1. Dr. Hasan Fahmawi, MRCP(UK), FRCP(Edin)
LEUKAEMIAS
Dr. Hasan Fahmawi, MRCP(UK), FRCP(Edin)

2. Haematological malignancies
Haematological malignancies arise when the processes controlling proliferation or apoptosis are corrupted in blood cells due to acquired mutations in key regulatory genes. If mature differentiated cells are involved, the cells will have low growth fraction and produce indolent neoplasms, e.g. low grade lymphoma and chronic leukaemia, when patients has an expected survival of many years. In contrast, if more primitive stem or progenitor cells are involved the cells can have the highest growth factors of all human neoplasms, producing rapidly progressive, life threatening illnesses, e.g. acute leukaemias and high- grade lymphomas. In general Haematological neoplasms are diseases of the elderly except ALL, which is common in children, and Hodgkin’s lymphoma in years.

3. Leukaemias
These are malignant disorders of the haematopoietic stem cell compartment ,characterised by increased number of white cells in the bone marrow and or peripheral tissue.
Incidence 10/ per annum, of which under half are acute leukaemias. Males are more frequently affected 3:2 in acute leukaemias, 2:1 in chronic lymphocytic leukaemias and 1.3:1 in chronic myeloid leukaemias.

4. Acute Leukaemia (ALL, AML)
There is failure of cell maturation in acute leukaemia, proliferation of cells which are not mature leads to accumulation of primitive cells that take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spells in to the blood. AML is 4-5 times more common than ALL, which is common in children 1-5 yrs. of age.
The clinical features are usually those of bone marrow failure (anemia , infection and bleeding).
Investigations : anaemia or raised MCV, WBC ,000, platelets in the majority is below 100,000, severe thrombocytopaenia is usual but not invariable. The blast cells are seen in blood film, but may be few or absent.
Bone marrow will confirm the diagnosis, which is hypercellular and replaced by blast cells (more than 20%) . Presence of Auer rods in the cytoplasm of blast
cells in AML. Classification and prognosis by immunophenotyping, as well as chromosome and molecular analysis.

7. Treatment
Chemotherapy, HSCT, supportive therapy, mainly after transplant, packed RBC, platelets, bacterial infection, fever 38 or above lasting more than one hr. in a neutropenic patient indicates possible sepsis and requires treatment. Viral and fungal infections must be treated.
Tumour lysis syndrome: hyperkalaemia, hyperuricaemia, hyperphophataemia, and hypocalcaemia. This may lead to renal failure. Hydration and allopurinol are given, but dialysis may be needed.

8. Aplastic Anaemia
Failure of the pluripotent stem cells because of an autoimmune attack, producing hypoplasia of the bone marrow with pancytopaenia in the blood, and causes of secondary aplastic anaemia must be excluded, as well e.g. Fanconi’s anaemia.
Clinical features: symptoms of bone marrow failure, usually anaemia or bleeding , and less commonly infection.
CBC: demonstrates pancytopaenia, low reticulocytes and often macrocytosis. Bone marrow aspirate and trephine reveal hypocellularity.
Management: all patients require blood product support and aggressive management of infection. In patients below 35 yrs., bone marrow HSCT , (provided they have no other comorbidities) and have compatible sibling.
In older patients Anti-thymocyte globin ATG and Ciclosporin. Thrombopoietin receptor agonist. TPO-RA

9. Secondary aplastic anaemia
It is important to check the reported side effects of drugs taken over in the proceeding few months. In some instances, the cytopaenia is more selective and affects only one cell line, most often the neutrophils. Frequently, this is an incidental finding, with no ill effect.
An underlying cause should be treated or removed, but otherwise management is like the idiopathic form as well as the symptoms.

11. Chronic Lymphocytic Leukaemia CLL
The most common variety of leukaemia, male to female ratio is 2:1 and the median age of presentation is yrs.
In CLL B-lymphocytes which would normally respond to antigen by transformation and antibody formation, fail to do so. An ever-increasing mass of immuno-incompetent cells accumulate, to the detriment of immune function and normal bone marrow haematopoiesis.
Clinical features: insidious onset, and 70% are diagnosed incidentally by routine CBC, others present as anaemia, infection, painless lymphadenopathy and systemic manifestations such as night sweats or weight loss; these more often occur later in the course of the disease.
Investigations: the diagnosis is based on the peripheral blood findings of mature lymphocytes over 5 millions with characteristic morphology and cell surface markers. Reticulocytes and Coomb’s test, serum immunoglobulin levels to establish the level of hypogammaglobulinaemia . Bone marrow is not essential for the diagnosis, but only in difficult cases, to establish prognosis and to monitor treatment.

14. Management
No treatment is required in clinical stage A and life expectancy in old age is normal. Treatment is required only if there is bone marrow failure, massive or progressive lymphadenopathy, splenomegaly, systemic symptoms such as weight loss or night sweats, or rapidly increasing lymphocyte count, autoimmune haemolytic anaemia or thrombocytopaenia. Treatment is based on the age and fitness of the patient and mutations. Fludarabine plus alkylating agent cyclophosphamide, rituximab, bendamustin and oral chlorambucil. CLL cells are dependent on abnormal or persistent signaling through B- cell receptor BCR pathway. Drugs that inhibit this pathway are now available and show great promise. Ibrutinib, inhibits Bruton’s tyrosine kinase and idelalisib inhibits P13 kinase, both are components of the BCR. Bone marrow failure or autoimmune cytopaenia may respond to glucocorticoid treatment. Supportive care is increasingly required in progressive disease, such as transfusion for symptomatic anaemia or thrombocytopaenia, prompt treatment for infection, and for patient with hypogammaglobulinaemia, immunoglobulin replacement. Radiotherapy may be used for large lymph nodes causing discomfort or local obstruction or for symptomatic splenomegaly. Splenectomy may be required for low blood count due to autoimmune destruction or to hypersplenism, and can relieve massive splenomegaly. Prognosis: advanced cases die from their disease or infection, treated cases with chemotherapy and rituximab, 90% are alive 4 years later. Rarely CLL transform to aggressive high grade lymphoma, called Richter’s transformation.

15. Prolymphocytic leukaemia
PLL, is variety of CLL, affects mainly males, over 60 yrs. 25% are of
T cell variety. There is massive splenomegaly with little lymphadenopathy and a very high leukocyte count.
Hairy cell leukaemia: this is a rare chronic lymphoproliferative disorder, male to female ratio 1:6, splenomegaly in 90% of patients, but lymph node enlargement is unusual.
Severe neutropaenia, monocytopaenia and the characteristic hairy cells in the blood and bone marrow are typical.
Cladribine has been shown to produce long lasting remission.

16. HSCT
It has offered the only hope of cure for a variety of Haematological and non- haematological disorders, it has been refined and extended, as standards of treatment improved. The type is defined according to the donor and source of stem cell.
Allogenic, the main stem cell come from either a related donor (usually HLA identical sibling) or a closely HLA-matched volunteer unrelated donor(VUD). (HLA) Human Leukocyte Antigen. The conditioning treatment (chemotherapy with or without radiotherapy) is myeloablative or recently non-myeloablative.
Autologous, the stem cells are harvested from the patient and stored in the vapour phase of liquid nitrogen until required. Stem cell can be harvested from the bone marrow or from the blood, used for myeloma or lymphoma. Cells taken from peripheral blood, these cells engraft more quickly, recovery in 2-3 weeks, no GVHD, no immunosuppression. Mortality is around 5% but recurrence rate is higher.