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 years, with a peak incidence at 55years.

3 CML. Historical vs. Modern Perspective ParameterHistoricalModern CourseFatalIndolent PrognosisPoorExcellent 7-yr survival40%90% Frontline Rx Allogeneic SCT; IFN-  Imatinib Second line Rx? New Tyrosine Kinase Inhibitors; allo SCT

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 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. 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

a. Complete Blood Count(CBC): N/N anaemia. WBC count range x 10 9 /L(mean 220x 10 9 /L). Platelet count x10 9 /L(mean 445x10 9 /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

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 or hydroxyurea mg/day orally the effects should be monitored 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

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

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) mg daily( mg x2) 3-DASATINIB (SPRYCEL) 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.