Myeloproliferative

Fifth stage

Medicine
Lec-6
د.محمد حارث

20/11/2016

Myeloproliferative disorder
Clonal evolutionClonal 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.





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)










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
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 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.
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 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)
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 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.

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.