Chronic Myelogenous Leukemia CML

Definition (Moyo Om Pmc 2006.81 973)

• Myeloproliferative disorder with overproduction of myeloid cells that can differentiate

• Philadelphia chromosome (Ph) t(9;22) - Bcr-Abl fusion t Abl kinase activity

2-5% of Pts have a cryptic Ph chr.. but are BCR-ABL PCR ® and respond to imatinib 5% of Pts are Ph chr. & BCR-ABL ; likely distinct disease & does not respond to imatinib

Epidemiology and risk factors

• 4300 new cases y in U.S.; median age 50 at presentation; 15% of adult leukemias

• i risk with irradiation; no clear relation to cytotoxic drugs

Clinical manifestations

• Triphasic clinical course; 85% present in the chronic phase

• Chronic phase: often asymptomatic but common features are fatigue, malaise, weight loss, night sweats, abdominal fullness (splenomegaly 50%)

• Accelerated phase: refractory leukocytosis and worsening symptoms — fever, weight loss, progressive splenomegaly, bone pain, bleeding, infections, pruritus (basophilia)

• Blastic phase acute leukemia — severe constitutional symptoms, infection, bleeding.

and possible leukostasis (see "Acute Leukemia")

Diagnostic evaluation

• Peripheral smear leukocytosis (often 100.000 jil). left-shifted with all stages of myeloid maturation-, anemia, thrombocytosis, basophilia

• Bone marrow: hypercellular. i myeloid to erythroid ratio, i leuk alkaline phosphatase

• Accelerated. 10-20% blasts. 20% basos. pits 100k. i spleen size, karyotypic prog.

• Blastic: 20% blasts (2 3 myeloid. 1 3 lymphoid), may see extramedullar leukemia

Treatment (nejm 2003:3491451 & 2006:355:2406)

• Imatinib. a selective inhibitor of the Bcr-Abl tyrosine kinase active in chronic, accelerated, and blastic phases (but less as disease advances) higher response rates than prior standard of IFN • ara-C (nejm 2003:348 994.1423) consider for all Pts in chronic phase

• Imatinib resistance associated with BCR-ABL mutation or amplification newer tyrosine kinase inhibitors such as dasatinib and nilotinib inhibit most imatinib resistance mutations in Bcr-Abl except forT315l (nejm 2006:354:2531.2542)

• Allogeneic HSCT: consider for Pts w available donor who present in accelerated or blastic phase; reasonable option for Pts with relapsed refractory disease to imatinib

Goals of Imatinib Therapy

Response

Definition

Goal time

Hematologic

WBC 10K. Pit 450. -'5% myelocytes & metamyelocytes. <20% basos. no immature cells in blood, no extramedullary involvement

3 mo

Cytogenetic Molecular

Absence of the Ph chromosome in metaphase cells 3-log reduction by quantitative PCR

12 mo 12-18 mo

Prognosis

• Chronic phase CML Rx'd w imatinib: 89% overall survival. 7% progression to blast phase at 5 y (NEJM 2006:355:2408)

• Accelerated phase CML Rx'd w imatinib: 50% overall survival at 4 y (Cancw

200S: 103:2099)

• Poor prognostic factors: 7 age. T platelet count, î spleen size, 1 percentage of blasts

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