Chronic Myelogenous Leukemia

CML

Philadelphia Chromosome

Philadelphia Chromosome Translocation in CML Results in BCR-ABL Oncogene

Stem cell disorder

Characterized by myeloproliferation

Well-described clinical course

9 9q+

22Ph22q-

BCRABL

BCRABL

Translocation

Transcription and translation

Inhibition byTKI

BCR-ABL fusionprotein

CML

Constitutive tyrosine kinase

Phosphorylation of multiple substrates

Mitogenic signaling and genomic instability increased

Apoptosis and stromal regulation decreased

*Clonal myeloproliferative disorder resulting from neoplastic transformation of pluripotent stem cells (affect myeloid, erythroid & megakaryocytic lineages)* proliferation, apoptosis*Cytogenetic hallmark: Ph chromosome positivity

Definition

*7% to 15% of all adult leukemias (5th leukemia in USA)

*Median age at diagnosis: 55 years (20% to 30% of patients ≥ 60 years)

Epidemiology

*Fatal disorder with poor prognosis*Median survival: 3-5 years (2 years without

treatment)

*Allogeneic SCT curative in 40% to 70% of patients (Associated with mortality and toxicity)

*Interferon alfa ± cytarabine: CCyR of 20% to 30%Median survival: 6-7 yearsAlso associated with adverse events

*Other options: hydroxyurea, busulfan

CML: Historical Context Until 2000

* The exact cause is not found* Pathogenesis is well established with

consequences on treatment & prognosis*Possible association with ionizing radiation &

exposure to industrial benzene

Etiology

Asymptomatic – accidentally discovered on routine CBC

Anemia – easy fatigability, malaise, shortness of breath, chest pain, palpitation

High metabolic rate - weight loss, feverLt hypochondrial discomfort, easy satietyBleeding- skin ecchymoses, bruises, petechiaeUGI ulceration & bleeding (↑ s histamine due to

basophilia)Thrombosis – thrombocytosis, leukocytosisHeadache, bone pain, gouty arthritis, leukostasis,

priapism

Clinical Manifestations

Pallor, cutaneous bleeding, splenomegaly (one of the largest spleens)

No lymphadenopathyFeverWeight Loss Hepatomegaly – less common than splenomegaly

Physical Signs

*85% of patients diagnosed with chronic-phase CML

*50% of patients asymptomatic Symptomatic patients exhibit

Constitutional symptomsLeft upper quadrant discomfortEarly satietypurpura ,Splenomegaly, hepatomegaly

1- Benign Phase – in which the disease behavior & response is predictable(Stable phase)

2- Accelerated phase – tumor burden increases rapidly with more systemic symptoms & increasing difficulty in control of disease

3- Acute phase – Blastic crisis may be AML,ALL, AUL

Patient may present in accelerated or acute phase for the first time

Clinical Course

CBC- Hb↓, PCV↓, WBC↑ > 10000/µlDifferential count – Neutrophilic leukocytosis

different stages seen (blasts, promyelocytes, myelocytes, metamyelocytes, stab or band forms), eosinophilia, basophilia

Thrombocytosis or thrombocytopeniaLAP score ↓ or absentSTC I, III ↑, SLDH↑, S histamine↑, S uric

acid↑

Diagnosis

Bone Marrow Aspirate & Biopsy- hypercellular, devoid of fat, myeloid hyperplasia, ↑retculin or collagen fibers, M:E ratio 15-20:1

Cytogenetics- Philadelphia chromosome positivity 95% (Ph –ve 5%) shortened long arm of chromosome22

Molecular biology- BCR/ABL gene positive

Dx-cont

CMLCP

LAP score- CML

LAP+2 CML

* Balanced reciprocal translocation between chromosome 22 & chromosome 9 [t(9;22)] that brings BCR gene in juxtaposition with ABL gene forming a new hybrid gene BCR/ABL that codes for synthesis of a chimeric protein P210 that shows tyrosine kinase activity causing uncontrolled proliferation of the malignant clone

Pathogenesis

1- Leukemoid reaction rarely WBC count exceeds 30000, not clonal, BM no blasts excess, seen in overwhelming sepsis & disseminated TB.

2- MDS – CMML stage.3- chronic corticosteroids use

(demargination).4- other MPD.

DD

Parameter Historical Perspective (Until 2000)

Modern Perspective (Since 2000)

Course Fatal Indolent

Prognosis Poor Excellent

Median survival, yrs 3-6 ≥25*

Frontline treatment Allogeneic SCT, interferon alfa

Imatinib

Second-line treatment Not established Allogeneic SCT, novel TKIs

CML: Overview of Historical vs Modern PerspectiveTreatment

Targeted Therapy- 1- Imatinib mesylate 400 mg/d - TKI targets the pathogenetic mechanism - revolutionized treatment causing CCyR &

CMRS/E skin rash, edema, myelosuppression,

hepatitis2- Dasatinib & Nilotinib 2nd line for imatinib

failure or hypersensitivity3- high dose imatinib 600-800 mg/d

Treatment Lines

* BMT when enter accelerated phase prior to acute phase

* Interferon-α + cytosine arabinoside* Hydroxyurea orally* Busulfan (myleran) orally – no more used now

because of severe & protracted myelosuppression

Other ttt

1- Allopurinol2- H-2 blockers3- PPI4- Blood transfusion5- platelet transfusion

Other ttt- supportive

It was an inevitably fatal diseaseWith recent treatment became a curable

disease compatible with long survivalNewer agents are evolvingImproving BMT &SCT resultsOnce the patient enters the acute phase the

only hope remains in transplantation & TKI are used as bridging to that

Prognosis

Poor Prognostic Factors in CML •Older age

•Splenomegaly •Anemia

•Thrombocytosis, thrombocytopenia • Blasts, promyelocytes, basophils

•Marrow fibrosis •Cytogenetic clonal evolution

(Euro ,)MDACC Prognostic Models: Sokal, Hasford