Chronic Leukemias

Question 1

chronic lymphocytic leukemia is a neoplasm of _____

Answer 1

chronic lymphocytic leukemia: neoplasm of naive B cells

most commonly presents as leukemia, but can also present as small lymphocytic lymphoma when there is generalized lymphadenopathy

Question 2

what is the most common chronic leukemia of adults (disease of older adults, with mean age of 70)

Answer 2

chronic lymphocytic leukemia (CLL)

[can also present as small lymphocytic lymphoma]

Question 3

how do patients with CLL (chronic lymphocytic leukemia) present?

Answer 3

usually asymptomatic, incidental finding of elevated WBC count (>5K lymphocytes)

increased B lymphocytes on peripheral smear, smudge cells - leukemic cells are more fragile and get squished during peripheral smear

if symptomatic - fatigue, weight loss, early satiety, infections, lymphadenopathy, hepatosplenomegaly

Question 4

how does CLL (chronic lymphocytic leukemia) disrupt normal immune function? (2)

what can these issues lead to?

Answer 4

decreased normal antibody production —> hypogammaglobinuria (not making antibodies) - susceptible to bacterial infections

increased AUTO-antibody production —> RBC/platelet destruction —> Warm AIHI, immune thrombocytopenia

Question 5

when CLL becomes aggressive, it can undergo a “Richter transformation” to become…

what is a key sign of this?

Answer 5

as CLL (chronic lymphocytic leukemia) acquires more mutations, it can transform to diffuse large B cell lymphoma (about 10% of patients)

very poor prognosis

sign: patient with CLL presenting with rapidly enlarging lymph node

Question 6

why does it make sense that CLL (chronic lymphocytic leukemia) tumor cells are monoclonal?

Answer 6

one progenitor cell acquires mutation, now all tumor cells are derived from this one —> monoclonal

Question 7

what is distinct about the immunophenotype of CLL (chronic lymphocytic leukemia) tumor cells?

Answer 7

CLL is B cell disease, but…
both B (CD20) and T (CD5) cell markers are expressed!

along with surface Ig (IgM or IgM + IgD)

Question 8

what does histological pathology of small lymphocyte lymphoma look like?

Answer 8

remember that small lymphocytic lymphoma is the alternative presentation of chronic lymphocytic leukemia (B cell disease)

histologically - a sheet/sea of small lymphocytes, loss of lymph node architecture

Question 9

if patients with CLL are asymptomatic, they are only monitored closely (60% will never require treatment)

however, if they are symptomatic, the “drug of choice” is…

Answer 9

ibrutinib: Bruton Tyrosine Kinase small molecule inhibitor —> inhibits malignant B cell proliferation [IBrutinib = Inhibit B cells]

[remember that pre-B cell receptor activates BTK, allowing maturation to occur]

adverse effects: low cell counts, HTN, increased risk of skin cancer

Question 10

what kind of cancer does this describe?
- patients frequently asymptomatic
- disrupts normal immune function (can cause warm AIHA, thrombocytopenia)
- smudge cells on peripheral smear
- B cells markers + CD5
- treat with Ibrutinib

Answer 10

CLL (chronic lymphocytic leukemia): most common chronic leukemia in adults (older adults, avg aged 70)

B cell disease but has CD5 T cell marker!

Ibrutinib: small molecule inhibitor of Bruton Tyrosine Kinase (required for malignant B-cell proliferation)

Question 11

what kind of cancer Hairy Cell Leukemia? what mutation causes it?

Answer 11

named for histological presentation - cells look hairy

rare, mostly older men, very slowly progressing

B cell neoplasm with BOTH B (CD19, CD20 + monoclonal Ig) and T (CD25 + CD103) cell markers

due to GOF mutation in BRAF V600E (RAF - serine/threonine kinase, activates proliferation)

Question 12

how does Hairy Cell Leukemia present?

Answer 12

pancytopenia (weak, fatigue, “dry tap”)

splenomegaly (expansion of red pulp)

LOW levels of monocytes (unusual infections - mycobacterium avium intracellulare)

Question 13

what cell markers are important for identifying Hairy Cell Leukemia? (2)

Answer 13

1. flow cytometry:
   B cell neoplasm with BOTH B (CD19, CD20 + monoclonal Ig) and T (CD25 + CD103) cell markers
2. TRAP+ (Tartrate-resistant acid phosphatase) - seen via staining, resistant to acid

*note that CD103 mediates cell migration, typically only found on T and DC cells

Question 14

how is Hairy Cell Leukemia treated, a chronic B cell leukemia? (2)

Answer 14

very slow developing, so watch and wait if symptoms are limited

treatment:
1. RAF inhibitors (cells carry BRAF V600E mutation)
2. purine analogs: Cladribine (2-CdA) or pentostatin - disrupt DNA synthesis

Question 15

what kind of cancer does this describe?
- rare, slow developing
- pancytopenia + splenomegaly
- “dry tap” on bone marrow biopsy
- BRAF mutation
- TRAP+
- Rx: Cladribine

Answer 15

Hairy Cell Leukemia (chronic B cell)

all cells have BRAF V600E mutation (of RAF - serine/threonine kinase)

Cladribine: purine analog (looks like adenosine), first line of treatment

Question 16

chronic myeloid leukemia is a disease of what kind of cells? which patients does it most commonly affect?

Answer 16

myeloproliferative neoplasm of granulocytes

most commonly affects middle age adults

Question 17

what mutation is associated with Chronic Myeloid Leukemia (CML), a myeloproliferative neoplasm of granulocytes?

Answer 17

Philadelphia chromosome: t(9;22) —> produces BCR-ABL chimeric protein with GOF

BCR: GTP exchange factor, has dimerization domain
ABL: tyrosine kinase

BCR-ABL: constitutively active tyrosine kinase, trapped in cytoplasm

*note that BCR-ABL (Philadelphia) translocation occurs in hematopoietic stem cells (found in all hematopoietic cells, but preferentially expands neutrophils)

Question 18

how does CML (chronic myeloid leukemia) present? How do you distinguish between infection and CML?

Answer 18

fatigue, weight loss, fever, night sweats, splenomegaly

incidental finding of increased WBC

infection: high neutrophils (leukemoid reaction)

CML: leukocytosis (100K) of neutrophils and other granulocytes - basophilia is key

Question 19

what kind of cancer is basophilia an extremely key finding for?

Answer 19

CML: chronic myeloid leukemia - disease of granulocytes (mostly neutrophils, but all granulocytes increased)

rarely see basophilia other than this

Question 20

what is abnormal about the granulocytes in CML (chronic myeloid leukemia) - aka, what enzyme do they lack?

Answer 20

CML granulocytes have decreased leukocyte alkaline phosphatase

morphologically look normal

Question 21

why does it make sense that if untreated, chronic myeloid leukemia can lead to development of acute myeloid or lymphoid leukemia (blast crisis)?

Answer 21

CML cells have Philadelphia translocation - disregulated growth

acquire more mutations, some of which will inhibit maturation and accelerate growth

remember than translocation is in hematopoietic stem cells (top of the pyramid), so blast crisis can occur in myeloid or lymphoid blasts

Question 22

how can CML (chronic myeloid leukemia) be diagnosed? (5)

Answer 22

1. Philadelphia translocation: BCR-ABL identified via FISH or PCR
2. elevated WBC with basophilia (all granulocytes affected)
3. hyper-cellular bone marrow
4. decreased expression of leukocyte alkaline phosphatase (LAP)
5. peripheral smear shows mature myeloid cells with progenitors

Question 23

how is CML (chronic myeloid leukemia) treated?

Answer 23

Imatinib: small molecule inhibitor of tyrosine kinase - specific for ABL

oral drug, well tolerated

[also dasatinib, nilotinib]