LYMPHOPROLIFERATIVE

DISORDERS
Chronic Lymphocytic Leukemia-CLL
 CLL
• Chronic lymphocytic leukemia (CLL) is one of
the chronic lymphoproliferative disorders
(lymphoid neoplasms).
• It is characterized by a progressive
accumulation of functionally incompetent
lymphocytes, which are monoclonal in origin.
• CLL is identical disease with SLL at different
stages
 Epidemiology of CLL
• The most common type of lymphoid leukemia
in the West-
– 30% of all leukemias
• Median age 60yrs
– 10% below the age of 50yrs
• Men are more affected- M:F= 2:1
 Clinical Features
 25 %-asymptomatic (routine blood exam)
 Painless LN swelling
› Cervical usually
› Wax & wean
 Other features of immunodeficiency
› Infection, respiratory
 Sxs of autoimmune phenomenon
› Anemia & bleeding
› Increased reaction to insect bite
 Sxs due to organomegaly
 B-symptoms
• Signs
– Pallor
– GeneralizedLAP
– Hepatosplenomegaly
– Skin
• Bleeding
• Vasculitis
• Leukemic Cutis
– Other organs
• Waldeyer’s Ring
• Membranoproliferative glomerulonephritis
 Lab Features
 Anemia
 AIHA
 INFILTRATION
 BLEEDING
 Lymphocytosis
 SMUDGE / BASKET CELLS
 Granulocytes
 Thrombocytopenia
 Other tests
 Organ function test
 Uric acid & LDH
 Coomb’s test
 Serum protien Electrophoresis
 CXR &CT scan
 Dx of CLL
• Dx of CLL is based on
– CBC & differential
– Peripheral blood smear examination
– Flowcytometry study
• BM examination is not required to establish
the dx of CLL.
• Indications for BM examination in CLL
– Doubtful cases
– No Flowcytometry
– Work up of Anemia & Thrombocytopenia
– prognosis
 Dx of CLL
• Diagnostic Criteria
– The following 2 criteria must be met to dx CLL
• Absolute lymphocyte count in the PB ≥ 5000/µL, with a
preponderant population of mature appearing small
lymphocytes
• Demonstration of clonality of the circulating B-
lymphocytes by flowcytometry
 Dx of CLL
• Monoclonal B-cell lymphocytosis (MBL)
– PB absolute lymphocytosis < 5,000/µL and
– No LAP
• CLL versus Small Lymphocytic Lymphoma (SLL)
– The same disease with identical markers/clonality
– SLL is diagnozed
• LAP
• Without cytopenia &
• PB absolute lymphocytosis < 5,000/µL
 INDICATIONS FOR TREATMENT IN
CLL
• Disease-related progressive symptoms
• Progressively worsening anemia or
thrombocytopenia
• Autoimmune (Coombs-positive) hemolytic
anemia or autoimmune thrombocytopenia
• Bulky lymphadenopathy
• Massive splenomegaly /hypersplenism
 INDICATIONS FOR TREATMENT IN
CLL
• Increased susceptibility to bacterial
infections.
– hypogammaglobulinemia,
• Severe neutropenia or agranulocytosis
• Progressive hyperlymphocytosis.
 > 150 × 109 /L.
• Hyperviscosity syndrome associated with
hyperlymphocytosis
• a short doubling time (≤12 months)
 Prognostic features in chronic
lymphocytic leukemia
Poor prognostic features
• High Rai or Binet stages
• Diffuse pattern of lymphocyte marrow infiltration
• Lymphocyte doubling time <12 months
 Treatment of CLL
 Early stage & stable disease
 Observation without Rx
 Use of growth factors & IVIg
 Chemotherapy
 Alkylating agent ( Chlorambucil, Cyclophosphamide)
 Nucleoside Analogues(purine analogues) – Fludarabine,
Cladribine
 Monoclonal Antibodies
 Rituximab (against CD20)
 Alemtuzimab ( against CD52)
 Combination Chemotherapy
 Fludarabine + Cyclophosphamide (FC)
 Fludarabine + Rituximab (FR)
 Fludarabine + Cyclophosphamide + Rituximab(FCR)
 Multiple Myeloma

Definition : Malignant proliferation of plasma cell

Epidemiology :
- 1% of malignancy, 13% of hematologic malignancy
- M/F = 2/1, Black/White = 2/1
- Median age 70 yr
Risk factors : Radiation, Benzene, Dye, Chemicals
Etiologic factors :
- Genetics
- Chronic antigenic stimulation
CLINICAL FEATURES OF MULTIPLE MYELOMA

Clinical Finding Underlying Cause and Pathogenetic Mechanism

BONE PAIN Tumor expansion, production of osteoclast

lytic bone lesions activating factor by tumor cells, osteoblast
pathologic fractures inhibitory factors
Hypercalcemia
osteoporosis

RECURRENT INFECTIONS Hypogammaglobulinemia, low CD4 count, decreased

neutrophil migration

EASY FATIGUE/ANEMIA Bone marrow infiltration, production of inhibitory

factors, hemolysis, decreased red cell production,
decreased erythropoietin levels
Renal failure Hypercalcemia, light chain deposition, amyloidosis,
urate nephropathy, drug toxicity (nonsteroidal anti-
inflammatory agents, bisphosphonates), contrast
dye

Neurologic symptoms Hyperviscosity, cryoglobulinemia, amyloid deposits,

hypercalcemia, nerve compression, antineuronal
antibody, POEMS syndrome, therapy-related
toxicity

Nausea and vomiting Renal failure, hypercalcemia

Bleeding/clotting disorder Interference with clotting factors, antibody to
clotting factors, amyloid damage of endothelium,
platelet dysfunction, antibody coating of platelet,
therapy-related hypercoagulable defects
 Diagnostic criteria of MM & it’s variants
• Asymptomatic Myeloma (Smoldering Myeloma)
– M protein in serum > 30 g/L and/or
– Bone marrow clonal plasma cells > 10%
– No myeloma-related organ or tissue impairment (no end organ damage,
including bone lesions) or symptoms
• Symptomatic Multiple Myeloma
– M protein in serum and/or urine
– Bone marrow (clonal) plasma cells or plasmacytoma
– Myeloma-related organ or tissue impairment (end organ damage, including
bone lesions)
 Investigations

• End organ damage

– CBC, anemia
– ESR↑
– Bone marrow aspiration/peripheral film
– RFT,Serum calcium, uric acid
– Skeletal Survey
– CT / MRI / PET

• Prognostic varible
– LDH
– Beta 2 microglobulin,Albumin,
– CRP,Soluble IL6
 Investigations

• Genetics
• Karyotype Abnorma % patient Median
– Hyperdiploidy lity Survival
– Translocations of 14q32 t(11;14) 15% >60 mos
(IgG locus)
• FISH Normal 50 mos
– t(11;14) del 50% 30 mos
– del 13q14 13q34
– t(4;14) / t(4;16) t (4;14) 15% 20 mos
– del 17p13 del 10% 15 mos
17p13
Multiple myeloma (marrow). The cells bear characteristic morphologic features of plasma cells,
round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a
densely basophilic cytoplasm, and a perinuclear clear zone containing the Golgi apparatus.
Binucleate and multinucleate malignant plasma cells can be seen.
 Multiple myeloma lytic lesions

Bony lesions in multiple myeloma. The skull demonstrates the typical "punched out"
lesions characteristic of multiple myeloma. The lesion represents a purely osteolytic
lesion with little or no osteoblastic activity
 TREATMENT
• Supportive treatment
– hydration,antipain
– bisphosphonates
– glucocorticoid therapy,natriuresis.
– Calcitonin, Plasmapheresis
– Prophylactic administration of IV globulin
– erythropoietin along with hematinics (iron, folate,
cobalamin)
• Chemotherapy/radiotherapy/SCT
 Specific teatment
• Melphalan Prednisone

• High dose dexamethasone based

– VAD – vincristine, adriamycin, dex
– Pulse Dex – 40 mg d 1-4, 9-12, 17-20
• CR < 10 % ORR 60%
• Response duration 12-15 months
• Overall Survival – 3-5 years
Current New Therapeutic Options
• Thalidomide (®Thalomid)

• Lenolidomide (®Revlamid)

• Bortezomib (®Velcade)