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Chronic Myeloid Leukemia. Leukemia. ALL, AML, CLL 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

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Presentation Transcript
leukemia
Leukemia
  • ALL, AML, CLL
  • 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
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

Pathophysiology
how you are diagnosed
Usually by accident!

Routine WBC test shows elevated leukocytes

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

S/SX: lethargy, pallor, night sweats, weight loss, anorexia, fever, lymphadenopathy, splenomegaly

How you are diagnosed
staging of cml
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
treatment options
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

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)

Treatment Options:
how to measure treatment
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

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

How to measure treatment
new treatments tyrosine kinase inhibitors
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

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

The first generation TK inhibitor for CML is imatinib mesylate

New Treatments: Tyrosine Kinase Inhibitors
imatinib mesylate
Imatinib mesylate
  • First generation TK inhibitor
  • Dosed in 400mg and 800mg tablets
  • 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 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)
    • Most can be alleviated with common medications and are not a cause of discontinuation
  • Resistance occurs
slide12
A small number of patients show some resistance to Imatanib
  • 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
  • Two 2nd generation TKIs have proven to be more potent and are in trials to determine effectiveness against resistance to imatanib
2 nd generation tkis
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

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

2nd Generation TKIs
references
References
  • Faderl S, Kantarjian HM. Chronic Myelogenous Leukemia and Other Myeloproliferative Disorders. [ BOOK, check citing!]. ACP Medicine. 2006. vol 2(2570-79)
  • Fausel C. Novel treatment strategies for chronic myeloid leukemia. Am J Health-Syst Pharm. 2006 Dec 1; 63(Suppl 8): S15-S20.
  • Grigg A, Hughes T. Role of Allogenic Stem Cell Transplantation for Chronic Myeloid Leukemia in the Imatinib Era. Biol Blood Marrow Transplant. 2006 Mar 29; 12:795-807.
  • http://www.gleevec.com/info/page/safety_info
  • http://www.cmlmedicalmonitor.com/medical-monitor/education/ayd_response.asp?trial=show
  • http://www.pharmcast.com/Patents/Yr2002/Mar2002/032602/6362162_CML032602.htm
  • http://images.google.com/images?q=PHILADELPHIA+CHROMOSOME+image&hl=en&sa=X&oi=images&ct=title
  • http://commons.wikimedia.org/wiki/Image:Bcr-abl_fusion_gene.jpg