2. Chronic Myeloid Leukemia

3. Leukemia ALL, AML, CLL ALL, AML, CLL Chronic Myelogenous Leukemia Chronic Myelogenous Leukemia –Cancer of the granulocytes or monocytes, compared to leukocytes in lymphocytic leukemias –Comprises about 14% of all adult leukemias –Males slightly higher than females –One of the first cancers to have a specific genetic link to a chromosomal mutation identified for the disease  Philadelphia Chromosome

4. Pathophysiology Disorder of the stem cells in bone marrow General infection fighting cells are the most harmed > granulocytes and monocytes (aka, neutrophils) These immature cells take over the body’s mature neutrophils and hinder the body’s ability to fight infection properly CML is caused by a genetic mutation with chromosomes 9 and 22 in the body Abl on chromosome 9 is translocated to chromosome 22 and fuses with Bcr This ABL-BCR protein is an unregulated tyrosine kinase and thus, is the source of the reproduction of immature granulocytes Other functions include: upstream changes of DNA repair mechanisms, suppression of the body’s programmed cell death proteins, and changes in cytoskeletal structures

7. How you are diagnosed Usually by accident! Usually by accident!  Routine WBC test shows elevated leukocytes Routine WBC test shows elevated leukocytes Confirmed with bone marrow biopsy and FISH and/or PCR that shows presence of Philadelphia Chromosome Confirmed with bone marrow biopsy and FISH and/or PCR that shows presence of Philadelphia Chromosome Presence of myeloid cells in peripheral blood determines staging of disease Presence of myeloid cells in peripheral blood determines staging of disease S/SX: lethargy, pallor, night sweats, weight loss, anorexia, fever, lymphadenopathy, splenomegaly S/SX: lethargy, pallor, night sweats, weight loss, anorexia, fever, lymphadenopathy, splenomegaly

8. STAGING OF CML - Three main stages, determined by percentage of blast cells in the blood -Chronic Phase -Patient usually diagnosed -Fewer than 10% of cells in blood and bone marrow are granulocytes -Prognosis: (with imatinib) 5yr: 70%, 10yr: 30-40% -Accelerated Phase -10-19% of cells are granulocytes -Blastic Phase, aka “blast crisis” -Fulminant symptoms of disease, multiple organ involvement -20-30% or more granulocytes in bone marrow and blood -Prognosis: UNPROMISING, 2 months, may extend survival with newer drugs or chemotherapy

9. Treatment Options: Pharmacotherapy Pharmacotherapy –Newer drugs are prolonging chronic phase and increasing the number of patients who enter into remission –They are easier on the body versus SCT –Old Standard: hydroxyurea (no possible cytogenic response) or interferon alpha + cytarabine –New Standard: tyrosine kinase inhibitors  Imatinib, dasatanib, nilotonib Stem Cell Transplant Stem Cell Transplant –Using bone marrow from a donor to “resupply” the patient –Can be the only “curative” measure, although many drawbacks  Must be good candidates for surgery  Must have a relatively short time from diagnosis to transplant  Matching donor  Possible relapse of CML  Rejection (GVHD)

10. How to measure treatment Hematologic response Hematologic response –The response that reflects a decrease in white blood cell count and platelets –A hematological response in CML would be shown when a patient went from about a 10% granulocyte count to a 4% granulocyte count –Good prognostic sign Cytogenic response Cytogenic response –Reduction or elimination of Ph+ cells in bone marrow –Can be Complete, Major or Minor  0%, 1-34%, 35-90% respectively in bone marrow cells –Done by FISH and/or PCR –Chronic phase patients who have cytogenic responses have a significant increase in survival and a deterrence to progression to accelerated or blast phases –Better prognostic sign

11. New Treatments: Tyrosine Kinase Inhibitors Enzyme that is able to transfer a phosphate group from ATP to a tyrosine residue in a protein Enzyme that is able to transfer a phosphate group from ATP to a tyrosine residue in a protein Main proponents of signal transduction of enzymes in body, in bone marrow, this is one of many proteins that plays a large role in hematopoeisis Main proponents of signal transduction of enzymes in body, in bone marrow, this is one of many proteins that plays a large role in hematopoeisis In CML, the BRC-ABL gene is a tyrosine kinase that is constituently active, and thus produces unregulated granulocytes In CML, the BRC-ABL gene is a tyrosine kinase that is constituently active, and thus produces unregulated granulocytes A great advance in the treatment of CML was to develop a tyrosine kinase inhibitor, that “turns off’ the active TK in the body, specific to the mutated gene, BRC-ABL A great advance in the treatment of CML was to develop a tyrosine kinase inhibitor, that “turns off’ the active TK in the body, specific to the mutated gene, BRC-ABL The first generation TK inhibitor for CML is imatinib mesylate The first generation TK inhibitor for CML is imatinib mesylate

12. Imatinib mesylate First generation TK inhibitor First generation TK inhibitor Dosed in 400mg and 800mg tablets Dosed in 400mg and 800mg tablets Binds the closed form of the ATP binding site in BRC-ABL Binds the closed form of the ATP binding site in BRC-ABL IRIS study: 97% pts in hematological remission and major cytogenic remission was 87% compared to interferon alpha + cytarabine after 19 months IRIS study: 97% pts in hematological remission and major cytogenic remission was 87% compared to interferon alpha + cytarabine after 19 months IRIS Follow-up five year study: if patient shows a 3-log molecular response to imatanib, then probability of progression-free survival at 4 years is 98% (Frame 2006) IRIS Follow-up five year study: if patient shows a 3-log molecular response to imatanib, then probability of progression-free survival at 4 years is 98% (Frame 2006) Side Effects: Fluid retention (76%), diarrhea (30-60%), nausea (43-73%), fatigue, muscle cramps, bone pain, rash, neutropenia, thrombocytopenia (although might be signs of effectiveness) Side Effects: Fluid retention (76%), diarrhea (30-60%), nausea (43-73%), fatigue, muscle cramps, bone pain, rash, neutropenia, thrombocytopenia (although might be signs of effectiveness) –Most can be alleviated with common medications and are not a cause of discontinuation Resistance occurs Resistance occurs

13. A small number of patients show some resistance to Imatanib A small number of patients show some resistance to Imatanib The BRC-ABL transcript has the ability to mutate and thus make imatinib ineffective The BRC-ABL transcript has the ability to mutate and thus make imatinib ineffective Imatinib binds to the closed conformation and BRC-ABL can mutate to the open conformation and thus makes imatanib ineffective Imatinib binds to the closed conformation and BRC-ABL can mutate to the open conformation and thus makes imatanib ineffective Two 2 nd generation TKIs have proven to be more potent and are in trials to determine effectiveness against resistance to imatanib Two 2 nd generation TKIs have proven to be more potent and are in trials to determine effectiveness against resistance to imatanib

14. 2nd Generation TKIs Dasatanib Dasatanib –aka Sprycel; 300 times more potent than imatanib –Binds to multiple conformational states (open and closed), unlike imatanib –Very new drug, approved in July, 2006 for further clinical trials –Side Effects: myelosuppression which can lead to bleeding, infection and fatigue, fluid retention, headache, skin rash, nausea –Can be used in patients who are resistant to imatanib Nilotonib Nilotonib –Structurally similar to imatanib –20 to 50 times more potent than imatanib –Binds in the closed conformation –Not FDA approved, still under scrutiny COMBOS with dasatanib, nilotonib and imatinib have proven that they do not inhibit each other, and prove useful in pilot experiments with resistant cell clones COMBOS with dasatanib, nilotonib and imatinib have proven that they do not inhibit each other, and prove useful in pilot experiments with resistant cell clones

15. Treatment Algorithm

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