A myeloprolifrative stem cell disorder resulting in Proliferation of all haematopoietic lineages but manifestation Predominantly in the granulocytic series. The disease occurs chiefly between 30 and 80 years, with A peak incidence at the 55 years. *accounts for 20% of all leukaemis. *found in all races. *the aetiology is unknown.

1. CHRONIC LEUKAEMIA

2. Chronic myeloid leukaemia:
A myeloprolifrative stem cell disorder resulting in
Proliferation of all haematopoietic lineages but
manifestation Predominantly in the granulocytic series.
The disease occurs chiefly between 30 and 80 years, with
A peak incidence at the 55 years.
*accounts for 20% of all leukaemis.
*found in all races.
*the aetiology is unknown.

3. Cytogenetic and molecular aspects :
The defining characteristic of CML is a chromosome abnormality
Known as the philadelphia (Ph) chromosome.
This is a shortened chromosome 22 and is the result of
A reciprocal translocation of material with chromosome 9.
The break on chromosome 22 occurs in the breakpoient
Cluster region (BCR ).the fragment from chromosome 9 that
Joins the BCR carries the abl oncogene, which form a fusion
Gene with the remains of the BCR.

6. This BCR ABL chimeric gene codes for a 210 kDa
Protein with tyrosine kinase activity, which plays
A causative role in the disease, influencing cellular
Proliferation, differentiation and survival.
In some apparently Ph chromosome –negative patients
The BCR ABL gene product is detectable by molecular
Techniques.

7. Natural history :
The disease has three phases:
*a chronic phase, in which the disease is responsive to treatment
And is easily controlled, lasting 3-5 years.
*an accelerated phase (not always seen), in which disease control
Becomes more difficult.
*blast crisis, in which the disease transform into an acute leukaemia,
Either myeloid (70%) or lymphoblastic (30%), which is refractory to
Treatment.
Blast crisis occurs at a rate of 10% per year and is the cause of death
In the majority of patients.
Patients survival is therefore dictated by the timing of blast crisis,
Which can not be predicted.

8. Patients who are Ph chromosome- and also
BCR ABL-negative tend to be older, with lower
Platelet counts and higher absolute monocyte
Counts, and respond poorly to treatment, with
A median survival of less than one year.
Prior to imatinib therapy approximately 10% of
patients per year would transform. In those treated
with imatinib for up to 5 years, only between 0.5-2.5%
have transformed each year.

9. Clinical features
Symptoms at presentation may include lethargy, weight
loss, abdominal discomfort and sweating, but about 25%
of patients are asymptomatic at diagnosis.
Splenomegaly is present in 90%; in about 10%, the
enlargement is massive, extending to over 15 cm below the
costal margin. A friction rub may be heard in cases of
splenic infarction.
Hepatomegaly occurs in about 50%. Lymphadenopathy
is unusual.

10. Investigations
FBC results are variable between patients.
There is usually a normocytic, normochromic
anaemia.
The leucocyte count can vary from 10 to 600 × 109/L. In
about one-third of patients there is a very high platelet
count, sometimes as high as 2000 × 109/L.
Investigations:

11. In the blood film the full range of
granulocyte precursors from
myeloblasts to mature neutrophils is
seen but the predominant cells are
neutrophils and myelocytes .
Myeloblasts usually constitute less
than 10% of all white cells.

12. There is often an absolute increase in eosinophils and
basophils, and nucleated red cells are common.
If the disease progresses through an accelerated
phase, the percentage of more primitive cells
increases.
Blast transformation is characterised by a dramatic
increase in the number of circulating blasts.

13. In patients with thrombocytosis,
very high platelet counts may
persist during treatment, in both
chronic and accelerated phases, but
usually drop dramatically at blast
transformation. Basophilia tends to
increase as the disease progresses

17. Bone marrow should be obtained to:
1-confirm the diagnosis and phase of
disease by morphology.
2- chromosome analysis to demonstrate
the presence of the Ph chromosome.
3-and RNA analysis to demonstrate the
presence of the BCR ABL gene product.
Blood LDH levels are elevated and the uric
acid level may be high due to increased cell
breakdown

18. Imatinib specifically inhibits BCR ABL tyrosine kinase
activity and reduces the uncontrolled proliferation of
white cells. It is recommended as first-line therapy in
chronic phase CML, producing complete cytogenetic
response (disappearance of the Ph chromosome) in
76% at 18 months of therapy . Patients are monitored
by repeated bone marrow examination until in a
complete cytogenetic response, and then by 3-
monthly real-time quantitative polymerase chain
reaction (PCR) for BCR ABL mRNA transcripts in
blood.
Management:
Chronic phase:

19. For those failing to respond or progress on imatinib,
options include second-generation tyrosine kinase
inhibitors such as dasatinib or nilotinib, allogeneic
bone marrow transplantation or classical cytotoxic
drugs such as hydroxycarbamide (hydroxyurea) or
interferon

20. Hydroxycarbamide was previously used widely for
initial control of disease, and is still useful in this
context or in palliative situations. It does not diminish
the frequency of the Ph chromosome or affect the
onset of blast cell transformation.
Interferonalfa was considered first-line treatment
before imatinib was developed

21. It is given alone or with the chemotherapy agent Ara-C,
and can Induce and maintain control of this disease in
chronic phase in 70%Of patients.
It causes reduction in the percentage of Ph-positive
cells in about 20% of patients, and prolongs survival in
those who achieve this.
Interferon therapy causes flu-like symptoms initially
and although Some of those may be controlled with
paracetamol , others such asSever bone pain and sever
weight loss are reasons for
Discontinuatio

22. Allogeneic or syngeneic stem cell transplantation
From a matched sibling donor :
Patients in the chronic phase of CML who are younger
Than 65 years who have an identical twin or histocompa-
Table sibling can be transplanted after intensive therapy .
The best result are obtained in patients in early chronic phase when about
80% can expect probable cure.
The result of transplantation in accelerated and blast transformation are
Significantly worse.
Studies are way to investigate the role of imatinib in transplantation for CML.

23. Accelerated phase and blast crisis
Management is more difficult. For patients presenting in
accelerated phase, imatinib is indicated if the patient has
not already received it. Hydroxycarbamide can be an
effective single agent and low-dose cytarabine can also
be tried. When blast transformation occurs, the type of
blast cell should be determined. Response to
appropriate acute leukaemia treatment is better if
disease is lymphoblastic than if myeloblastic. Given the
very poor response in myeloblastic transformation, there
is a strong case for supportive therapy only, particularly
in older patients.
Accelerated phase and blast crisis

24. Chronic lymphocytic leukaemia (CLL ) :
The most common variety of leukaemia, accounting for 30% of cases.
*male to female ratio is 2:1
*median age at presentation is between65 and 70.
*in this disease B lymphocytes, which would normally respond to
Antigens by transformation and antibody formation, fail to do so.
*an ever-increasing mass of immuno-incompetentcells accumulate,
To detriment of immune function and normal bone marrow
Haematopoiesis.

25. Clinical features :
The onset is very insidious.
In around 70% of patients the diagnosis is made
Incidentally on a routine full blood count.
Presenting problems may be anaemia, infections,
Painless Lymphadenopathy and systemic symptoms
Such as night sweats or weight loss.
However, those more often occur later in the progress of
Disease.

26. Investigations
the diagnosis is based on the peripheral blood finding of
9
A mature lymphocytosis(more than 5x10/l)with
Characteristic morphology and cell surface markers.
Immunophenotyping reveals the lymphocytes to be
Monoclonal B –cells expressing the b-cell antigens CD19
And CD23 with either kappa or lambda immunoglobulin
Light chains and, characteristically , T-cell antigen, CD5.

27. CLL blood film morphology

28. OTHER TEST :
Reticulocytosis and positive direct coombs test as autoimmune
Haemolytic anaemia may occur.
Serum immunoglobulin level should be estimated to establish the
Degree of immunosuppression.
*bone marrow examination by aspirate and trephine is not essential
For the diagnosis of CLL , but may be helpful in difficult cases, for
Prognosis( diffuse marrow involvement tend to do worse ) and to
The main prognostic factor is a stageMonitor response to therapy.
0f disease.
Other poor prognostic factors include :
*newer markers such as CD38 expression.
*mutation of IgVH genes.
*Cytogenetic abnormalities of chromosome 11or 17 .

29. Staging of CLL :
Clinical stage A (60% of patients )
*no anaemia or thrombocytopenia and less than three areas of
Lymphoid enlargement.
Clinical stage B (30% of patients )
*no anemia or thrombocytopenia, with three or more involved areas of
Lymphoid enlargement.
Clinical stage C (10% of patients )
*anaemia and /or thrombocytopenia, regardless of the number of areas of
Lymphoid enlargement.

30. Management :
No specific treatment is required for most clinical stage A patients unless
Progression occur.
Life expectancy is usually normal in older patients.
Treatment is only required if :
*there is evidence of bone marrow failure
*massive or progressive Lymphadenopathy or splenomegaly .
*systemic symptoms such as weight loss or night sweats.
*a rapidly increasing lymphocyte count.
*autoimmune haemolytic anaemia or thrombocytopenia .

31. Initial therapy for those requiring treatment
(stages B and C ) Consist of oral chemotherapy
with alkylating agent chlorambucil.
This will reduce the abnormal lymphocyte
mass and produce Symptomatic improvement
in most patientsGiven orally , Well tolerated
started with 2-4 mg /day can be advance
To 6-8 mg/dayif the patient not experience
intoleratable hematologic side effects.
.

32. More recently, the purine analogue
fludarabine, in combination with the
alkylating agent cyclophosphamide, has
increased remission rates and disease-
free survival, although there is an
increased risk of infection. Bone marrow
failure or autoimmune cytopenias may
respond to corticosteroid treatment.

33. Supportive care is required in:
*progressive disease, e.g. transfusion for symptomatic
Anaemia or thrombocytopenia.
*prompt treatment of infections and for some patients
With hypogammaglobulinaemia, immunoglobulin
Replacement.
Radiotherapy may be used for lymph nodes causing
Discomfort or local obstruction , and for symptomatic
Splenomegaly.
Splenectomy may be required to improve low blood
Counts due to autoimmune destruction or to
Hypersplenism, and can relieve massive splenomegaly.

34. Prognosis :
The majority of clinical stage A patients have a normal
life expectancy but patients with advanced CLL are
more likely to die from their disease or infectious
complications.
Survival is influenced by prognostic features
of the leukaemia and whether patients can tolerate
intensive treatment.
In those treated with chemotherapy and rituximab, 90%
are alive 4 years later.

35. Prolymphocytic leukaemia
This is a variant of CLL found mainly in males
over the age of 60 years ;25% of the cases are
of T –cell variety.
There is a massive splenomegaly with little
lymphadenopathy and a very high
leucocyte count, often in excess of 400x 109,
The characteristic cell is a large lymphocyte with
prominent nucleolus.

38. PB morphology from a typical case of T-PLL showing medium-sized
lymphoid cells with a regular nuclear outline, single nucleolus, and
intense basophilic cytoplasm.

39. This is a malignancy of medium-sized (about twice
the size of a normal small lymphocyte), round
lymphocytes with a prominent nucleolus and light
blue cytoplasm on Wright's stain.

40. Clinical presentation is generally
from symptoms of splenomegaly
or incidental detection of an
elevated WBC count. The clinical
course can be rapid.

41. Nucleoside analogues like
fludarabine and cladribine and
combination chemotherapy
(cyclophosphamide, doxorubicin,
vincristine, prednisone, or CHOP)
have produced responses. CHOP
plus rituximab may be more
effective than CHOP alone.
Treatment :

42. but the disease is sufficiently
rare that large series have not
been reported. Splenectomy
can produce palliation of
symptoms but appears to
have little or no impact on the
course of the disease.

43. Treatment is generally unsuccessful and the
prognosis very poor.
Leukapharesis, splenectomy and chemotherapy
May be tried

44. Hairy cell leukaemia
This is a rare chronic lymphoprolifrative
B-cell disorder.
The male to female ratio is 6:1 and the median
age at diagnosis is 50 years.

45. Some studies suggest that prior exposure to radiation and
organic solvents is more frequent among HCL patients.
Etiology
Some investigators have speculated on an etiologic role for
the Epstein-Barr virus in the development of HCL, but the
proposal has been disputed.

46. Patients usually present with pancytopenia.
Absolute neutropenia and Monocytopenia are nearly
Constant features.
The blood film and bone marrow biopsy contain hairy cell
which are lymphocytes that have prominent cytoplasmic
Projections and give the disease its name.

50. Clinical features:
The diagnostic triad consist of pancytopenia,
Splenomegaly and circulating hairy cells.

51. 25%of patients present with fatigue and
weakness.
25% present with easy bruising from
thrombocytopenia or opportunistic infection from
leucopenia,
25%present with early satiety or abdominal
fullness from splenomegaly.
25%present with incidental finding of
splenomegaly or abnormal blood count on
routine examination for un unrelated condition.

52. Splenomegaly, which may be massive, is found in 90
percent of patients. Hepatomegaly can occur.
Palpable superficial lymphadenopathy is uncommon
and is usually localized when found. However, as a
result of the routine use of computerized axial
tomography scans in the evaluation of patients with
lymphoproliferative disorders, significant deep
adenopathy has been found to be present in up to
one-third of patients with HCL.

53. In 3 % of patients, the disease
manifests as a painful bony
lesion (osteolytic) in the axial
skeleton or long bones, most
commonly involving the
proximal femur.

54. Investigations:
Sever neutropenia
Monocytopenia
The characteristic hairy cells in the blood film
morphology and bone marrow.
These cells usually type as B-lymphocytes
And also characteristically express CD25
And CD103.

55. Recently, all patients with hairy
cell leukaemia have been
found to have a mutation in the
BRAF gene.

56. Laboratory Features
Blood
At the time of diagnosis, pancytopenia occurs
in 50 percent of patients; the remaining half
usually have bicytopenia.
.
Anemia is present in about three-quarters
of patients and about one-third of patients
have a hemoglobin of less than 9.0 g/dL.

57. Treatment :
90% of patients require treatment at presentation
or during the course of the disease.
Indications :
1- anaemia when Hb% less than 8-10 g/dl.
2-thrombocytopenia when platelet countless than
50-100x10 /l.
3-Neutropenia with absolute neutrophil count less
than 0.5-1.0x10/l , especially when associated
with recurrent serious infection.

58. treatment
Over recent years a number of treatments
Have been shown to produce long lasting
Remissions.
Cladribine and deoxycofromycin are
Effective in producing long period of
Disease control.