CLL Foundations

Question 1

what are chronic lymphoproliferative disorders?

Answer 1

CLPD are a group of diseases arising from a malignant clonal proliferation of lymphocytes

CLPD usually involves proliferation of mature B cells and rarely T cells

the malignancy can involve peripheral blood, bone marrow, spleen, and/or lymph nodes and other lymphoid tissues

Question 2

what are the types of disorders that classify as chronic lymphoproliferative disorders?

Answer 2

• chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) - main one**
• hairy cell leukemia
• prolymphocytic leukemia
• large granulated lymphocyte leukemia

Question 3

CLPD involves proliferation of what type of cells?

Answer 3

Mature B cells (and rarely, T cells)

Question 4

what are the symptoms people with CLPD present with initially?

Answer 4

can be completely asymptomatic or present with lymphadenopathy, fevers/chills, night sweats, and/or weight loss

splenomegaly due to progressive growth of lymphatic tissue

in contrast to acute leukemia, these patients do not manifest the signs of bone marrow failure until late in the disease

Question 5

what does the blood smear of someone with CLPD show?

Answer 5

1. numerous lymphocytes
2. leukocytosis
3. smudge cells = lymphocytes that have been destroyed in the blood smear process

Question 6

What cellular abnormalities are associated with CLL on a peripheral blood smear?

Answer 6

leukocytosis and smudge cells

Question 7

how do you treat CLPD?

Answer 7

usually don’t cause pain, slow-growing and not immediately problematic

treatment is only required if symptoms of the lymphoproliferation are bothersome or progressive, and typically a “watch-and-wait” approach is taken

if you do have to treat it, then there are some drugs you can use to do so

Question 8

what drugs are used to treat CLPD if you do have to treat it?

Answer 8

• chemotherapy
• radiation therapy
• monoclonal antibodies
• steroids
• ibrutinib (a small molecule inhibitor)
• idelalisib (works by inducing apoptosis)
• venetoclax (works by inducing programmed cell death)

Question 9

what does ibrutinib do?

Answer 9

treats CLPD

a small molecule inhibitor

Question 10

what does idelalisib do?

Answer 10

treats CLPD

works by inducing apoptosis

Question 11

what does venetoclax do?

Answer 11

treats CLPD

works by inducing programmed cell death

Question 12

What features of CLL/SLL make it the ‘poster child’ for chronic lymphoproliferative disorders?

Answer 12

CLL/SLL involves malignant clonal proliferation of mature lymphocytes, typically runs a prolonged and indolent course, and can involve the marrow, blood, or lymph nodes.

Question 13

what is immunophenotyping?

Answer 13

a key diagnostic test used to differentiate the different lymphoproliferative disorders

Question 14

how does immunophenotyping work?

Answer 14

it works is similar to a barcode scanner that reads a specific pattern of white and black lines to obtain details about a certain item in the grocery store

the same concept is used in medicine to identify unique proteins or antigens expressed by cells in order to classify them

antigens on the surface of leukemia cells are identified using special antibodies that bind to them specifically, allowing for their classification

the technique used is called flow cytometry immunophenotyping, which involves the measurement (-metry) of cellular (cyto-) properties as they are moving in a fluid stream (flow) past a fixed set of detectors

among the chronic lymphoproliferative disorders, specific disorders have characteristic cell surface markers. the detection of the specific groupings of cell surface proteins (labeled as CD for clusters of differentiation) on abnormal cells leads us to determine the specific type of leukemia or lymphoma

Question 15

What does immunophynotyping detect on a test?

Answer 15

cell surface antigens

each disorder has its own immunophenotype!!!

Question 16

what is the surface proteins detected on T-cells?

Answer 16

CD3

CD5

Question 17

what is the surface proteins detected on helper T-cells?

Answer 17

CD4

Question 18

what is the surface proteins detected cytotoxic T cells?

Answer 18

CD8

Question 19

what is the surface proteins detected on B-cells?

Answer 19

Ig

CD10

CD23

CD19

CD19

CD20

CD21

Question 20

what is the immunophenotye for CLL/SLL?

Answer 20

CLL/SLL is perhaps the best known of the chronic lymphocytic disorders and it will show:

1. negative for TdT (terminal deoxynucleotidal transferase)
2. positive for B-cell antigens CD19, CD20, CD21
3. positive for monoclonal surface Ig
4. Ppositive for T-cell antigen CD5

Question 21

explain the absence of TdT in CLL/SLL

Answer 21

The absence of TdT makes sense, as this is an enzyme only found in lymphoblasts

here we have mature cells in a chronic disease

Question 22

explain why B-cell antigens and monoclonal surface Ig are positive in CLL/SLL

Answer 22

B-cell antigens and the monoclonal surface Ig are expected since this is a B-cell disorder

Question 23

explain why T-cell antigen CD5 is positive in CLL/SLL

Answer 23

for a short period of time during maturation, B cells actually express CD5

Question 24

What is the immunophenotype of a B-cell?

Answer 24

B cells most commonly express immunoglobulin (Ig), CD19, CD20, and/or CD21

Question 25

Many cases of chronic lymphoproliferative disorders are suspected from a routine CBC showing a lymphocytic predominant leukocytosis. Which of the following is the best next step to work-up our patient for a malignancy?

Answer 25

flow cytometry the first step in working up a patient for a chronic lymphoproliferative disorder after initial suspicion from a CBC and/or smear is to obtain immunophenotyping on the blood this will tell us what surface markers the cells are expressing and therefore help us determine if this is a benign or malignant leukocytosis after flow cytometry is performed, a bone marrow biopsy is not required to confirm the diagnosis of a malignancy

Question 26

Chronic lymphoproliferative disorders can often be suspected on a routine blood count, with diagnosis confirmed by further testing with immunophenotyping and marrow biopsy. Patients often have no symptoms at time of diagnosis. What is the best course for treatment when diagnosed with virtually no symptom burden?

Answer 26

watch and wait chronic lymphoproliferative disorders can last for years without any clinical development. therefore, frequent laboratory checks may be employed for a long while until the patient becomes symptomatic, which would then prompt treatment

Question 27

A 65-year-old man is found to have an elevated WBC on a routine CBC. The peripheral smear shows many small, mature-appearing lymphocytes. Flow cytometry is then performed on the blood sample to further characterize these cells. What will the immunophenotype be if this population of cells is found to be benign?

Answer 27

lots of CD3+ cells, smaller amount of CD20+ cells CD20 is a marker of B-cells, and CD3 is a marker for T-cells the normal make-up of blood is about 60-80% T cells, 10-20% B cells, and 5-10% NK cells hence, we would expect there to be more T cells (CD3) than B cells (CD20) in the population if this were a benign process