L5a

Summary of CML

	Definition		Lab/clinical
CML	Stem cell defect inducing overabundance  of granulocytes (predominantly), through . . . • Increased granulocyte proliferation • Premature release of granulocytes from the marrow (and other sites) into the peripheral blood • Prolonged granulocyte lifespan (via inhibition of apoptosis) BCR-ABL1 GENE REARRANGEMENT: • t(9;22)(q34;q11.2) • abnormal tyrosine kinase Rx: Gleevec and second-generation tyrosine kinase inhibitors • Present in all hematopoietic lineages • Identified (cytogenetically and/or genotypically) in 100% of cases of true CML	BCR-ABL1 9;22	CLINICAL FEATURES:Slow, insidious onset SYMPTOMS: General leukemic symptoms, especially abdominal discomfort due to splenomegaly SIGNS: Pallor, petechiae, HSM bone (esp. sternal) tenderness PERIPHERAL BLOOD FINDINGS: • Granulocytosis (WBC up to 250,000), with all stages    of maturation present • Anemia • Thrombocytopenia; thrombocytosis (30%) • Increased LDH, uric acid, vitamin B12 • LAP score decreased Hypercellular (near 100%) BM ACUTE BLAST TRANSFORMATION (“CRISIS”): • If unsuccessfully treated, occurs in nearly all cases,  usually within 1 to 4 years • Often preceded by “accelerated” phase • Definition:  >20% blasts in peripheral blood and/or bone marrow • AML  70% of cases;  ALL 30%
Markedly increased neutrophilic precursors with  progressive maturation, ↑eosinophils and basophils +/- ↑ megakaryocytes

 

What is causing the increase in WBCs?

•       CML is the result of a stem cell defect à overabundance of granulocytes due to increased proliferation, premature release, and prolonged lifespan (from apoptosis inhibition)

Why does she have petechiae?

• When there is an increase in a neoplastic monoclonal cell line there is a subsequent inhibition of normal clones. 
• 1. Increased proliferation, as a result of:
•  Inability to differentiate and mature → acute leukemias
•   Increased mitosis → acute and chronic leukemia
• 2. Increased survival of progeny → chronic leukemias
• 3. Inhibition of normal hematopoietic clones → acute and chronic leukemias
• This means that there will be less megakaryocytes (and thus less platelets) so thrombocytopenia will be seen. This will lead to insufficient clotting abilities and the presence of petechiae. Other normal cell lines will be decreased as well (for example: the patient may have anemia from a decrease in RBCs).

Would you expect the LAP score to be increased, decreased, or show no change? - decreased

LEUKOCYTE ALKALINE PHOSPHATASE (LAP)  SCORE • 100 peripheral blood neutrophils are scored 0 – 4+ for amount of alkaline phos. • Normal range = 15 – 150 • Decreased in chronic myelogenous leukemia • Normal to increased in leukemoid reaction, polycythemia vera, primary myelofibrosis, etc. LAP increased when there is a left shift = leukemoid reaction!!!!

Describe the bone marrow:

•          Hypercellular (100%),
•         The aspirate shows all levels of maturation, excess granulocytes (lots of PMN precursors), ↑ basophils/eosinophils

What do you think she has? CML

• lack of blasts and the presence of cells at various levels of maturation tells us we are dealing with a chronic (not acute) leukemia
• the abundance of WBCs tells us that the origin is myeloid

What translocation is typically associated with the form of leukemia?

• 9;22 - Philadelphia chromosome
• Tyrosine kinase (normally TK must be activated - however due to the translocation TK is constitutively active in CML --> proliferation)

What can we use to treat this type of leukemia and what does it target?

• Gleevac: imatinib: tyrosine kinase inhibitor

What is the patient at risk for if we do not treat her lymphoma?

• acute blast crisis (>20% blasts) -- 70% AML