Chronic Lymphocytic Leukemia (CLL) and Others

Question 1

<p>What are some distinctions and overlapping features of CLL and other lymphomas?</p>

Answer 1

<ul>
<li>—Clonal leukemic proliferations of either B- or T-cell lymphocytes that have a <strong>&ldquo;mature&rdquo; phenotype</strong></li>
<li><strong>—Involve blood and bone marrow</strong> &ndash; may also infiltrate other organs such as lymph node and spleen</li>
<li>—Diseases of <strong>older adults</strong></li>
<li>—Survivals months or years without therapy - usually considered <strong>incurable</strong></li>
<li>—Leukemias initially manifest in <strong>bone marrow and blood</strong> while lymphomas present in <strong>lymph nodes, spleen, etc.</strong></li>
<li>—Leukemias may involve <strong>lymph nodes</strong></li>
<li>—Lymphomas may infiltrate <strong>blood and marrow</strong></li>
<li>—Designation as leukemia or lymphoma may be <strong>arbitrary</strong></li>
</ul>

Question 2

<p>What are the major classifications of CLL?</p>

Answer 2

<ul>
<li><strong>—B-Cell</strong>
<ul>
<li>—Chronic lymphocytic leukemia</li>
<li>—Hairy cell leukemia</li>
<li>—Prolymphocytic leukemia</li>
</ul>
</li>
<li><strong>—T-Cell</strong>
<ul>
<li>—Large granular lymphocyte leukemia</li>
<li>—Adult T-cell leukemia/lymphoma&nbsp;</li>
<li>—S&eacute;zary syndrome</li>
<li>—Prolymphocytic leukemia<br></br>
&nbsp;</li>
</ul>
</li>
</ul>

Question 3

<p>What is the epidiomology and etiology of CLL?</p>

Answer 3

<ul>
<li>CLL most common leukemia in <strong>Western countries</strong> (rare in some Eastern countries such as Japan)</li>
<li>—Middle age to elderly</li>
<li>— M>F</li>
<li><strong>—Etiology unknown</strong>
<ul>
<li>—Probable genetic&nbsp;predisposition<br></br>
&nbsp;</li>
</ul>
</li>
</ul>

Question 4

<p>What are the features of small lymphocytic lymphoma (SLL)? How is it differentiated from CLL?</p>

Answer 4

<ul>
<li><strong>—No leukemia</strong> but lymph node or other tissue morphology and immunophenotype <strong>identical to CLL</strong></li>
<li>—Much rarer than CLL</li>
<li>—CLL and SLL considered to be <strong>same diseases</strong> with different manifestations</li>
<li>—Designation CLL/SLL often used to include both diseases</li>
</ul>

Question 5

<p>What are some of the common peripheral blood findings at diagnosis for CLL?</p>

Answer 5

<ul>
<li><strong>—Elevated leukocyte count</strong>

<ul>
<li><u>—Clonal B lymphocytosis</u> (>5000/uL) - small lymphocytes with condensed chromatin</li>
<li>—May be <u>neutropenia</u></li>
</ul>
</li>
<li>—Hb/Hct <strong>normal or decreased</strong></li>
<li>—Platelet count <strong>normal or decreased</strong></li>
<li><strong>**Note</strong>: If there are <5000 clonal B cells,&nbsp;call it monoclonal B lymphocytosis.</li>
</ul>

Question 6

<p>What is monoclonal B cell lymphocytosis?</p>

Answer 6

<ul>
<li><strong>—6-7% of individuals >60 yr</strong> have monoclonal B-lymphocytosis (MBL) detected in PB (usually CLL-type immunophenotype)</li>
<li><strong>—< 5000</strong> clonal B cells in peripheral blood (arbitrary cutoff)</li>
<li>—No cytopenias, organomegaly, etc.</li>
<li>—Precursor lesion - ~1%/yr progress to CLL—</li>
</ul>

Question 7

<p>What are the clinical findings of CLL?</p>

Answer 7

<ul>
<li>—Patients often <strong>asymptomatic</strong></li>
<li>—Weakness, fatigue, weight loss</li>
<li>—Lymphadenopathy and/or splenomegaly may be present</li>
<li><strong>—Infections</strong> &ndash; common complication, especially in later stages of disease
<ul>
<li><u>—Bacterial most common</u>, especially with encapsulated organisms (i.e. Streptococcus or Staphylooccus) &ndash; often <u>pneumonia</u></li>
<li><u>—Viral and fungal</u> infections also occur&nbsp;&nbsp;</li>
</ul>
</li>
</ul>

Question 8

<p>What are some common histological findings of CLL?</p>

Answer 8

<ul>
<li>White count elevated with anemia and thrombocytopenia</li>
<li>Large <strong>“smudge” cell</strong> on left common in CLL</li>
<li>All of the lymphocytes <strong>look alike</strong> – cookie cutter cells, same mold</li>
<li>Chromatin patterns are <strong>very condensed</strong>, no nucleoli, scant cytoplasm, <strong>textbook picture</strong></li>
</ul>

Question 9

<p>What is the immunophenotype of CLL?</p>

Answer 9

<ul>
<li>—Disease of activated, antigen experienced <strong>B cells</strong></li>
<li>—Expresses B-cell antigens: <strong>CD19, CD20 (weak)</strong></li>
<li><strong>—Monotypic</strong>: low density surface Ig: IgM+/- IgD with kappa or lambda light chains</li>
<li>—Positive for <strong>CD5</strong>, a T-cell associated antigen</li>
<li>—Expresses <strong>CD23</strong>, an activation antigen</li>
</ul>

Question 10

<p>What is the importance of proliferation centers in CLL?</p>

Answer 10

<ul>
<li>Can see a <strong>diffuse proliferation of lymphocytes</strong>, often will see a <strong>proliferation center</strong></li>
<li>Some of the cells in the cells in these centers are bigger with <strong>nucleoli</strong></li>
<li><strong>Centers of mitosis</strong>, which keeps the disease going</li>
</ul>

Question 11

<p>What are the immune complications of CLL?</p>

Answer 11

<ul>
<li><strong>—Hypogammaglobulinemia</strong> - ~6-%</li>
<li>—Inability to make specific antibody</li>
<li><strong>—Autoimmune disorders</strong>
<ul>
<li>—Autoimmune hemolytic anemia- ~10-25%</li>
<li>—Autoimmune thrombocytopenia- ~2%</li>
</ul>
</li>
<li><strong>—T cells also abnormal</strong></li>
</ul>

Question 12

<p>What is the clinical course of CLL?</p>

Answer 12

<ul>
<li><strong>—Slowly progressive disease</strong></li>
<li><strong>—Survivals variable</strong>
<ul>
<li>—overall survival <u>10-15 years</u></li>
<li><u>—1/3 of patients</u>: >25 years (never need therapy)</li>
<li><u>—1/3 of patients</u>: more aggressive disease (med. survival &ndash; 8 yrs) &ndash; need therapy<br></br>
&nbsp;</li>
</ul>
</li>
</ul>

Question 13

<p>Describe the clinical staging of CLL.</p>

Answer 13

<ul>
<li><strong>Stage 0</strong> &ndash; lymphocytosis in blood and marrow</li>
<li><strong>Stage 1</strong> &ndash; lymphocytosis plus lymphadenopathy</li>
<li><strong>Stage 2</strong> &ndash; lymphocytosis with hepatomegaly &nbsp; and/or splenomegaly</li>
<li><strong>Stage 3</strong> &ndash; lymphocytosis with anemia</li>
<li><strong>Stage 4</strong> &ndash; lymphocytosis with thrombocytopenia</li>
</ul>

Question 14

<p>Describe the genetics of CLL.</p>

Answer 14

<ul>
<li>—High incidence (~ 80%) of clonal abnormalities but <strong>none specific for CLL</strong>

<ul>
<li><u>—Deletion 13q14</u> &ndash; most common (50%)</li>
<li><u>—trisomy 12</u> (20%)</li>
<li><u>—Deletions of 11q</u> (site of ATM gene), <u>17p (TP53)</u> less common</li>
</ul>
</li>
<li><strong>—Prognostic information</strong>
<ul>
<li><u>13q sole abnormality</u> &ndash; good prognosis</li>
<li><u>11q,17p</u>&nbsp;&ndash; poorer prognosis</li>
</ul>
</li>
<li><strong>About 50% of CLL&rsquo;s&nbsp;<span>exhibit somatic mutation&nbsp;<span>of IgVH</span></span></strong><span><span>&nbsp;- good prognosis of survival</span></span>
<ul>
<li><span><span>​</span></span>—Mutated CLL is associated with better survivals than unmutated CLL&nbsp;</li>
</ul>
</li>
</ul>

Question 15

<p>How often does CLL transform into a high grade &nbsp;lymphoma?</p>

Answer 15

<ul>
<li>—Diffuse large B-cell lymphoma</li>
<li>—Develops in <strong>2-8%</strong> of CLL</li>
<li>—Majority (not all) clonally related to original CLL</li>
<li><strong>—Survival&nbsp; <1 year</strong></li>
</ul>

Question 16

<p>What is the treatment for CLL?</p>

Answer 16

<ul>
<li>—Traditionally <strong>&ldquo;watch and wait&rdquo;</strong> for early stage CLL

<ul>
<li>—Chlorambucil has been standard therapy</li>
<li>—CLL incurable</li>
</ul>
</li>
<li><strong>—Now more effective therapies</strong>
<ul>
<li>—Purine analogues, MoAb, transplantation</li>
<li>—Targeted therapy<br></br>
&nbsp;</li>
</ul>
</li>
</ul>

Question 17

<p>What is Hariy Cell Leukemia?</p>

Answer 17

<ul>
<li>—<strong>Rare</strong> clonal disorder of B lymphocytes</li>
<li>—Affects adults (median age <strong>~55 years</strong>)</li>
<li><strong>—Males >> females</strong></li>
<li>—Etiology unknown</li>
</ul>

Question 18

<p>What are the clinical features of Hairy Cell Leukemia?</p>

Answer 18

<ul>
<li>—<strong>Pancytopenia (50%) or cytopenias (100%)</strong>

<ul>
<li>—Leukocyte count <u>usually low</u> (neutropenia, monocytopenia)</li>
<li><u>—Hairy cells</u> usually present but may be rare</li>
<li>—Anemia and/or thrombocytopenia frequent</li>
</ul>
</li>
<li>—Peripheral lymphadenopathy <u>usually absent</u></li>
<li>—Splenomegaly (80%)</li>
</ul>

Question 19

<p>What are the presenting signs and symptoms of hairy cell leukemia?</p>

Answer 19

<ul>
<li>—Fatigue, weakness, weight loss</li>
<li>—Abdominal discomfort</li>
<li>—Infections</li>
<li>—Bleeding</li>
</ul>

Question 20

<p>What are the histologic and immunohistologic findings of hairy cell leukemia?</p>

Answer 20

<ul>
<li><strong>Histology</strong>

<ul>
<li><u>Hairycells</u> - membraneprojections</li>
<li>Mone marrow core shows, cells<u>wide apart</u> (fried eggs)</li>
</ul>
</li>
<li><strong>Immunophenotype</strong>
<ul>
<li>—Express <u>B-cell</u> surface antigens (CD19,CD20)</li>
<li>—Monoclonal surface <u>immunoglobulin</u>
<ul>
<li>—Kappa or lambda</li>
</ul>
</li>
<li>—Negative for <u>CD5</u></li>
<li>—Positive for <u>CD11c, CD25, CD103</u></li>
</ul>
</li>
</ul>

Question 21

<p>What are the genetics of hairy cell leukemia?</p>

Answer 21

<ul>
<li>—Gene sequencing identified <strong>BRAF mutation</strong> in majority/all HCL</li>
<li>—Mutation lies in activation loop of the <strong>kinase domain of BRAF</strong> &ndash; explains the activation of the Raf-MEK-ERK pathway in HCL</li>
<li>—BRAF mutation is <strong>key driver of HCL</strong> and a rational therapeutic target</li>
</ul>

Question 22

<p>What is the clinical course of hairy cell leukemia?</p>

Answer 22

<ul>
<li>—Indolent, <strong>slowly progressive</strong> disease</li>
<li>—Complications include infection, bleeding</li>
<li><strong>—Effective medical therapies</strong>
<ul>
<li>—>90% respond to purine analogue therapy</li>
</ul>
</li>
<li>—Survival - <strong>years</strong><br></br>
&nbsp;</li>
</ul>

Question 23

<p>What is large granular lymphocyte leukemia and what are the clinical characteristics?</p>

Answer 23

<ul>
<li><strong>—Rare disorder</strong>

<ul>
<li>—Most common in <u>older adults</u> (45-75 yrs)</li>
</ul>
</li>
<li>—In most cases lymphocytes exhibit mature <strong>T cytotoxic </strong>phenotype (CD3+, CD8+, CD4-, CD56-/+, CD57+, CD16+, )
<ul>
<li>—Clonal T-cell receptor gene rearrangement</li>
</ul>
</li>
<li><strong>—STAT3 mutations</strong> in many LGLLs &ndash; involvement of JAK/STAT in pathogenesis&nbsp;</li>
<li><strong>Clinical Presentation</strong>
<ul>
<li>—Peripheral blood <u>increase in LGL&rsquo;s</u> &ndash; no underlying cause</li>
<li><u>—Neutropenia</u> (recurrent infections) most common, other lineages can be decreased</li>
<li><u>—Polyclonal</u> hypergammaglobulinia</li>
<li><u>—Splenomegaly</u></li>
<li>—Subset have <u>rheumatoid arthritis</u></li>
</ul>
</li>
</ul>

Question 24

<p>What are the histologic findings and immunohistological characteristics of large granular lymphocyte leukemia?</p>

Answer 24

<p>Listen to lecture!</p>

Question 25

<p>What is the clinical course of large&nbsp;granular lymphocyte leukemia?</p>

Answer 25

<ul>
<li><strong>—Clinical course variable</strong>

<ul>
<li>—Usually indolent</li>
</ul>
</li>
<li><strong>—No specific therapy</strong>
<ul>
<li>—Chemotherapy</li>
<li>—Steroids<br></br>
&nbsp;</li>
</ul>
</li>
</ul>

Question 26

<p>What is adult T-cell Laukdemia/Lymphoma (ATLL)?</p>

Answer 26

<ul>
<li>Aggressive malignancy of <strong>T-lymphocytes</strong></li>
<li>First described in SW Japan; also occurs in Africa, Caribbean basin, northern areas of South America, and SW United States</li>
<li><strong>Caused by HTLV-1 retrovirus</strong>- must be infected!
<ul>
<li><strong>HTLV-1</strong> integrated into DNA of T-lymphocytes</li>
<li>—Virus transmitted by:
<ul>
<li>blood transfusions</li>
<li>needle exchange</li>
<li>sexual contact</li>
<li>breast feeding</li>
<li>transplacentally</li>
</ul>
</li>
</ul>
</li>
<li><strong>—Initial stage is carrier stage</strong></li>
<li>—Disease expression occurs in <strong>adult</strong> (in small subset of carriers)</li>
</ul>

Question 27

<p>What are the histological and immunohistochemicalfindings of ATLL?</p>

Answer 27

<ul>
<li>—Leukocyte counts variable; often <strong>>100,000/uL</strong></li>
<li><strong>—Lymphadenopathy, splenomegaly, skin lesions common</strong></li>
<li>—May have <strong>hypercalcemia</strong>, bone lesions</li>
<li>—Abnormal lymphocytes have <strong>“flower-like” nuclei</strong></li>
<li>—Lymphocytes are <strong>CD3+, CD7-, CD4+, CD8-, CD25+</strong></li>
</ul>

Question 28

<p>What ist he clinical course of ATLL?</p>

Answer 28

<ul>
<li>—Usually acute course with median survival <strong>4-5 months</strong></li>
<li>—Often unresponsive to <strong>chemotherapy</strong></li>
<li>—More chronic forms also occur<br></br>
&nbsp;</li>
</ul>

Question 29

<p>What is Sezary Syndrome?</p>

Answer 29

<ul>
<li>—Leukemic form of <strong>cutaneous T-cell lymphoma</strong></li>
<li>—Generalized erythroderma</li>
<li><strong>—Hyperkeratosis</strong> of palms and soles</li>
<li>—Pruritis</li>
<li>—Lymphadenopathy</li>
</ul>

Question 30

<p>What are the immunohistochemical and histological findings of Sezary Sydrome?</p>

Answer 30

<ul>
<li>—Lymphoma cells with <strong>cerebriform nuclei</strong></li>
<li>—Circulate in the <strong>blood</strong> (leukemic)</li>
<li><strong>—Mature T- helper</strong> phenotype (CD3+, CD4+, CD8-)</li>
<li>—Cells express adhesion molecules that contribute to <strong>“homing” to skin—</strong></li>
</ul>

Question 31

<p>What is the therapy of Sezary Syndrome?</p>

Answer 31

<ul>
<li><span>—Primarily directed toward the <strong>erythroderma</strong></span></li>
<li>—Topical or systemic</li>
<li>—Median survival &ndash; <strong>about 5 years—</strong></li>
</ul>

Question 32

<p>What are the prominent featuresof T cell prolymphocytic leukemia?</p>

Answer 32

<ul>
<li><strong>—Rare</strong> leukemia of adults,</li>
<li><strong>—Hepatosplenomegaly and lymphadenopathy</strong></li>
<li>—Lymphocyte count often <strong>>100x10⁹/L</strong></li>
<li>—Usually <strong>aggressive</strong></li>
<li><strong>—Most CD4+, subset CD4+/CD8+</strong></li>
<li>—Most frequent genetic abnormality is inv(14)involving <strong>TCL1</strong> → constitutive activation of TCL-1
<ul>
<li>—May respond well to <strong>Campath</strong> (monoclonal antibody to CD52)</li>
</ul>
</li>
</ul>