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Fifth stage
Medicine
Lec-6
.د
محمد حارث
20/11/2016
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.
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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)
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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
• Features of anaemia
– Pallor, dyspnoea, tachycardia
• Abnormal platelet function
– Bruising, epistaxis, menorrhagia
• Hyperleukocytosis
– thrombosis
– Increased purine breakdown : gout
– Visual disturbances
– Priapism
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
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– Blast & promyelocyte > 30% in blood
– Basophil 20% in blood
– Thrombocytopenia
– Cytogenetic: clonal evolution
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)
LABORATORY FINDINGS:
a. Complete Blood Count(CBC):
N/N anaemia.
WBC count range 9.5-600 x 10
9
/L(mean 220x 10
9
/L) .
Platelet count 162-2000 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.
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
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CML - principles of treatment:
• Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosis
o Hydration
o Chemotherapy (busulphan, Hydoxyurea)
• Control and prolong chronic phase
o alpha interferon+chemotherapy
o imatinib mesylate
o chemotherapy (hydroxyurea)
• Eradicate malignant clone (curative)
o allogeneic transplantation
o alpha interferon ?
o imatinib mesylate/STI 571 ?(Tyrosine kinase inhibitor)
• Chemotherapy ;
o Hydroxycarbamide or hydroxyurea 1000-1500 mg/day orally the effects should
be monitored every 2-6 weeks.
Fewer side effect
o Acts by inhibiting the enzyme ribonucleotide reductase
o Haematological remissions obtain in 80%.
o However disease progression not altered and persistence of Ph chromosome
containing clone.
1. HSCT (Hematopoietic stem cell transplantation):
Intensive chemotherapy and total body irradiation (TBI) are followed by the transplantation
of HLA matched allogeneic stem cell.
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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.
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.