1. CASE STUDY
Leukemia

2. A-30 year old white male presented with: a three-weak history of moderate shortness of breath, left upper quadrant pain, he denied weight loss, night sweats or fever Past medical history was not relevant

3. On physical examination,the patient was in no apperent distress.
Lungs were clear to auscultation.
Abdominal palpation revealed an enlarged and non tender spleen,15cm below the left costal margin with no hepatomegaly.

4. On admission,
peripheral blood counts showed a leukocytosis of
130 x 10/1 with immature myeloid forms (13% bands,
54% neutrophils, 10% lymphocytes, 5% monocytes, 4%
basophils, 5% metamyelocytes, 4% myelocytes,
4% promyelocytes and 2% blast cells),
hematocrit of 35%
platelet count of 435 x 109/l.
Biochemistry analysis demonstrated a raised serum LDH, of 1500 IU/1,
uric acid of 10.4 mmol/1.
Renal and hepatic functions were within normal limits.
Bone marrow aspirate showed an increased cellularity with myeloid hyperplasia and a marked basophilia. Megakaryocytes were also increased with hypolobulated forms

5. Trephine demonstrated marked hypercellularity with loss of fat spaces and no evidence of bone marrow fibrosis.
An abdominal ultrasonography showed an enlarged homogenous spleen with no focal lesions.
Conventional cytogenetic analysis demonstrated the typical translocation between chromosome 9 and 22, the Ph chromosome, in 100% of the metaphases analysed.

6. The patient was diagnosed a Philadelphia-positive
chronic myeloid leukaemia (Ph+ CML) stage I according
to Kantarjian's prognostic classification,
and started cytoreductive treatment with hydroxyurea given orally at conventional dosages (20-50 mg/kg per day) with good initial control of peripheral blood counts, partial reduction of the enlarged spleen and improvement of his general condition.
In accordance to our local protocol,
one month after the diagnosis and beginning of therapy
hydroxyurea was stopped and IFN-a was started at increasing doses, up to 9 x 106 IU s.c. daily, with minimal
side effects (flu-like symptoms) and good control of leukocyte counts with no significant haematological toxicity.
After 3 months of IFN-a treatment, the spleen was no
longer palpable, but there was no significant cytogenetic response.

7. CML
CML is defined as a stem cell disorder suggested as Philadelphia chromosome found in all stem cells. So there is replacement of normal B.M cells by cells with an abnormal chromosome – Philadelphia or (ph) chromosome t (9; 22)(q34; q11).
Constitute six different types of leukemia.

8. Types of CML

9. The incidence of CML
CML comprises <20% of all leukaemia, its rarer than CLL. The incidence rate is 1-2/100,000-1 population; with a peak of incidence in the middle age people.
The disease occur in either sex (male: female 1.4:1), however,it may occur in children, neonates and very old people.

10. What is philadelphia chromosome

11. Ph chromosome
Is the chromosome which result from the t(9;22)(q34;q11) part of the Abelson proto-oncogene ABL is moved to the BCR gene on chromosome 22 & part of chromosome 22 moves to chromosome 9.
The abnormal chromosome 22 is the Ph

12. Pathogenesis
Genetic abnormality CML is the result of an acquired genetic abnormality A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome The oncogene BCR-ABL encodes an enzyme – tyrosine phosphokinase (usually p210)
The function of the normal abl gene product ( p145abl ) is incompletely understood but it is known to have tyrosine kinase activity and may play a role in the regulation of several different growth factor receptors, including those for epidermal growth factor, platelet derived growth factor, and colony stimulating factor receptors.

13. Pathogenesis,cont;
The normal bcr gene product (p160bcr ) is known to have serine/threonine kinase activity and shows considerable homology to a number of cell cycle proteins. It is thought to play an important role in cellular signal transduction.
The chimeric bcr-abl fusion gene produces a chimeric protein of molecular weight 210,000 daltons (p210bcr-abl ). This protein has much more powerful tyrosine kinase activity than p145abl and has been shown to interact with its substrates in an altered manner. (p210bcr-abl ) has a great serine / threonine activity that enhance

14. Clinical presentation
Increasing splenomegally, which is associated with discomfort, pain or indigestion.
Refractory anaemia that include pallor, weakness and tachychardia.
Bruising, epistaxis due to abnormal platelet functions.
Gout or renal impairment due to hyperuricemia.
Visual disturbances.
Increase requirement to chemotherapy to maintain remission.
Massive increasing of circulating granulocytes.

15. Phases of CML
Chronic phase
Accelerated phase
Plastic phase

16. Clinical presentation of Ph+ CML

17. Treatment Chemotherapy: Tyrosine kinase inhibitor: Interferon-a:
Stem cell transplant.