Title 27. CHEMOTHERAPY OF LEUKEMIA.pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  Leukaemia is a cancer of blood-forming cells.  Leukaemias are classified into two broad groups according to the type of blood-forming cell that has become malignant. These are called lymphatic leukaemia and myeloid (or non-lymphatic) leukaemia.  In lymphatic leukaemia the cells that have become malignant are the bone marrow cells that normally make lymphocytes. Lymph nodes and lymphoid tissue are usually involved and some nodes become enlarged. In myeloid leukaemia the cells that have become malignant are cells in the bone marrow that normally make the other types of white blood cells (that is myeloid cells that make polymorphs and other white cell types). The spleen usually becomes involved and enlarged.  Leukaemias may be acute or chronic according to whether the disease would tend to run a rapid and rapidly fatal course (acute leukaemia) or whether the disease would progress more slowly (chronic leukaemia).  Thus there are four main types of leukaemia: 1. Acute lymphocytic (lymphatic) leukaemia (ALL) 2. Acute myeloid (non-lymphatic or granulocytic) leukaemia (AML or ANLL.) 3. Chronic lymphocytic leukaemia (CLL) 4. Chronic myeloid (non-lymphocytic or granulocytic) leukaemia (CML or CNLL or CGL)  It is important to distinguish between the major types of leukaemia because they tend to run different courses and respond differently to different treatments. 1) ACUTE LYMPHATIC (LYMPHOBLASTIC) LEUKAEMIA (ALL):  This is the most common form of leukaemia in children with an age peak of about 5 years. Symptoms are caused by replacement of normal blood-forming cells of bone marrow by malignant leukaemic cells and infiltration (invasion) of other tissues such as spleen, lymph nodes, tonsils and sometimes liver, kidneys, lungs and brain. CHEMOTHERAPY OF LEUKEMIA
PHARMD GURU Page 2  Fever, weakness, anorexia (loss of appetite), pallor, and infection are common. Infection is especially common in the region of the tonsils or anus and the lungs may also become infected causing pneumonia. There may be pain in bones or joints.  Lymph nodes, tonsils and spleen are commonly enlarged. Sometimes the liver and kidneys are enlarged.  Platelets may be deficient and there may be petechial spots or bruising or signs of bleeding from any site especially from the gums, the digestive tract or anus. Bleeding in the brain or from the lungs may also occur. Thrombosis (clots) may also develop in veins.  Meningitis due to leukaemic cell spread into the meninges frequently occurs in patients with ALL unless prevented by radiotherapy or chemotherapy. 2) ACUTE MYELOID LEUKAEMIA: AML more commonly affects adults. Anaemia, bleeding or bruising and infection are the likely presenting features. But as with ALL, general ill health with fever, lassitude, loss of appetite and involvement of other tissues or organs with septicaemic infection is likely. INVESTIGATIONS:  The diagnosis of leukaemia can be made only after careful examination of blood and bone marrow. Blood is taken by a needle from a vein in the arm and bone marrow is usually taken with a small instrument that is used to puncture a bone of the pelvis (the iliac crest). Bone puncture is painful so it is done under local or even general anaesthesia. A pathologist then examines the blood and bone marrow for leukaemic cells and for other features of leukaemia. These may include anaemia (with a reduction in numbers of red blood cells), reduction in number of normal white blood cells, and reduction in the number of platelets. About one third of patients with acute leukaemia will have an elevated white blood count, one third will have a low white blood count and in one third the white cell count is about normal.  Patients with AML are usually found to have abnormalities of chromosomes. There may also be changes in blood chemistry, including increased uric acid, that may be associated with features of gout.
PHARMD GURU Page 3  Cytogenetic studies on bone marrow are now part of a full investigation of leukaemia patients. These studies identify specific molecular genetic syndromes and help in selecting the best therapy. They also give a good indication of the likely prognosis. TREATMENT:  Encouraging progress has been made in recent years in the treatment of the acute leukaemias.  The best opportunity to achieve the maximum cure of leukaemia is when the disease is first diagnosed. Cells that remain after the first treatment tend to develop resistance to drugs. It is therefore important that patients with acute leukaemia should immediately be referred to a readily available specialist clinic so that the most effective treatment can be given under expert supervision without delay.  Chemotherapy using cytotoxic drugs and cortisone forms the basis of modern treatment. Combinations of effective cytotoxic drugs have produced best results.  With the best current treatment methods, more than 90% of children and about 80% of adults with ALL now achieve complete remission (that is, the disease apparently disappears and the patient feels and looks well again).  Because after a time most ALL patients will develop the disease in the meninges, the lining around the brain, and because anti-cancer drugs do not pass in high concentration into the nervous system, injections of cytotoxic drugs are given into the meningeal space around the brain and the brain is also treated by radiotherapy. In the case of AML, nervous system involvement does not occur so often but this treatment is also given immediately there is any sign that there may be brain or central nervous system involvement.  With AML, good results of chemotherapy have not been as reliable as with ALL. Recently, in attempts to further improve results, bone marrow transplantation has been used effectively, especially in younger people (aged under 50). In marrow transplantation the leukaemic cells are destroyed by big doses of chemotherapy and radiotherapy (total body irradiation). This is a dangerous procedure and is carried out only in highly expert units within specialised hospitals. The patient is then given an infusion of bone marrow taken from a matched donor (that is, a donor with similar body cells unlikely to cause a
PHARMD GURU Page 4 rejection reaction). The best donor is often a sibling or other family member. Bone marrow transplantation involves a number of risks and should therefore be carried out only by appropriately trained experts, in specially equipped hospitals. Results have been most encouraging in this otherwise fatal illness. An alternative source of haemopoietic stem cells for transplantation is to use peripheral blood stem cells or umbilical cord stem cells Blood stem cells are collected from the blood after stimulation by colony stimulating factors (like G- CSF). Although controversial from an ethical and moral point of view embryonal stem cells may have the ability to respond in the bone marrow in a similar way to bone marrow derived cells.  In recent years, treatment with immunotherapy has been further investigated. Although major success has not as yet been achieved there have been interesting results that give hope for better treatments in the future.  Transplantation of matched unrelated bone marrow (bone marrow from a matched donor person not related to the patient) is used to elicit graft vs. leukaemia effect. The immunological effect of the graft might be as important or even more important than chemotherapy. In recent years mini-allogeneic transplants have been used (allogeneic stem cells are used without myelo- ablative chemotherapy). Studies are proceeding to determine whether such interventions might be safer and equally effective.  During the acute illness there may be special problems of anaemia, lowered resistance to infection, bleeding or even clotting. These may require blood transfusion or platelet transfusion and antibiotics or other treatment for infection. Aspirin should be strictly avoided because it interferes with blood clotting. 3) CHRONIC LYMPHOCYTIC (LYMPHATIC) LEUKAEMIA: CLL tends to occur in older people with an average age of about 60 years and is usually a very slowly progressive disease. In this disease there is an overproduction of mature and relatively normal looking lymphocytes resulting in increased numbers of lymphocytes in the blood. CLINICAL PRESENTATION: The most obvious feature is lymph-node enlargement. Enlarged lymph nodes may be felt as lumps in the sides of the neck, in the axillae or groins. Enlarged lymph nodes