Myeloproliferative disorder Clonal evolution Clonal evolution & stepwise progression to fibrosis, marrow failure or acute blast phase

Chronic myelogenous leukemia(CML) Description : CML is a myeloproliferative disorder characterized by increased proliferation of granulocyte, and evidence of myeloproliferation involve liver and spleen. -CML accounts for 20% of all leukemia affecting pts. between 30-80 years, with a peak incidence at 55years.

CML. Historical vs. Modern Perspective Parameter Historical Modern Course Fatal Indolent Prognosis Poor Excellent 7-yr survival 40% 90% Frontline Rx Allogeneic SCT; IFN- Imatinib Second line Rx ? New Tyrosine Kinase Inhibitors; allo SCT 3 3

ETIOLOGY Not clear Little evidence of genetic factors linked to the disease Increased incidence Survivors of the atomic disasters at Nagasaki & Hiroshima Post radiation therapy CML is an acquired abnormality that involves the stem cells and is characterized by specific chromosomal abnormality (translocation) between the long arm of chromosome 22 and 9 which is called philadelphia chromosome (ph). Approximately 95 % of patients with CML have this abnormality. The chromosome has been found in all myeloid and lymphoid cell indicating the involvement of the pluripotential stem cell.

Leukaemogenesis Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine kinase activity BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokines It protects hematopoietic cells from programmed cell death (apoptosis)

Phases of chronic myeloid leukemia Chronic phase Accelerated phase Blast crisis 5 years

CLINICAL FEATURES Chronic Phase : 25% asymptomatic at time of diagnosis Chronic Phase : Splenomegaly in 90% of patients . In about 10% the enlargement is massive. Afriction rub may be heard in cases of splenic infarction. Hepatomegaly 50%. Lymhadenopathy is unusual. Symptoms related to hypermetabolism Weight loss Anorexia Lassitude Night sweats Stable disease, no cancer out side bone marrow or spleen, Median duration 3 years, range several months to > 20 years 15cm

Clinical Features - cont… Features of anaemia Pallor, dyspnoea, tachycardia Abnormal platelet function Bruising, epistaxis, menorrhagia Hyperleukocytosis thrombosis Increased purine breakdown : gout Visual disturbances Priapism

Phases- Cont. Accelerated phase Median duration is 3.5 – 5 yrs before evolving to more aggressive phases Clinical features Increasing splenomegaly refractory to chemotherapy Increasing chemotherapy requirement Lab features Blasts>15% in blood Blast & promyelocyte > 30% in blood Basophil 20% in blood Thrombocytopenia Cytogenetic: clonal evolution

Phases-Cont. CML-ALL CML-AML Blastic phase Resembles acute leukaemia Diagnosis requires > 20% blast in marrow 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase Survival : 9 mos vs 3 mos (lym vs myeloid) CML-ALL CML-AML

LABORATORY FINDINGS a. Complete Blood Count(CBC): N/N anaemia. WBC count range 9.5-600 x 109/L(mean 220x 109/L) . Platelet count 162-2000 x109/L(mean 445x109/L) In the blood film all stages of maturation are present from myeloblast to neutrophil, myeloblast less than 10%. Basophilia &oesonophils may increase as the disease progresses.

LABORATORY FINDINGS- Cont. b. Bone marrow; Hypercellular (reduced fat spaces) Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1) Myelocyte predominant , blasts less 10% Megakaryocytes increased & dysplastic Increase reticulin fibrosis in 30-40%. *For chromosomal analysis(Ph chromosome), *RNA analysis for BCR-ABL. c. other laboratory findings : Serum B12 and transcobalamin increased Serum uric acid increased Lactate dehydrogenase increased

CML - principles of treatment Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis Hydration Chemotherapy (busulphan, Hydoxyurea) Control and prolong chronic phase alpha interferon+chemotherapy imatinib mesylate chemotherapy (hydroxyurea)

CML - principles of treatment Eradicate malignant clone (curative) allogeneic transplantation alpha interferon ? imatinib mesylate/STI 571 ?(Tyrosine kinase inhibitor) Chemotherapy ; Hydroxycarbamide(Hydroxyurea) 1000-1500 mg/day orally the effects should be monitered every 2-6 weeks. Fewer side effect Acts by inhibiting the enzyme ribonucleotide reductase Haematological remissions obtain in 80%. However disease progression not altered and persistence of Ph chromosome . containing clone

1-HSCT Intensive chemotherapy and total body irradiation (TBI) are followed by the transplantation of HLA matched allogeneic stem cell.

3-.Tyrosine kinase activity inhibitor 1- IMATINIB mesylate/ (STI 571, GLIVEC) 400 mg single dose orally. Acts specifically by blocking the binding site for ATP in the Abl kinase. 2-NILOTINIB (TASIGNA) 600-800 mg daily(300-400 mg x2) 3-DASATINIB (SPRYCEL) 50-70 mg once or twice daily 4-Ponatinib

Variants of CML *Ph-negative CML BCR-ABL negative; About 5% of patients with haematologically acceptable CML lack the Ph chromosome. older patient mostly male with lower platelet count and higher absolute monocyte count. Respond poorly to treatment. Median survival less than 1 year.

Variants of CML-Cont. *Juvenile CML Rare. Affecting children <12 year-old. C/F – anaemia, or lymphadenopathy with hepatosplenomegaly, skin rashes. Lab findings – leucocytosis with variable numbers of blast in the peripheral blood. Marrow is hypercellular but lacks chromosomal abnormalities. Responds poorly to standard cytotoxic drugs.