Exam 13 - Heme25,26 - Chronic Lymphocytic Leukemia And Myeloma

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Chronic Lymphocytic Leukemia is a lymphoproliferative disorder caused by a clonal expansion of ..., long-lived lymphocytes.

The lymphocytes are typically ... cell in origin, and are functionally defective.

CLL is ...-phase, i.e. blood-born

SLL (Small Lymphocytic Lymphoma) is the ...-phase analog.

Both phases may exist concurrently.

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mature
B
liquid
solid

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CLL Epidemiology:

Western Hemisphere-
-Most common of all western leukemias, 30%
->95% are ...-cell in origin
-More prevalent in males, 2:1 M:F
-Median age at diagnosis ...-...
-Increases with age, prevalence 40/10,000 by 70’s
-Virtually non-existent in ...
-Only leukemia not associated with ...

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B
60-65
children
radiation

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Clinical Presentation:

40% present by routine blood tests in asymptomatic patients.

... is the universal finding on peripheral blood smears: 5,000/mcL up to 500,000/mcL.

Symptoms of ...(sludging) are uncommon in CLL, (possible in CML)

Symptoms: fever, night sweats, weight loss, adenopathy, hepatosplenomegally

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Lymphocytosis
leukostasis

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smudge cell usually suggests ...

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chronic lymphocytic leukemia

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Clinical features: CLL

Elevated peripheral smear white count with absolute lymphocytes greater than 5,000. “... cells” are common and raise suspicion of diagnosis.

Bone marrow architecture disrupted; infiltration can be 30-100% of all cells. Diffuse infiltrates of lymphocytes carry a ... prognosis.

Anemia and thrombocytopenia in advanced stages.

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Smudge
worse

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Clinical Features – CLL:

About half of patients have ... antibodies, (hypogammaglobulinemia), even in early stage, with resulting bacterial and viral infection risk.

Low titer ... antibodies are common.

... against red cell and platelet antigens are common, leading to autoimmune hemolysis and thrombocytopenia.

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low
monoclonal
Auto-antibodies

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Diagnostic Criteria of CLL:

Sustained absolute peripheral blood lymphocyte count of 10,000/mcL or greater (Classical Criterion)

Documentation of monoclonal B-cell phenotype lymphocytes by ... of blood or marrow, whatever the absolute lymphocyte count (Modern Criterion)

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flow cytometry

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Diagnostic Phenotyping: Flow Cytometry:

The surface expression of antigens can be detected by labeled antibody panels.

Each cell can be individually analyzed, and the results quantitated graphically.

CLL cells express the pan-B cell antigens CD19
and CD20, along with ..., a mature T-cell antigen. Most cells are CD23+ and FMC7-.
Surface IgM (+/- IgD)is weakly positive in 90%.

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CD5

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Staging and Prognosis:

Tumor burden. Failed apoptosis. These cells start crowding out other cells and median survival rate ...

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decreases

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Common Molecular findings via FISH analysis:

... have an aggressive clinical course and poor survival

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17p13

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Immunoglobulin Variable Gene Hypermutation and Prognosis:

Originally thought that B-CLL cells arose from pregerminal center, immunologically naïve B lymphocytes.

Immunoglobulin variable (V) gene mutations in germinal center determine class and specificity of antibody production.

Now recognized that half of all CLL cases exhibit V gene hypermutation consistent with ... center memory B cells.

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postgerminal

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B Cell V Gene Mutation Significance:

Patients with hypermutated V gene, post-germinal center B-CLL have markedly ... prognoses than those with unmutated V genes.

This distinction holds true even with early stage disease.

CD38 expression correlates with unmutated V gene B-CLL; thus CD38 can be a readily available surrogate marker of prognosis.

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better

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Other autoimmune diseases in CLL: Rheumatoid Arthritis, Lupus, Hashimoto’s Thyroditis, Grave’s Disease.

All have to do with ... regulation

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B-cell

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...:

A minority of CLL (or other low-grade B-cell lymphoma) patients experience evolution into aggressive lymphoproliferative disorders.
-Usually Diffuse Large Cell Lymphoma (DLL)
-Rarely acute lymphocytic leukemia (ALL)
-Presents with rapid clinical worsening: fever, weight loss, sweats, progressive lymphadenopathy, enlarging spleen, rising LDH.
-Survival can be poor; treatment is with aggressive chemotherapy and/or radiation.

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Richter Transformation

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CLL Tx: Stem cell transplantation:

... stem cell transplantation fails due to failure of disease eradication from induction and conditioning chemotherapy.

... stem cell transplantation takes advantage of GVL (graft vs. leukemia) effect, but limited by older age of CLL patients. Still considered experimental, but best option for long-term disease control and potential cure.

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Autologous
Allogeneic

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Other B-cell Lymphoproliferative Disorders: ...:

Termed Lymphoplasmacytoid Lymphoma in WHO Classification.

Low grade malignancy of B-lymphocytes that produce monoclonal IgM; hyperviscosity features (visual disturbances, headache, bleeding, vascular sludging, cardiopulmonary collapse). May require plasmapheresis to remove IgM.

Plasma cell disorder like myeloma, but treated like CLL!

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Waldenstrom’s Macroglobulinemia

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Myeloma and Plasma Cell Dyscrasias section

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ok

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POEMS syndrome :

What’s it stand for?

A form of a plasma cell dyscrasia that presents in younger patients (51) who have longer survivals than myeloma (median 8 years).

Progressive neuropathy responds to myeloma therapy.

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Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin changes (hyperpigment, hypertrichosis)

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Pathogenesis (plasma cell dyscrasias):

Emergence of a limited number of clonal plasma cells (i.e. MGUS)

Complex genetic events/genomic instablility (translocations of 14q32 and deletions of 13)

Marrow microenvironment changes:
-Induction of angiogenesis
-Suppression of cell mediated immune surveillance
-Paracrine signaling loops involving ... and ... (Vascular Endothelial Growth Factor)

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IL-6
VEGF

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Medical Evaluation:

Complete Blood Count (CBC)

Chemistry profile (CMP)

Skeletal Survey (Plain X-rays of axial and appendicular skeleton). Note- ... do not routinely image myeloma lesions!

MRI for sensitive detection of marrow lesions and for evaluation of vertebral/cord lesions.

Bone marrow biopsy/aspiration for extent of tumor and for cytogenetics/FISH and Plasma Cell Labeling Index

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Bone Scans

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Medical Evaluation, cont.:

SPEP/UPEP: Serum and urine protein electropheresis and immunofixation to identify and quantify the monoclonal protein, “M Spike”.
-Most common IgG, then IgA, then light chain.
-IgD and IgE uncommon, hard to identify M spike.
-1-3% non-secretory (no heavy or light chains).
-20% produce only light chains which may only show in urine (small enough to pass through glomeruli).

... - an index of lymphocyte activation.

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Beta-2 Microglobulin

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look at slide 56

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ok

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Diagnostic Criteria for MGUS:

M Protein: IgG< ... g/dL or IgA< ... g/dL

Urine light chains <1g/24

Marrow plasmacytosis <10%

No lytic bone lesions

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3.5
2.0

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Diagnostic Criteria for Smoldering Myeloma:

M protein: IgG<... g/dL or IgA<... g/dL

Either no ... lesions or limited lesions (<3)

Marrow plasmacytosis <30%

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7
5
bone

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Diagnostic Criteria for Multiple Myeloma:

Marrow plasmacytosis > ... % --> myeloma

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30

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Myeloma Treatment:

MGUS- observation at 6 month intervals.

Smoldering Myeloma- observation at 3 month intervals with skeletal surveys every 6 months.

Plasmacytoma of bone- ... and careful observation. Majority progress to myeloma at ... years. 20% free of disease at 10 years.

Solitary soft tissue plasmacytoma- higher chance of cure with radiation: 70% at 10 years.

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radiation
2

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Myeloma Adjunctive Treatment:

Radiation therapy
-Pain control
-Impending ...
-Impending cord compression

Vertebroplasty/Kyphoplasty
-Maintain Renal Function
*Avoid NSAIDs, IV Contrast

Bisphosphonates
-Monitor renal function
-Monitor for osteonecrosis of jaw

-Erythropoietin for anemia
-PCP, HVZ, Fungal prophylaxis
-IVIg for recurring infections
-Plasmapheresis for (IG...) symptomatic hyperviscosity

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fracture
M

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if someone shows up with an impending fracture or fracture of hip, you want to get them to the ... really quick!

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radiation oncologist

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Complications of Myeloma Treatment:

-Neuropathy from multiple agents: Revlimid, Thalidomide, Bortezomib, Vincristine, steroids, even the myeloma proper.
-Bacterial and viral infections from chemotherapy induced neutropenia
-Opportunistic infections (Zoster, PCP)
-Venous thrombosis from Dexamethasone, Thalidomide, and Revlimid
-Bleeding from thrombocytopenia
-Need for transfusions, growth factor support
-... of bone (jaw) from bisphosphonates

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Osteonecrosis

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AL (Primary) Amyloidosis:

10% of myeloma patients have evidence of concurrent ....

Infiltrative protein with light-chain sequences for each patient identical to the light chains in the M-protein.

Tissue biopsy shows ... after Congo Red stain, under polarized light.

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amyloidosis
apple green birefringence

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AL Amyloidosis:

Clinical Presentations- Extremely Polymorphic
-De novo or in setting of MGUS/Myeloma/Wald.
-Unexplained marked weight loss/fatigue
-Cardiomyopathy, orthostatic hypotension
-Macroglossia, ... edema
-Nephrotic syndrome, hepatomegaly
-Carpal tunnel syndrome (hemodialysis patients with elevated Beta-2 microglobulin)

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periorbital

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people with AL amyloidosis usually present with ... and ...

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macroglossia and periorbital edema