Chronic Lymphocytic Leukemia: Clinical Correlates and Issues Flashcards
What is the most common leukemia in adults? (EXAM)
Chronic lymphocytic leukemia!
What is the flow cytometry phenotype in CLL? (EXAM)
CD5+CD19+CD20+CD23+
What is the survival, diagnosis and treatment of Chronic Lymphocytic leukemia?
- 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
What is the pathophysiology of CLL?
- 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
What is the key thing you don’t want to miss with CLL? (EXAM)
Mantle cell lymphoma!
-mantle cells look similar under the microscope but they’re more nasty to treat than CLL
What is the difference between CLL and SLL?
SLL is the tissue phase of CLL
What is the phenotype of CLL in flow cytometry? (EXAM)
CD5+CD19+CD20+CD23+
What is the differential for CLL?
- Follicular lymphoma
- Mantle cell lymphoma with leukemic phase
- Prolymphocytic leukemia
- SLVL
- HCL
What is Mantle cell lymphoma and its phenotype (flow cytometry)?
Nasty, aggressive NHL
-CD5+CD23-CyclinD1+
What do you see in a blood smear of CLL?
- Heterogeneity in the appearance of abnormal lymphocytes in CLL
- See abundance of abnormal lymphocytes
What are the clinical features of CLL?
- 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
What are some autoimmune complications of CLL?
- 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
What’s the key red cell aplasia differential diagnosis?
Parvovirus B19 - can cause red cell aplasia, most common in adults
What are the two staging systems CLL?
- Rai
- Binet
What is the Rai system?
Rai 0 - lymphocytosis
Rai 1 - lymphadenopathy
Rai 2 - splenomegaly
Rai 3 - HgB
What is the Binet system?
A: lymphocytosis +/- 1-3 sites lymphadenopathy
B: lymphocytosis with > 3 sites lymphadenopathy
C: lymphocytosis + anemia and/or thrombocytosis
Why is staging important?
Higher staging = less median survival
What does a Rai 0 stage tell you?
Median survival: >10 years
What does Rai 1 stage tell you?
Median survival: 7 years
What does Rai 3 stage tell you?
Median survival: 2-5 years
What are poor prognostic factors for CLL?
- 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+
What are CLL-cytogenetic abnormalities, ranked from best to least?
- 13q-
- Normal karyotype
- Trisomy 12
- 11q-
- 17p-
What should you ALWAYS get with CLL? (EXAM)
FISH studies (cytogenetics)
What do mutated heavy chain (VH) genes indicate in CLL?
Better survival
What if the lab cannot perform Ig gene mutation (FISH) studies?
- 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
What is ZAP-70 expression? What does it tell us?
- Correlates with Ig VH gene mutations
- Correlates with CD38+ expression
- ZAP-70+ = Poorer prognosis
What does under 200 CD4+ cells indicate?
You have AIDs
When should you treat CLL?
- 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
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
Therapeutic options for CLL
What is the best way to treat CLL?
- 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
What is the only curative modality for CLL?
Allogenic transplant
- Need matched-sib donor
- Substantial morbidity/mortality
- The price of curing CLL is GVHD
60 yr, f, excellent health, high WBC:
Patient has M0 CLL
What does 13q- CLL show on blood smear?
- Normal lymphocytes are dark purple and others are “smudge cells”
- The mechanical streaking burst the cells - very flimsy
What is the key clinical question for leukemias?
When was the last time you felt normal?
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?
- 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
What can happen with patients who are in remission from CLL?
- 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
What does DOE stand for?
Dyspenea on exertions
65 yr old, F, remission for CLL, has fatigue & DOE, Pale, little tachycardic:
- She has very low hemoglobin
- Blood smear: very light staining RBCs, also see spherocytes!!
- Spherocytes = Autoimmune hemolytic anemia! = Diagnosis!!
What is orthopnea?
Patient gets shot of breath when they’re laying flat - they use many pillows to sit themselves up - sleep in a chair
What is tachycardia?
Heart rate above 100
When do you see spherocytes and nucleated RBCs on blood smears?
Presence of autoimmune hemolytic anemia
What’s important about AIHA (autoimmune hemolytic anemia)?
- Common auto-immune sequel of CLL
- Presence of AIHA does NOT necessarily correlate with disease activity
- Treated successfully with prednisone!
Where does erythropoietin come from?
Kidneys!
59 yr old, M, 10 yrs with CLL, not on therapy, DOE, low hemoglobin, high WBC, Extremely high erythropoietin:
Diagnosis?
- PRCA (pure red cell aplasia - autoimmune phenomenon)
- Auto-immune neutropenia
- Immune-mediated thrombocytopenia
How long do red cells last in our bodies?
About 120 days!
What drug has been approved for autoimmune complications of CLL by the FDA recently?
Ibrutinib
-For Mantle Cell lymphoma patients who have received one prior therapy
What is the therapeutic target for ibrutinib? What is ibrutinib?
- BCR signaling pathway (leads to NF-kB activation)
- BTK inhibitor - orally active (reversible)
What is important to know about Imbruvica?
- 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
How does Imbruvica (ibrutinib) affect pregnancy?
- 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
What to know about Ibrutinib?
- Paradigm changing therapy!!
- Oral pill!!
