CML

 Stem cell disorder  Characterized by myeloproliferation  Well-described clinical course 9 9q+ 22 Ph 22q- BCR ABL BCR ABL Translocation Transcription and translation Inhibition by TKI BCR-ABL fusion protein 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

*7% to 15% of all adult leukemias (5 th leukemia in USA) *Median age at diagnosis: 55 years (20% to 30% of patients ≥ 60 years)

*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 years Also associated with adverse events *Other options: hydroxyurea, busulfan

* The exact cause is not found * Pathogenesis is well established with consequences on treatment & prognosis *Possible association with ionizing radiation & exposure to industrial benzene

Asymptomatic – accidentally discovered on routine CBC Anemia – easy fatigability, malaise, shortness of breath, chest pain, palpitation High metabolic rate - weight loss, fever Lt hypochondrial discomfort, easy satiety Bleeding- skin ecchymoses, bruises, petechiae UGI ulceration & bleeding (↑ s histamine due to basophilia) Thrombosis – thrombocytosis, leukocytosis Headache, bone pain, gouty arthritis, leukostasis, priapism

Pallor, cutaneous bleeding, splenomegaly (one of the largest spleens) No lymphadenopathy Fever Weight Loss Hepatomegaly – less common than splenomegaly

*85% of patients diagnosed with chronic-phase CML *50% of patients asymptomatic Symptomatic patients exhibit Constitutional symptoms Left upper quadrant discomfort Early satiety purpura,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

CBC- Hb↓, PCV↓, WBC↑ > 10000/µl Differential count – Neutrophilic leukocytosis different stages seen (blasts, promyelocytes, myelocytes, metamyelocytes, stab or band forms), eosinophilia, basophilia Thrombocytosis or thrombocytopenia LAP score ↓ or absent STC I, III ↑, SLDH↑, S histamine↑, S uric acid↑

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

* 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

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.

ParameterHistorical Perspective (Until 2000) Modern Perspective (Since 2000) CourseFatalIndolent PrognosisPoorExcellent Median survival, yrs3-6≥ 25* Frontline treatmentAllogeneic SCT, interferon alfa Imatinib Second-line treatmentNot establishedAllogeneic SCT, novel TKIs

Targeted Therapy- 1- Imatinib mesylate 400 mg/d - TKI targets the pathogenetic mechanism - revolutionized treatment causing CCyR & CMR S/E skin rash, edema, myelosuppression, hepatitis 2- Dasatinib & Nilotinib 2 nd line for imatinib failure or hypersensitivity 3- high dose imatinib mg/d

* 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

1- Allopurinol 2- H-2 blockers 3- PPI 4- Blood transfusion 5- platelet transfusion

It was an inevitably fatal disease With recent treatment became a curable disease compatible with long survival Newer agents are evolving Improving BMT &SCT results Once the patient enters the acute phase the only hope remains in transplantation & TKI are used as bridging to that

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