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Incidence of lymphoid neoplasms by subtype and race, 1992-2001. Blood 2006;107:265. CHRONIC LYMPHOCYTIC LEUKEMIA. 25-30% of all leukemia in Western Hemisphere Rare at age < 40; incidence rises with age B-cell phenotype

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Incidence of lymphoid neoplasms by subtype and race, 1992-2001


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chronic lymphocytic leukemia
CHRONIC LYMPHOCYTIC LEUKEMIA

25-30% of all leukemia in Western Hemisphere

Rare at age < 40; incidence rises with age

B-cell phenotype

About half of cases resemble “naïve” B-cells, half have post-germinal center phenotype with mutated Ig Vh gene

Unmutated Ig Vh gene associated with worse prognosis

Dx: persistent, absolute lymphocytosis in blood & marrow

Confirm clonal B-cell population via flow cytometry

Most patients have diffuse lymph node involvement

slide4

CHRONIC LYMPHOCYTIC LEUKEMIA

Smudge cell

Blood smear

Nodular marrow infiltration

Packed marrow

chronic lymphocytic leukemia5

COMPLICATIONS

CHRONIC LYMPHOCYTIC LEUKEMIA

Constitutional symptoms (fatigue)

Anemia, thrombocytopenia

Progressive lymph node enlargement

Other organ infiltration

Infection (bacteria, fungi, zoster, Pneumocystis)

Autoimmune hemolysis/thrombocytopenia

Transformation to aggressive lymphoma

Other solid tumors (skin, lung, GI most common)

chronic lymphocytic leukemia treatment options
CHRONIC LYMPHOCYTIC LEUKEMIATreatment options
  • Chlorambucil (25-35% overall response, 2-10% CR)
  • Cytoxan, vincristine, prednisone (CVP)
  • Nucleoside analogs (fludarabine, cladribine)
    • Response rates higher than chlorambucil but overall survival similar; somewhat more toxic
  • Rituximab, other immunotoxins
  • More aggressive chemotherapy for refractory disease
  • IVIG for hypogammaglobulinemic patients with recurrent infection
  • No advantage to treating asymptomatic disease
slide8

Fludarabine Compared with Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia

NEJM 2000;343:1750

Event-free survival

Overall survival

slide9

Fludarabine Compared with Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia

NEJM 2000;343:1750

slide10

FLUDARABINE WITH SEQUENTIAL OR CONCURRENT RITUXIMAB IN PREVIOUSLY UNTREATED, SYMPTOMATIC CLL

Blood 2003;101:6

Event free survival

Overall survival

non hodgkins lymphoma

BIOLOGY

NON-HODGKINS LYMPHOMA

Often associated with chromosome translocations linking oncogene with immunoglobulin gene (B-cell phenotypes) or T-cell receptor gene (T-cell phenotypes)

Etiology:

EBV, HTLV-1

Immunodeficiency states

Environmental (pesticides, etc)

Familial predisposition

non hodgkins lymphoma13

CLASSIFICATION

NON-HODGKINS LYMPHOMA

"Favorable" (indolent)

Intermediate

High-grade (aggressive)

non hodgkin s lymphoma

INFORMATION USED IN CLASSIFICATION

NON-HODGKIN'S LYMPHOMA

Morphology

Immunohistochemistry

Immunophenotype (flow cytometry)

Cytogenetics

Molecular features (gene expression, etc)

Clinical setting

Pattern of spread

slide15

Low-grade non-Hodgkin’s lymphomas

Small lymphocytic lymphoma/CLL

Follicular lymphoma

slide16

Intermediate- and high-grade non-Hodgkin’s lymphomas

Large B-cell lymphoma

Burkitt’s lymphoma

non hodgkins lymphomas

"FAVORABLE" SUBTYPES

NON-HODGKINS LYMPHOMAS

Follicular (nodular) or diffuse histology

Small, well-differentiated cells or small cleaved cells

Primarily B-cell phenotype

Slow growth

Usually advanced stage at presentation

Asymptomatic patients may not need Rx

Often good response to initial treatment

High relapse rate (? incurable) but prolonged survival possible

follicular lymphoma
FOLLICULAR LYMPHOMA
  • About 20% of all non-Hodgkin’s lymphoma
  • Median age about 60; rare in young people
  • Usually presents with widespread disease
    • <20% stage I, 50% stage IV; 40-50% have marrow involvement
  • Typically CD20+, CD5-, CD10+
  • t(14;18), overexpression of BCL-2 oncogene
survival in follicular lymhoma
SURVIVAL IN FOLLICULAR LYMHOMA

J Clin Oncol 23:5019-5026

non hodgkins lymphoma treatment options for low grade disease
NON HODGKINS LYMPHOMATreatment options for low grade disease
  • Low dose alkylators (chlorambucil)
  • Cytoxan, vincristine, prednisone (CVP)
  • Nucleoside analogs (fludarabine, cladribine)
  • Rituximab, other immunotoxins
  • Local XRT
  • More aggressive chemotherapy/ABMT for refractory/transformed disease
  • No advantage to treating asymptomatic disease
slide22

Immediate treatment vs watchful waiting in asymptomatic patients with advanced stage low-grade NHL

Lancet 2003;362:516

non hodgkins lymphomas24

INTERMEDIATE SUBTYPES

NON-HODGKINS LYMPHOMAS

Diffuse histology (> 90%)

Large cells or small cleaved cells

B-cell or T-cell phenotype

Moderate growth rates

May present in extranodal sites

40-50% curable with combination chemotherapy

diffuse large cell lymphoma
Diffuse large cell lymphoma
  • About 30% of NHL
  • Median age about 65; can occur in young people
  • About equal proportions of localized and disseminated disease at presentation. Often involves extranodal tissue
  • CD20+
  • t(14;18), t(8;14), t(3;14)
  • Oncogenes: BCL-2, C-MYC, BCL-6
slide27

Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for Advanced Non-Hodgkin's Lymphoma

NEJM 1993;328:1002

Time to treatment failure

Overall survival

slide28

CHOP vs CHOP + rituximab in elderly patients with large B-cell lymphoma

J Clin Oncol 2005;23:4117

Event-free survival

Overall survival

slide29

Event-free survival

All patients

“High intermediate” risk pts

Initial Treatment of Aggressive Lymphoma with High-Dose Chemotherapy and Autologous Stem-Cell Support

N Engl J Med 2004;350:1287

non hodgkins lymphoma30

AGGRESSIVE SUBTYPES

NON-HODGKINS LYMPHOMA

Blastic morphology

"small non-cleaved" = Burkitt's

lymphoblastic

Propensity for marrow, blood, CNS involvement

Rapid growth

Cure possible with aggressive combination chemotherapy

burkitt lymphoma
BURKITT LYMPHOMA
  • <1% of NHL
  • Median age 31; some cases in children
    • Same as L3 ALL
  • Most present with localized disease, about 40% with disseminated disease. Extranodal involvement common (up to 80% of pts)
  • Very fast-growing, most have high LDH
  • CD20+, CD10+, CD5-, tdT-
  • t(8;14), t(2;8), t(8;22) with overexpression of C-MYC
non hodgkins lymphoma survival vs time
NON-HODGKINS LYMPHOMA: SURVIVAL VS TIME

100

% SURVIVING

INTERMEDIATE & HIGH GRADE

LOW GRADE

0

10 yrs

survival patterns in nhl 1
Survival patterns in NHL - 1

ALCL, anaplastic large T/null-cell lymphoma; MZ, MALT, marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; FL, follicular lymphoma

Blood 1997;89:3909-3918

survival patterns in nhl 2
Survival patterns in NHL - 2

MZ, nodal, marginal zone B-cell lymphoma of nodal type; LP, lymphoplasmacytoid lymphoma; SL, small lymphocytic lymphoma

Blood 1997;89:3909-3918

survival patterns in nhl 3
Survival patterns in NHL - 3

Med LBC, primary mediastinal large B-cell lymphoma; DLCBL, diffuse large B-cell lymphoma; HG, BL, high-grade B-cell Burkitt-like lymphoma

Blood 1997;89:3909-3918

survival patterns in nhl 4
Survival patterns in NHL - 4

T-LB, precursor Tlymphoblastic lymphoma; PTCL, peripheral T-cell lymphoma; MC, mantle cell lymphoma.

Blood 1997;89:3909-3918

slide38

HODGKIN’S DISEASE

Cervical lymphadenopathy

Hilar and mediastinal lymphadenopathy

slide39

Hodgkin’s disease: Reed-Sternberg cell (blue arrow) and Hodgkin’s cell (red arrow) in marrow biopsy

hodgkin s disease

NEJM 2003; 349:1324

EPIDEMIOLOGY

HODGKIN'S DISEASE

Annual incidence in US: 5-7 cases/100,000 persons

Median age approx 30 yrs

Bimodal age distribution

More common in upper socioeconomic strata

Role of EBV in pathogenesis

hodgkin s disease42

BIOLOGY

HODGKIN'S DISEASE

Virtually all cases originate in lymph nodes

Most present with supradiaphragmatic disease

Initial spread to adjacent node groups

Immune response to tumor

Non-malignant lymphocyte infiltration

Fibrosis/sclerosis

Constitutional signs

hodgkin s disease43

STAGING

HODGKIN'S DISEASE

I - single node or group of contiguous nodes

II - two node groups, same side of diaphragm

III - nodes (or spleen), both sides of diaphragm

IV - extranodal (other than by direct extension)

(liver, marrow, lung most common)

"B" symptoms: fever, weight loss, night sweats

slide44

HODGKIN’S DISEASE

Potential sites of lymphatic spread

hodgkin s disease45

TREATMENT

HODGKIN'S DISEASE

Stage I or IIA: radiotherapy or combined modality (chemo + local XRT)

Stage IIB or greater: combination chemotherapy (ABVD, etc)

Bulky tumors may require both modalities

Cure rates > 70-80% possible

slide48

Long-term cause-specific mortality in patients treated for Hodgkins disease

J Clin Oncol 2003;21:3431

plasma cell dyscrasias

CLASSIFICATION

PLASMA CELL DYSCRASIAS

Monoclonal gammopathy of uncertain significance (MGUS)

"Benign"/idiopathic

Associated with other diseases (autoimmune, infectious, non-heme cancer, etc)

Plasma cell or lymphoid malignancy

Waldenstrom's macroglobulinemia

Other lymphoproliferative disorders

Smoldering multiple myeloma

Multiple myeloma

slide50

Incidence of plasma cell neoplasm by race, sex, and age, 1992-2001 (predominantly multiple myeloma)

Blood 2006;107:265

monoclonal gammopathy

COMPLICATIONS

MONOCLONAL GAMMOPATHY

Hyperviscosity (IgM >> IgA > IgG)

Renal dysfunction (light chains)

Glomerular

Tubular

Neuropathy

Other organ damage (rare)

Cryoglobulinemia (types I and II)

Amyloidosis

slide52

Brit J Haematol 2004; 124:565

CRYOGLOBULINEMIA IN IgM GAMMOPATHY

slide54

MULTIPLE MYELOMA

Serum and urine protein electrophoresis

Monoclonal IgG

Free light chain

Serum

Urine

slide55

MULTIPLE MYELOMA

Lytic bone lesions

Nephropathy

multiple myeloma

EPIDEMIOLOGY

MULTIPLE MYELOMA

Incidence in US approx 3 cases/100,000/yr

98% of cases > 40 yrs old

Risk factors:

genetic

radiation exposure

? chemical exposure

multiple myeloma57

CLINICAL MANIFESTATIONS

MULTIPLE MYELOMA

Anemia progressing to pancytopenia

Bone pain/destruction

Hypercalcemia

Humoral immune defect

Local effects of plasmacytomas

Systemic effects of paraprotein

multiple myeloma58

DIAGNOSIS

MULTIPLE MYELOMA

Monoclonal paraprotein

Intact immunoglobulin in serum (SPEP)

Light chains in serum or urine (IEP)

Marrow plasmacytosis (> 20% - may be patchy)

Lytic bone lesions

Plasmacytoma

multiple myeloma59

INDICATIONS FOR TREATMENT

MULTIPLE MYELOMA

Symptomatic disease

Bone destruction

Anemia

Organ dysfunction

Hypercalcemia

Increasing paraprotein or ß2-microglobulin level

multiple myeloma61

TREATMENT

MULTIPLE MYELOMA

Initial treatment: alkylating agent + prednisone

Alternative: vincristine, adriamycin + dexamethasone (VAD)

High dose cytoxan, thalidomide for relapsed or refractory disease

Proteasome inhibitor (bortezomib)

Median survival 3-4 yrs; essentially no cures with chemotherapy alone

Auto-BMT prolongs survival

Allo-BMT has curative potential for younger pts

slide62

Overall and progression-free survival in multiple myeloma: standard chemotherapy vs high-dose chemotherapy with stem cell rescue

NEJM 2003;348:1875