoma (REAL): – (1990s) the REAL classification, based on immunophenotypic

and genetic features, identifying distinct clinicopathologic NHL entities

World Health Organization (WHO): – (2001) classification, based on the major 3 cell types

WHO: – (Sep 2008) revised classification became available

30 mature B-cell lymphoma subtypes 21 T- and NK-cell lymphoma subtypes 9 precursor B-cell lymphomas/leukemias 5 types of Hodgkin’s lymphoma

Jaffe et al. Blood. 2008;112:4384-4399; Vardiman et al. Blood. 2009;114: 937-951.

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Updated WHO Classification: 2008

B-cell neoplasms

I. Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).

II. Peripheral (“Mature”) B-cell neoplasms. A. B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.B. B-cell prolymphocytic leukemia.C. Lymphoplasmacytic lymphoma/immunocytoma. D. MCL.E. FL.F. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic

tissue (MALT) type.G. Nodal marginal zone B-cell lymphoma ( monocytoid B-cells).H. Splenic marginal zone lymphoma ( villous lymphocytes). I. Hairy cell leukemia.J. Plasmacytoma/plasma cell myeloma.K. DLBCL.L. Burkitt lymphoma.

Jaffe et al. Blood. 2008;112:4384-4399; Vardiman et al. Blood. 2009;114:937-951.

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Updated WHO Classification: 2008 (cont’d)

T-cell and putative NK-cell neoplasms

I. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL.

II. Peripheral T-cell and NK-cell neoplasms.A. T-cell chronic lymphocytic leukemia/prolymphocytic leukemia.B. T-cell granular lymphocytic leukemia.C. Mycosis fungoides/Sézary syndrome.D. Peripheral T-cell lymphoma, not otherwise characterized.E. Hepatosplenic gamma/delta T-cell lymphoma.F. Subcutaneous panniculitis-like T-cell lymphoma.G. Angioimmunoblastic T-cell lymphoma.H. Extranodal T-/NK-cell lymphoma, nasal type.I. Enteropathy-associated T-cell lymphoma.J. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).K. Anaplastic large cell lymphoma, ALK+.L. Anaplastic large cell lymphoma, ALK-.M. Aggressive NK-cell leukemia.

Jaffe et al. Blood. 2008;112:4384-4399.

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WHO Classification of NHL by Disease Course

A. FL (follicular small cleaved cell [Grade 1], follicular mixed small cleaved and large cell [Grade 2], diffuse small cleaved cell)

B. CLL/SLL C. LL (Waldenström’s macroglobulinemia) D. Extranodal marginal zone B-cell lymphoma

(MALT lymphoma)E. Nodal marginal zone B-cell lymphoma

(monocytoid B-cell lymphoma) F. Splenic marginal zone lymphoma (splenic

lymphoma with villous lymphocytes) G.Hairy cell leukemia H. Mycosis fungoides/Sézary syndrome (CTCL) I. T-cell granular lymphocytic leukemia J. Primary cutaneous anaplastic large cell

lymphoma/lymphomatoid papulosis (CD30+) K. Nodular lymphocyte predominant Hodgkin's

lymphoma

A. Diffuse large cell lymphoma (includes diffuse mixed cell, diffuse large cell, immunoblastic, T-cell rich large B-cell lymphoma)

B. Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma

C. Precursor B- or T-cell lymphoblastic lymphoma/leukemia

D. Primary CNS lymphoma E. Adult T-cell leukemia/lymphoma (HTLV 1+) F. MCL G.Polymorphic posttransplantation

lymphoproliferative disorder (PTLD) H. AIDS-related lymphoma I. True histiocytic lymphoma J. Primary effusion lymphoma K. Aggressive NK-cell leukemia/blastic NK-cell

lymphoma L. B- or T-cell prolymphocytic leukemia

Indolent Aggressive

CTCL=cutaneous T-cell lymphoma; CNS=central nervous system.Jakić-Razumović et al. Croat Med J. 2002;43:527-534; DeVita et al, eds. Cancer Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2008.

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Nonhodgkin lymphoma

B Tnull

indolent agressive indolent agressive

FL, CLL DLBCL MF PTCL,SS

CNS

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WHO classification: indolent B NHL

• SLL/CLL

• lymphoplasmocytic lymfom (immunocytoma)/ W. makroglobulinemia

• marginal zone lymphomas

Nodal (monocytoid B) Extranodal

MALT

SLVL (splenic lymphoma with vilous lymphocytes)

• FOLLICULAR LYMPHOMA

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WHO classification: aggressive B NHL

• Difuse large B cell lymphoma (DLBL)

Histol. variants• imunoblastic

• plasmablastic

• anaplastic

Clin. subtypes• primary mediastinal

• primary with effusion

• Burkitt´s lymphoma

• Lymphoblastic lymphoma

• Mantle cell lymphoma (MCL)

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WHO classification NHL: T NHL

• Mycosis fungoides

• Peripheral Tcell lymphoma (PTCL)

• Sézary´s syndrome

• Anaplastic large cell Alk1 + (T/null)

• Rare T cell lymphomas (hepatosplenic ,

angiocentric)

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NHL: staging

• Ann Arbor system as in HL

• early stage: I, II

• late (advanced) stage: III, IV

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NHL - therapy

ChemotherapyRadiotherapy

Surgery

Monoclonal antibodies Autologous HSCT

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NHL: treatment - overwiew

• Histology, stage andf risk factor assessment crucial

• SLL/CLL: fludarabine + cyclophosphamide + Rituximab (anti CD20) - FCR,

• Follicular lymphoma: CHOP + Rituximab (R-CHOP) or R-COP

• DLBCL: CHOP + Rituximab , in risk types: escalated form of CHOP („MegaCHOP“) or time intensification: R-CHOP 14

•MCL: „Nordic protocol“´(R-CHOP + HD ARA-C + AutoHSCT)

•Burkitt´s: prostocols with high dose metothrexate

• Lymphoblastic lymphoma: as acute lymphoblastic leukemia

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NHL: treatment, overview II

• CHOP: Cyklofosfamid, Adriamycin, Vincristin, Prednison

• Rituximab: monoclonal antibody anti - CD20

• Prognosis: different, dependent on histol. subtype + risk factors f

• 70% patients with DLBCL and low risk factors 5 years survival

• 20% of patients with DLBCL and low risk factors 5 years survival.

Relaps of DLBCL: R- ESHAP + autologous HSCT

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Rituximab (MabThera®) antiCD20 chim.

Ofatumumab antiCD20 hum.

Alemtuzumab (MabCampath®) antiCD52 hum.

Y-90 Ibritumomab Tiuxetan antiCD20 chim. (Zevalin®) labeled

Gemtuzumab ozogamicin antiCD33 hum.

conjug.(Mylotarg®)

Monoclonal antibodies in the treatment of hematological malignancies

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AAntigenntigen CD20 CD20

Hydrofobic phosphoprotein, ~35kd, 167 AMK

Present in 93% B-NHL

Function: Ca channel + cell cyle involvement

Not on early precurors (pro-B) and on plasma cells.

Ref. Einfeld, D.A. 7(3) EMBO Journal 711 (1988)

Cytoplasm

LC1

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Rituximab (anti-CD20): structure

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Survival after Rituximab introduction to therapy, population study

Progression-Free Survival (y)

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Perc

ent

Surv

ival

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

log rank p=0.0009

Pre-Ritux

Post-Ritux

2-year OS

Pre Post

53% 77%

<60 y 69% 87%>60 y 40% 67%

All statistically significant

LH Sehn, ASH 2003 Abst. 88

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Radioimmunotherapy: crossfire

Unlabeld Ab Ab labeled with radioisotope

Illidge et al. Br J Haematol 2000;108:679688

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Radioimunotherapy:

90Y-Ibritumomab tiuxetan (Zevalin®)

EU

20

04

.04

06

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9090Y-Ibritumomab TiuxetanY-Ibritumomab Tiuxetan 9090Y-Ibritumomab TiuxetanY-Ibritumomab Tiuxetan

IbritumomabIbritumomab– murinemurine mono monoclonal Ab clonal Ab

antiCD20 similar to antiCD20 similar to rituximabrituximab

Tiuxetan (MX-DTPA)Tiuxetan (MX-DTPA)– Responsible for Responsible for

valence of valence of 9090YY

9090Y radionuY radionuclideclideBeta Beta raysrays

ChelatorChelator

MonoMonoklon.klon. Ab.Ab.

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9090Y-Ibritumomab TiuxetanY-Ibritumomab Tiuxetan ((Zevalin®), standard indications

Adult patients with relapsing or refractory CD20+ follicular lymphoma (FL)

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Principles of autologous hematopoietic stem cell transplantation

HSC harvest Myeloablative therapy

HSC reinfusion - transplantation

Bone marrow PBSC (mobilization)

freezing

Thaw of the HSCT

In vitro purging??

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Aggressive NHL

Characteristics and Current Treatment Options

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Diffuse Large B-Cell Lymphoma (DLBCL)

Most common type of “aggressive” lymphoma

Usually symptomatic with an aggressive disease course

Extranodal involvement is common

Two primary histologic subtypes: germinal center B cell like (GCB) and non-GCB

Curable in ~40-50%

Friedberg JW, et al. Non-Hodgkin’s lymphoma. In: DeVita VT, et al, eds. Cancer: Principles and Practice of Oncology, v2. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:2278-2292; Friedberg JW, et al. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008; 22(5): 941–ix.

Although the general cell type is large (defined as having a nucleus larger

than that of a macrophage or endothelial cell), there is considerable

variation in cell size and shape.

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NCCN Treatment Guidelines for First-Line Treatment of DLBCL in the US

NCCN=National Comprehensive Cancer Network; LRT=localized radiotherapy.NCCN Web site. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed October 16, 2009.

Stage III, IVStage III, IV R-CHOP 6-8 cycles or clinical trial

R-CHOP 6-8 cycles or clinical trial

R-CHOP 3 cycles LRTor

R-CHOP 6-8 cycles LRT


R-CHOP 6-8 cycles LRT

Stage I, IIStage I, II

R-CHOP 6-8 cycles LRTR-CHOP 6-8 cycles LRT

Adverse risk factors not

present

Adverse risk factors not

present

Adverse risk factors presentAdverse risk

factors present

Bulky (10 cm)

Bulky (10 cm)


R-CHOP 6-8 cycles RT


R-CHOP 6-8 cycles RT

Nonbulky (10 cm)

Nonbulky (10 cm)

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Candidate for High-Dose Therapy

(HDT)

Candidate for High-Dose Therapy

(HDT)

Rel/Ref DLBCLRel/Ref DLBCL

Not Candidate for HDT

Not Candidate for HDT

NCCN Treatment Guidelines for Treatment of Rel/Ref DLBCL in the US

Suggested 2nd-Line Regimens

Clinical TrialRituximabCEPP R

PEPCEPOCH R

Clinical TrialRituximabCEPP R

PEPCEPOCH R

DHAP RESHAP R

GDP RGemOx R

ICE RminiBEAM R

MINE R

DHAP RESHAP R

GDP RGemOx R

ICE RminiBEAM R

MINE R

Rel/Ref=relapsed/refractory; HDT=high-dose therapy.NCCN Web site. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed October 16, 2009.

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Mantle Cell Lymphoma (MCL)

Accounts for ~7% of adult NHL in the US and Europe

Characterised by the presence of the t(11,14)(q13;q32) translocation that results in overexpression of cyclin D1

70% of patients are in stage IV at diagnosis

Cell of origin: antigen-naïve peripheral B cell of the inner mantle zone

Not curable like indolent NHL, but with an aggressive disease course

DeVita et al. DePinho et al, eds. Cancer: Principles and Practice of Oncology Review. 8th ed. Philadelphia, PA. Lippincott Williams & Wilkins; 2008: 2008; http://pleiad.umdnj.edu/~dweiss/mantle/mantle_img.html. Accessed November 16, 2009.

The lymphoid nuclei are irregular. Traditionally they are described as “angulated.” In fact here the degree of indentation approaches what is seen in a different type of cell, the small-cleaved cell. In the center is a histiocyte with eosinophilic, granular cytoplasm, which is characteristic of many cases of MCL.

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CHOP R*R-HyperCVAD†

R EPOCHNORDIC regimen

Cladribine R[Any of the above RT]

CHOP R*R-HyperCVAD†

R EPOCHNORDIC regimen

Cladribine R[Any of the above RT]

NCCN Treatment Guidelines for First-Line Treatment of MCL in the US

RT=radiotherapy.*In selected older patients who cannot tolerate more intensive therapy.; †Modified HyperCVAD in patients >65 years of age. NCCN Web site. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed October 16, 2009.

Stages I, II (localized

presentation, extremely rare)

Stages I, II (localized

presentation, extremely rare)

Clinical trialClinical trial

Observation only in highly selected cases

Observation only in highly selected cases

Stages III, IVStages III, IV

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1 (Malignant) Lymphoma. 2 Malignant lymphoproliferation Def: clonal disease of lymphocyte in various...

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