Acute leukemia

Dr.Mousa Qasim Hussein 7th Dec.2015

Haematological malignancies arise when the processes controlling proliferation or apoptosis are corrupted in blood cells. If mature differentiated cells are involved, the cells will have a low growth fraction and produce indolent neoplasms, such as the low-grade lymphomas or chronic leukaemias, when patients have an expected survival of many years.

In contrast, if more primitive stem cells are involved, the cells can have the highest growth fractions of all human neoplasms, producing rapidly progressive, life-threatening illnesses such as the acute leukaemias or high-grade lymphomas

LEUKAEMIAS

are malignant disorders of the haematopoietic stem cell compartment, characteristically associated with increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukaemia may vary from a few days or weeks to many years, depending on the type.

Epidemiology

The incidence of leukaemia of all types in the population is approximately 10/100 000 per year, of which just under half are acute leukaemia. Males are affected more frequently than females, the ratio being about 3:2 in acute leukaemia, 2:1 in chronic lymphocytic leukaemia and 1.3:1 in chronic myeloid leukaemia. Acute lymphoblastic leukaemia shows a peak of incidence in the 1-5 age group. All forms of acute myeloid leukaemia have their lowest incidence in young adult life and there is a striking rise over the age of 50. Chronic leukaemias occur mainly in middle and old age.

Etiology

The cause of the leukaemia is unknown in the majority of patients. Several factors, however, are associated with the development of leukaemia
Ionising radiation
A significant increase in myeloid leukaemia followed the atomic bombing of Japanese cities An increase in leukaemia was observed after the use of radiotherapy for ankylosing spondylitis and diagnostic X-rays of the fetus in pregnancy
Cytotoxic drugs
These, particularly alkylating agents, may induce myeloid leukaemia, usually after a latent period of several years Exposure to benzene in industry
Retroviruses
One rare form of T-cell leukaemia/lymphoma appears to be associated with a retrovirus similar to the viruses causing leukaemia in cats and cattle
Genetic
There is a greatly increased incidence of leukaemia in the identical twin of patients with leukaemia Increased incidence occurs in Down's syndrome and certain other genetic disorders
Immunological
Immune deficiency states (e.g. hypogammaglobulinaemia) are associated with an increase in haematological malignancy


Terminology and classification
Leukaemias are traditionally classified into four main groups acute lymphoblastic leukaemia (ALL) acute myeloid leukaemia (AML) chronic lymphocytic leukaemia (CLL) chronic myeloid leukaemia (CML)

In acute leukaemia there is proliferation of primitive stem cells leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. In chronic leukaemia the malignant clone is able to differentiate, resulting in an accumulation of more mature cells.

Lymphocytic and lymphoblastic cells are those derived from the lymphoid stem cell (B cells and T cells). Myeloid refers to the other lineages, i.e. precursors of red cells, granulocytes, monocytes and platelets

The diagnosis of leukaemia is usually suspected from an abnormal blood count, often a raised white count, and is confirmed by examination of the bone marrow. This includes: 1- the morphology of the abnormal cells, 2-analysis of cell surface markers (immunophenotyping) 3- clone-specific chromosome abnormalities and molecular changes.

The features in the bone marrow not only provide an accurate diagnosis but also give valuable prognostic information, allowing therapy to be tailored to the patient's disease.

ACUTE LEUKAEMIA

- There is a failure of cell maturation in acute leukaemia. Proliferation of cells which do not mature leads to an accumulation of useless cells which take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spills into the blood. - Acute myeloid leukaemia is about four times more common than acute lymphoblastic leukaemia in adults. - In children the proportions are reversed, the lymphoblastic variety being more common


ALL clinical features Symptoms may appear insidiously or acutely. Presenting features reflect the degree of marrow failure And extramedullary spread. Half of patients present with fever which is induced by Pyrogenic cytokines e.g IL-1,IL-6 ,TNF released from Leukemic cells . Fever resolves writhen 72 hours after start therapy. *fatigue ,lethargy are common manifestation of anaemia In older patients. *more than fourth of patients, especially younger children May have bone pain, arthralgia because leukaemic Infiltration to the periosteum.


Arthralgia and bone pain less sever in adults. Less common symptoms include headache, vomiting, Altered mental functions, oliguria and anuria. Occasionlly patients present with life threatening infections Or bleeding ( intracranial haematomas) SIGNS : *pallor ,petechiae , ecchymosis. *liver, spleen and lymph nodes are the most common Extramedullary involvement. *anterior mediastinal mass is present in 7-10% of childhood Cases and 15%of adult cases.



A bulky mass can compress the great vessels and Trachea and lead to superior vena caval syndrome Or superior mediastinal syndrome, patients with this Syndrome present with cough, dyspnea, orthopnea, Dysphagia, stridor , cyanosis, facial oedema and Increased intracranial pressure and sometimes Syncope.


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Signs and symptoms that signals the onset of AML include: pallor, fatigue,weakness palpitations, and dyspnea on exertion. The signs and symptoms reflect the development of anemia; however weakness, loss of sense of well-being, and fatigue on exertion can be out of proportion to the severity of anemia .. 1

Easy bruising, petechiae, epistaxis, gingival bleeding, conjunctival hemorrhages, and prolonged bleeding from skin injuries reflect thrombocytopenia and are frequent early manifestations of the disease. Very infrequently, gastrointestinal, genitourinary, bronchopulmonary, or central nervous system (CNS) bleeding occurs at the onset of disease.


Pustules or other minor pyogenic infections of the skin and of minor cuts or wounds are most common.

Anorexia and weight loss are frequent findings. Fever is present in many patients at the time of diagnosis. Palpable splenomegaly or hepatomegaly occurs in approximately one third of patients. Lymphadenopathy is extremely uncommon except in the monocytic variant of AML.

Investigations

Bone marrow aspirate from this patient with AML shows a blast with an Auer rod (black arrow) as well as neutrophils with hypersegmented (blue arrow) and a hyposegmented (red arrow) nuclei.

Flow cytometric analysis of blasts labelled with the fluorescent antibodies anti-CD19 (y axis) and anti-CD10 (x axis). ALL blasts are positive for both CD19 and CD10 (arrow).



Chromosome analysis (karyotype) of blasts showing additional chromosomes X, 4, 6, 7, 14, 18 and 21.

Management

The first decision must be whether or not to give specific treatment. This is generally aggressive, has a number of side-effects, and may not be appropriate for the very elderly or patients with other serious disorders In these patients, supportive treatment can effect considerable improvement in well-being..

Specific therapy: the patient should be prepared in the ways listed: MANAGEMENT OF ACUTE LEUKAEMIA: SPECIFIC THERAPY 1.Existing infections identified and treated (e.g. urinary tract infection, oral candidiasis, dental, gingival and skin infections) 2.Anaemia corrected with red cell concentrate infusion 3.Thrombocytopenic bleeding controlled with platelet transfusion If possible 4.central venous catheter (e.g. Hickman line) inserted to facilitate access to the circulation for delivery of chemotherapy 5.Therapeutic regimen carefully explained to the patient and informed consent obtained

The aim of treatment is to destroy the leukaemic clone of cells without destroying the residual normal stem cell compartment from which repopulation of the haematopoietic tissues will occur. There are three phases: Remission induction. In this phase, the bulk of the tumour is destroyed by combination chemotherapy. The patient goes through a period of severe bone marrow hypoplasia, requiring intensive support and inpatient care from specially trained medical and nursing staff.

Remission consolidation. If remission has been achieved by induction therapy, residual disease is attacked by therapy during the consolidation phase. This consists of a number of courses of chemotherapy, again resulting in periods of marrow hypoplasia. In poor prognosis leukaemia this may include a stem cell transplant.

Remission maintenance. If the patient is still in remission after the consolidation phase for acute lymphoblastic leukaemia, a period of maintenance therapy is given, consisting of a repeating cycle of drug administration. This may extend for up to 3 years if relapse does not occur and is usually given on an outpatient basis.

In patients with ALL necessary to give prophylactic treatment to CNS as this is a sanctuary site where standered therapy dose not penetrate. This usually consist of a combination of cranial irradiation , intrathecal chemotherapy and high dose methotrexate which crosses the blood brain barrier.
Thereafter, specific therapy is discontinued and the patient observed.


Generally, if a patient fails to go into remission with induction treatment, alternative drug combinations may be tried, but the outlook is poor unless remission can be achieved. Disease which relapses during treatment or soon after the end of treatment carries a poor prognosis and is difficult to treat. The longer after the end of treatment that relapse occurs, the more likely it is that further treatment will be Effective.



In some patients, alternative palliative chemotherapy, not designed to achieve remission, may be used to curb excessive leucocyte proliferation. Drugs used for this purpose include hydroxycarbamide and mercaptopurine. The aim is to reduce the blast count without inducing bone marrow failure.

DRUGS COMMONLY USED IN THE TREATMENT OF ACUTE LEUKAEMIA

Phase
ALL
AML
Induction
Vincristine (i.v.)
Daunorubicin (i.v.)

Prednisolone (oral)

Cytarabine (i.v.)

L-asparaginase (i.m.)

Etoposide (i.v. and oral)

Daunorubicin (i.v.)

Methotrexate (intrathecal)

Consolidation

Daunorubicin (i.v.)
Cytarabine (i.v.)

Cytarabine (i.v.)

Amsacrine (i.v.)

Etoposide (i.v.)

Mitoxantrone (i.v.)

Methotrexate (i.v.)

Maintenance
Prednisolone (oral)

Vincristine (i.v.)

Mercaptopurine (oral)

Methotrexate (oral)

Supportive therapy Aggressive and potentially curative therapy which involves period of sever bone marrow failure would not be possible without adequate and skilled supportive care the following problems commonly arise.

The organisms most commonly associated with severe neutropenic sepsis are Gram-positive bacteria, such as Staphylococcus aureus and Staph. epidermidis,which are present on the skin and gain entry via cannulae and central lines. Gram-negative infectionsoften originate from the gastrointestinal tract, which is affected by chemotherapy-induced mucositis; organisms such as Escherichia coli, Pseudomonas and Klebsiella spp. are likely to cause rapid clinical deterioration and must be covered with the initial empirical antibiotictherapy. Gram-positive infection may require vancomycin therapy. If fever has not resolved after 3–5 days, empirical antifungal therapy (e.g. a liposomal amphotericin B preparation, voriconazole or caspofungin) isadded.

Patients with ALL are susceptible to infection with Pneumocystis jirovecii ( which causes a severe pneumonia. Prophylaxis with co-trimoxazole is given during chemotherapy. Treatment is with high-dose co-trimoxazole, initially intravenously,changing to oral treatment as soon as possible.
Oral and pharyngeal candida infection is common. Fluconazole is effective for the treatment of established local infection and for prophylaxis against systemic candidaemia.


For systemic fungal infection with Candida or aspergillosis,intravenous liposomal amphotericin or voriconazole is required.
Reactivation of herpes simplex infection occurs frequently around the lips and nose during ablative therapy for acute leukaemia, and is treated with aciclovir.. Herpes zoster manifesting as chickenpox or, after reactivation, as shingles should be treated in the early stage with high-dose aciclovir, as it can be fatal in immunocompromised patients

Psychological support: This is a key aspect of care . patients should be kept informed, and their questions answered. Delusions, hallucinations and paranoia are not uncommon during period of sever bone marrow failure and septicaemic episodes.


Prognosis Without treatment the median survival of patient with acute leukaemia is About 5weeks. This may be extended to number of months with supportive treatment. Patient who achieve remission with specific .therapy have a better outlook About 80% of adult patients under 60 years of age with ALL or AML achieve remission.


Advances in treatment have led to steady improvement in survival from leukaemia. Advances include the introduction of drugs such as ATRA (all transretinoic acid) in acute promyelocytic leukaemia, which has greatly reduced induction deaths from bleeding in this good-risk leukaemia. Current trials aim to improve survival, especially in standard and poor-risk disease, with strategies that include allogeneic BMT