Chronic Lymphocytic Leukemia: Clinical Correlates and Issues

Question 1

What is the most common leukemia in adults? (EXAM)

Answer 1

Chronic lymphocytic leukemia!

Question 2

What is the flow cytometry phenotype in CLL? (EXAM)

Answer 2

CD5+CD19+CD20+CD23+

Question 3

What is the survival, diagnosis and treatment of Chronic Lymphocytic leukemia?

Answer 3

• Median age of diagnosis is 65 years
• Median survival is 9 years
• Allogenic stem cell transplant only curative therapy
• Decision to treat based on age, performance status, symptoms, disease stage

Question 4

What is the pathophysiology of CLL?

Answer 4

• CLL is an uncontrolled clonal accumulation of mature lymphocytes
• Unclear mechanism of initiation
• Molecular characterization of CLL correlates with clinical outcomes
• Mutated Ig VH genes –> mutation in this case = better disease prognosis
• Unmutated Ig VH genes

Question 5

What is the key thing you don’t want to miss with CLL? (EXAM)

Answer 5

Mantle cell lymphoma!

-mantle cells look similar under the microscope but they’re more nasty to treat than CLL

Question 6

What is the difference between CLL and SLL?

Answer 6

SLL is the tissue phase of CLL

Question 7

What is the phenotype of CLL in flow cytometry? (EXAM)

Answer 7

CD5+CD19+CD20+CD23+

Question 8

What is the differential for CLL?

Answer 8

• Follicular lymphoma
• Mantle cell lymphoma with leukemic phase
• Prolymphocytic leukemia
• SLVL
• HCL

Question 9

What is Mantle cell lymphoma and its phenotype (flow cytometry)?

Answer 9

Nasty, aggressive NHL

-CD5+CD23-CyclinD1+

Question 10

What do you see in a blood smear of CLL?

Answer 10

• Heterogeneity in the appearance of abnormal lymphocytes in CLL
• See abundance of abnormal lymphocytes

Question 11

What are the clinical features of CLL?

Answer 11

• Patient can feel pretty well/normal
• Often an incidental diagnosis in an symptomatic patient
• Indolent disease common
• Progressive adenopathy often correlates with symptoms; fatigue, malaise, weight loss, fevers
• Progressive bone marrow involvement leads to severe cytopenias (reduction in blood cells), increased risk of infection
• Autoimmune sequelae and Richter’s transformations are long-term complications

Question 12

What are some autoimmune complications of CLL?

Answer 12

• AIHA (autoimmune hemolytic anemia)
• –Coombs’/DAT positive
• Pure red cell aplasia (bone marrow just not making red cells - look for reticulocytes!)
• ITP (immune mediated thrombocytopenia)
• Neutropenia

Question 13

What’s the key red cell aplasia differential diagnosis?

Answer 13

Parvovirus B19 - can cause red cell aplasia, most common in adults

Question 14

What are the two staging systems CLL?

Answer 14

• Rai

- Binet

Question 15

What is the Rai system?

Answer 15

Rai 0 - lymphocytosis
Rai 1 - lymphadenopathy
Rai 2 - splenomegaly
Rai 3 - HgB

Question 16

What is the Binet system?

Answer 16

A: lymphocytosis +/- 1-3 sites lymphadenopathy
B: lymphocytosis with > 3 sites lymphadenopathy
C: lymphocytosis + anemia and/or thrombocytosis

Question 17

Why is staging important?

Answer 17

Higher staging = less median survival

Question 18

What does a Rai 0 stage tell you?

Answer 18

Median survival: >10 years

Question 19

What does Rai 1 stage tell you?

Answer 19

Median survival: 7 years

Question 20

What does Rai 3 stage tell you?

Answer 20

Median survival: 2-5 years

Question 21

What are poor prognostic factors for CLL?

Answer 21

• Advanced stage at diagnosis
• Rapid lymphocyte doubling time
• Diffuse marrow infiltration
• Advanced age/male gender
• CLL-PLL (secondary PLL - prolymphocytic leukemia)
• Abnormal karyotype (abnormal cytogenetics)
• Elevated Beta2 -microglobulin, soluble CD23
• CD38+ or ZAP-70+

Question 22

What are CLL-cytogenetic abnormalities, ranked from best to least?

Answer 22

• 13q-
• Normal karyotype
• Trisomy 12
• 11q-
• 17p-

Question 23

What should you ALWAYS get with CLL? (EXAM)

Answer 23

FISH studies (cytogenetics)

Question 24

What do mutated heavy chain (VH) genes indicate in CLL?

Answer 24

Better survival

Question 25

What if the lab cannot perform Ig gene mutation (FISH) studies?

Answer 25

- CD38 may be a surrogate marker for Ig gene mutations - -Detect via flow cytometry (easily) - -CD38+ = unmutated Ig genes = poorer prognosis - -CD38- = mutated Ig genes = better prognosis - CD38+: 9 year median survival - CD38-: >20 years median survival

Question 26

What is ZAP-70 expression? What does it tell us?

Answer 26

- Correlates with Ig VH gene mutations - Correlates with CD38+ expression - ZAP-70+ = Poorer prognosis

Question 27

What does under 200 CD4+ cells indicate?

Answer 27

You have AIDs

Question 28

When should you treat CLL?

Answer 28

- Constitutional symptoms - Progressive lymphocytosis - Progressive lymphadenopathy - Progressive splenomegaly - Progressive bone marrow failure - Autoimmune complications - Richter's transformation or secondary PLL - Your patient is uncomfortable with observation

Question 29

What are these? (don't memorize) - Corticosteroids - Alkylating agents - Nucleoside analogs (same risk of infection as AIDs) - Monoclonal antibodies - Combination chemotherapy - Allogeneic stem cell transplantation - Ibrutinib

Answer 29

Therapeutic options for CLL

Question 30

What is the best way to treat CLL?

Answer 30

- Is there an indication to treat?? - Prognostic factors (stage, CD38 expression, ZAP-70, etc.) - Younger, good PS patients - --Clinical trail - --PCR or FCR - --Bendamustine plus rituximab - --Ibrutinib - Older, more frail patients - --Chlorambucil (+/- prednisone) - --Bendamustine plus rituximab - --Ibrutinib

Question 31

What is the only curative modality for CLL?

Answer 31

Allogenic transplant - Need matched-sib donor - Substantial morbidity/mortality - The price of curing CLL is GVHD

Question 32

60 yr, f, excellent health, high WBC:

Answer 32

Patient has M0 CLL

Question 33

What does 13q- CLL show on blood smear?

Answer 33

- Normal lymphocytes are dark purple and others are "smudge cells" - The mechanical streaking burst the cells - very flimsy

Question 34

What is the key clinical question for leukemias?

Answer 34

When was the last time you felt normal?

Question 35

57 yr, M, 3 months fevers, night sweats, speaks with hoarse voice, adenopathy in many areas. What causes hoarse voice and what does blood smear look like?

Answer 35

- Hoarse voice caused by (mediastinal adenopathy) lymph nodes in the chest swelling and paralyzing the recurrent laryngeal nerve (vocal cord) - A blood smear shows diffusely infiltrated - Treated with PCR immunotherapy

Question 36

What can happen with patients who are in remission from CLL?

Answer 36

- Prolymphocytes seen on blood smear - CLL transformed into secondary prolymphocytic leukemia (eccentrically placed nuclei) - --Richter's transformation - --New 17p- - Poor prognostic sign - Demonstrated refractory disease with BM failure and severe cytopenias

Question 37

What does DOE stand for?

Answer 37

Dyspenea on exertions

Question 38

65 yr old, F, remission for CLL, has fatigue & DOE, Pale, little tachycardic:

Answer 38

- She has very low hemoglobin - Blood smear: very light staining RBCs, also see spherocytes!! - Spherocytes = Autoimmune hemolytic anemia! = Diagnosis!!

Question 39

What is orthopnea?

Answer 39

Patient gets shot of breath when they're laying flat - they use many pillows to sit themselves up - sleep in a chair

Question 40

What is tachycardia?

Answer 40

Heart rate above 100

Question 41

When do you see spherocytes and nucleated RBCs on blood smears?

Answer 41

Presence of autoimmune hemolytic anemia

Question 42

What's important about AIHA (autoimmune hemolytic anemia)?

Answer 42

- Common auto-immune sequel of CLL - Presence of AIHA does NOT necessarily correlate with disease activity - Treated successfully with prednisone!

Question 43

Where does erythropoietin come from?

Answer 43

Kidneys!

Question 44

59 yr old, M, 10 yrs with CLL, not on therapy, DOE, low hemoglobin, high WBC, Extremely high erythropoietin:

Answer 44

Diagnosis? - PRCA (pure red cell aplasia - autoimmune phenomenon) - Auto-immune neutropenia - Immune-mediated thrombocytopenia

Question 45

How long do red cells last in our bodies?

Answer 45

About 120 days!

Question 46

What drug has been approved for autoimmune complications of CLL by the FDA recently?

Answer 46

Ibrutinib | -For Mantle Cell lymphoma patients who have received one prior therapy

Question 47

What is the therapeutic target for ibrutinib? What is ibrutinib?

Answer 47

- BCR signaling pathway (leads to NF-kB activation) | - BTK inhibitor - orally active (reversible)

Question 48

What is important to know about Imbruvica?

Answer 48

- Less than 1% is really exerted, so there are no renal impairment guidelines - Atrial fibrillation is a side effect - Extremely expensive = $11,000/month - If you stop the drug, it sets up resistance and then you can't use anything to fight the disease

Question 49

How does Imbruvica (ibrutinib) affect pregnancy?

Answer 49

- Pregnancy class D - --Organ malformation and low birth weight in rats - --Unclear if it is present in milk or nursing mothers - No indication in pediatrics

Question 50

What to know about Ibrutinib?

Answer 50

- Paradigm changing therapy!! | - Oral pill!!