1. PRIMARY THROMBOCYTHEMIA;-
-Also called essential thrombocytosis or essential thrombocythemia.
-It is due to malignant proliferation of megakaryocytes.
-It can occur at any age in adults but most commonly at a median age of 60.
-It is most commonly identified incidentally, but there may be tendencies for bleeding and/or thrombosis.
-Abnormalities of platelet function such as prolonged bleeding time and impaired platelet aggregation may be present.
-Very small percentage may transform to acute leukemia or to myelofibrosis.
-Platelet count ≥ 500,000/ul.
-Splenomegaly may be present.

2. Diagnosis requires the following :-
Exclusion of reactive thrombocytosis.
Platelet count ≥ 500,000/ul
Normal red cell mass.
Absence of Ph chromosome.
Presence of marrow iron ( because iron deficiency can cause thrombocytosis ).
Absence of myelofibrosis.
Splenomegaly.

3. Treatment;-
-Low-risk patients ( age < 40,platelet count < 1000,000/ul and no bleeding or thrombosis ) may require no treatment to reduce platelet count. Asprin is often recommended.
-For those with a platelet count >1000,000/ul or those with symptoms, treatment to control platelets should be given Hydroxycarbamide or anagrelide (an inhibitor of megakaryocyte maturation ) may be used. Aspirin is also recommended especially for patients with digital ischemia.
-Bleeding may respond to ε- aminocaproic acid.

4. Causes of thrombocytosis;-
Iron deficiency anemia.
Hyposplenism.
Postsplenectomy.
Hemolysis .
Hemorrhage .
Polycythemia vera .
Idiopathic myelofibrosis .
Essential thrombocythemia .
Chronic myeloid leukemia .
Correction of vit.B12,folic acid or iron deficiency .
Postsurgery .
Infection .
IBD .

5. Chronic myeloid leukemia ;-
-C.M.L, is a myeloproliferative disorder (MPD) characterized predominantly by increased granulocyte cell line associated with erythroid and platelet hyperplasia..The disease occurs chiefly between the ages of 30 and 80 years, with a peak incidence at 55 years. It is rare, with an annual incidence of 1/ , and accounts for 20% of all leukaemias.. The aetiology is unknown.

6. Cytogenetic and molecular aspects;-
-Approximately 95% of patients with CML have a chromosome abnormality known as the Philadelphia (Ph) chromosome t(9;22).Abl gene (Abelson) on chr. 9 fuse to BCR region (breakpoint cluster) on chr. 22 and generate (BCR-abl) oncogen (chimeric gene) and this gene cod for protein with tyrosine kinase activity, which induce leukemia in stem cell.
-5% of CML patients are Ph-negative but have evidence of the same molecular abnormality, those patient possess detectable BCR-abl oncogen

7. Natural history and Clinical features;-
CML has 3 phases:-
1- chronic phase:- Is indolent phase, last 3-5 years % of patients are asymptomatic-, nonspecific symptoms like tiredness, fatigue, anorexia, weight loss and abdominal discomfort with fever and sweating
>90% there is splenomegaly and in 10% is massive splenomegaly, 50% hepatomegaly ,Lymphadenopathy is unusual .This phase is responsive to treatment and is easily controlled .

9. 2- Accelerated phase: Characterized by fever weight loss, worsening splenomegaly and bone pain . Disease control became more difficult .,
3- Blast crisis phase: disease transformed into acute leukemia ; 70% into AML , 30% into ALL Death occurs in few weeks to months .

10. INVESTIGATION;-
1- Perepheral blood examination : Normocytic, normo chromic anemia. The mean haemoglobin is 10.5 g/dl. - The mean leukocyte count is 220 × 109/l with a range of
The mean platelet count is 445 × 109/l with a range of In the blood film the full range of granulocyte precursors from myeloblasts to mature neutrophils is seen . Myeloblasts are usually less than 10%. There is often an absolute increase in eosinophils and basophile, and nucleated red cells are common.

11. -There is a dramatic increase in the number of circulating myeloblasts as the disease enters blast transform . In about one-third of patients very high platelet counts are seen during treatment, both in chronic and accelerated phases, but these usually drop dramatically at blast transformation.

12. The peripheral blood is the most useful diagnostically.
2- B.M Examination : Bone marrow material should be obtained for chromosome analysis to demonstrate the presence of the Philadelphia chromosome.Increasingly, RNA analysis is being undertaken to demonstrate the presence of the chimeric BCR-abl gene.
3- Other characteristic findings on investigation include a very low neutrophil alkaline phosphatase score LDH levels are also substantially elevated.

13. Classification of CML;-
1- Ph-chromosome positive CML 95%..
2- Ph-chromosome negative, BCR-abl positive..
3- Ph-chromosome negative, BCR-abl negative.
4- Eosinophilic leukemia.

14. Management ;-
Response to treatment regimen in CML are now defined as;-
1-Hematological remission ( restoration of normal peripheral blood count).
2- Cytogenitic remission (loss of Philadelphia Chr.).
3- Molecular remission (loss of BCR-abl gene) .

15. Chemotherapy;-
Hydroxycarbamide (hydroxyurea): Is the most widely used oral agent to provide initial control of the disease A daily dose of around 2-4 g is used initially, and then tailored to maintain the white count in the normal range.Treatment with (hydroxyurea) alone, however, does not diminish the frequency of the Ph chromosome or affect the onset of blast cell transformation.

16. Three types of treatment given in chronic phase can affect survival and result in the loss of the Ph.chromosome; alpha interferon……………………… bone marrow transplant…………… imatinibe mesylate (Gleevic).

17. alpha interferon ;-
-This is given intramuscularly or subcutaneously at 3-9 mega units daily.
* It can induce and maintain control of this disease in chronic phase in about 70% of patients., reduction in the percentage of Ph-positive cells is seen in about 20% * apparent elimination of the Ph chromosome in about 5%.
There is evidence that interferon prolongs survival in those who achieve a significant reduction in Ph-positive cells.

18. Side effect:. Interferon therapy causes 'flu-like' symptoms initially: tiredness, somnolence, weight loss, dizziness, nausea, vomiting, and loss of taste, diarrhea and headache.
-The majority of patients tolerate the therapy well, particularly if the dose can be reduced to 3 mega units 3 times per week.
-It is unwise to use interferon therapy in patients over 75 years of age because of neurotoxicity.
-During treatment the aim should be to maintain the leukocyte count at low levels between 2 and 5 × 109/l.

19. Allogeneic bone marrow transplant ;-
This provides long-term remission.
The best results are obtained in patients in early chronic phase when about 80% can expect probable cure * Monitoring for relapse by detecting the presence of the BCR-abl protein.
The results of transplantation in accelerated and blast transformation phases are significantly worse.
The prospect of long-term survival in up to 40%.

20. Imatinibe mesylate (Gleevic);-
This agent is an inhibitor of the BCR-abl tyrosine kinase.
Early trials have demonstrated excellent activity in chronic phase disease.
>50% achieving Ph-chromosome negativity .
96% achieving hematological remission.
It is also very active in interferon-resistant cases, in accelerated phase and blast crisis.

21. Treatment ;-
Treatment of the accelerated phase and blast crisis of the disease is more difficult. In accelerated phase, hydroxycarbamide (hydroxyurea) can be an effective single agent; Low dose cytarabine can also be tried. Treatment of blastic phase depend on type of acute leukemia.

22. Prognosis ; -
-Patients treated conventionally have a 15% risk of death in the first 12 months.
-Median survival is about 45 months with chemotherapy, months with interferon; patients who have a significant reduction in the Ph chromosome with interferon do best.
-Patients receiving an allograft from a sibling early in chronic phase have an 80% chance of prolonged survival.

23. Philadelphia chromosome-negative chronic myeloid leukaemia ;-
-About half of these patients have the classical molecular abnormality (BCR-positive) without a demonstrable Ph- chromosome. They behave as Ph chromosome-positive patients and they should be managed in the same way. The remainder (BCR-negative) tend to be older, mostly males, , and respond poorly to treatment Median survival is less than 1 year.

24. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
This is the most common variety of leukaemia, accounting for 30% of cases The male to female ratio is 2: The majority of patients are over the age of 45, with a peak at B-cell CLL is most common while T-cell CLL is very rare .

25. Clinical features:
The onset is very insidious.; % of patients the diagnosis is made incidentally Anaemia,& or thrombocytopenia ; (caused by BM failure or Coombs +ve hemolytic anemia.; painless lymphadenopathy ……….. … splenomegaly;………………… infections , CLL causing immune dysregulation and hypogammaglobulinemia.Herpes zoster (shingles) is more common.

26. Investigations
1- Peripheral blood examination usually shows Mild anaemia. Hemolytic anaemia may occur and is usually warm autoimmune HA, BM failure causing normochromic normocytic anemia. Leukocyte count is between 50 and 200 × 109/l, although it may occasionally be greatly increased, up to 1000 × 109/l About 95% or more of these cells are mature lymphocytes. Platelet may be reduced (autoimmune thrombocytopenia).

27. 2- Bone marrow examination by aspirate and trephine may be helpful for diagnosis and prognosis & Patients with diffuse marrow involvement tend to do worse.
3- Chromosome analysis can be helpful; 30-50% of patients have chromosomal abnormalities. The most common abnormality involves chr. 11 or 17 & associated with a poorer prognosis .
4- Estimations of total proteins and immunoglobulin levels should be undertaken to establish the degree of immunosuppression which is common and progressive.

28. Staging

29. Management
Treatment depends upon the stage of the disease: Clinical stage A. No specific treatment is required. Life expectancy is normal in old patients. The patient should be reassured………………………………… Clinical stage B. Chemotherapy with chlorambucil may be initiated in symptomatic patients.,Initial therapy chlorambucil + prednisolne (40-60mg) orFludarabin. Majority of patients respond to this regimine . Local radiotherapy to lymph nodes may be given if causing discomfort.

30. Clinical stage C. Anemia may require transfusion with red cell concentrate……………… Prednisolone, 40 mg daily for 2-4 weeks for treatment of Bone marrow failure, if presen,. autoimmune hemolytic anemia and immune thrombocytopenia IV Gammaglobuline used for treatment of autoimmune phenomenon .

31. Cytotoxic therapy
Chlorambucil, Low – dose daily therapy: 5 mg orally daily, over long periods with dose adjustment according to blood counts Reduce the abnormal lymphocyte mass and produce symptomatic improvement in most patients. intermittent high-dose therapy, 0.4 mg/kg every 2 weeks, chlorambucil may be given as incrementing by 0.1 mg/kg until the maximum tolerated dose is reached. This is continued until the desired therapeutic effect is obtained. In stage C disease there is some evidence that more aggressive combination chemotherapy might be beneficial in terms of disease-free but not overall survival. Fludarabine, a synthetic nucleoside, appears to be the most active drug and is now available orally.
Rituximab and Alemtuzimab(human monoclonal antibody) used for refractory and recurrent CLL.

32. Radiotherapy
Total body irradiation using very small doses spread over 5 weeks in 10 fractions is effective and well tolerated, especially by the elderly. Local radiotherapy may be used to reduce spleen size or treat local problems due to the disease.

33. Infections
These must be vigorously treated. Recurrent viral or non-specific infections (often respiratory) sometimes respond to immunoglobulin replacement therapy.
Splenectomy
This may be required to treat;……………… autoimmune hemolytic anaemia Gross splenic enlargement.

34. Prognosis
The median survival for patients with chronic lymphocytic leukemia is about 6 years……………………… Clinical stage A patients has a normal life expectancy but Stage C patients have a median survival of between 2 and 3 years. Approximately 50% of patients' die of infection and 30% of causes unrelated to chronic lymphocytic leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia rarely transforms to an aggressive high-grade lymphoma, so-called Richter's transformation which carry poor prognosis

35. PROLYMPHOCYTIC LEUKAEMIA
This is a variant of chronic lymphatic leukaemia found mainly in males over the age of 60; 25% of cases are of the T-cell variety. There is massive splenomegaly with little lymphadenopathy and a very high leucocyte counte often in excess of 400 × 109/l; The characteristic cell is a large lymphocyte with a prominent nucleolus.Treatment is generally unsuccessful and the prognosis very poor. Leucopheresis, splenectomy and chemotherapy may be tried.

36. HAIRY CELL LEUKAEMIA
This is a rare chronic lymphoproliferative B-cell disorder The male to female ratio is 6:1. The median age at diagnosis is 50. Presenting symptoms are generally those of ill health and recurrent infections Splenomegaly occurs in 90% but lymph node enlargement is unusual.
Severe neutropenia, monocytopenia and the characteristic hairy cells in the blood and bone marrow are typical.

37. These cells usually type as B lymphocytes but characteristically express CD25 and CD Acharacteristic test is the demonstration that the acid phosphatase staining reaction in the cells is resistant to the action of tartrate. The neutrophil alkaline phosphatase score is almost always very high.
Over recent years a number of treatments have been shown to produce long-lasting remissions. Cladribine and deoxycoformycin are effective in producing long periods of disease control.