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
ParameterHistorical
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
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 activityBCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of cytokinesIt protects hematopoietic cells from programmed cell death (apoptosis)Phases of chronic myeloid leukemia
Chronic phaseAccelerated 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 years15cm
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 phaseMedian duration is 3.5 – 5 yrs before evolving to more aggressive phasesClinical featuresIncreasing splenomegaly refractory to chemotherapyIncreasing chemotherapy requirementLab featuresBlasts>15% in bloodBlast & promyelocyte > 30% in bloodBasophil 20% in bloodThrombocytopeniaCytogenetic: clonal evolutionPhases-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 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
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 & dysplasticIncrease reticulin fibrosis in 30-40%.*For chromosomal analysis(Ph chromosome), *RNA analysis for BCR-ABL.c. other laboratory findings : Serum B12 and transcobalamin increasedSerum uric acid increasedLactate dehydrogenase increasedCML - 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 1000-1500 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 cloneIntensive chemotherapy and total body irradiation (TBI) are followed by the transplantation of HLA matched allogeneic stem cell.
1. HSCT (Hematopoietic stem cell transplantation