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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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.
• Rare: paraneoplastic syndromes (AIHA, ITP, demyelinisation syndrome, aother neurologic syndromes, nephrotic syndrome.
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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.
• 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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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.
Autoimmune disorders
RA, SLE, dermatomyositis, MCTD, Sjögren´s
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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.
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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4141
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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4242
NHL: staging
• Ann Arbor system as in HL
• early stage: I, II
• late (advanced) stage: III, IV
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4343
NHL - therapy
ChemotherapyRadiotherapy
Surgery
Monoclonal antibodies Autologous HSCT
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4444
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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4545
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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4646
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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4747
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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4848
Rituximab (anti-CD20): structure
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4949
Survival after Rituximab introduction to therapy, population study
Progression-Free Survival (y)
43210
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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5050
Radioimmunotherapy: crossfire
Unlabeld Ab Ab labeled with radioisotope
Illidge et al. Br J Haematol 2000;108:679688
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5151
Radioimunotherapy:
90Y-Ibritumomab tiuxetan (Zevalin®)
EU
20
04
.04
06
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5252
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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5353
9090Y-Ibritumomab TiuxetanY-Ibritumomab Tiuxetan ((Zevalin®), standard indications
Adult patients with relapsing or refractory CD20+ follicular lymphoma (FL)
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5454
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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5555
Aggressive NHL
Characteristics and Current Treatment Options
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5656
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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5757
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 3 cycles LRTor
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 3 cycles LRTor
R-CHOP 6-8 cycles RT
R-CHOP 3 cycles LRTor
R-CHOP 6-8 cycles RT
Nonbulky (10 cm)
Nonbulky (10 cm)
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5858
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5959
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6060
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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6161
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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6262
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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