Acute leukemia

Prepared by:
Dr. Laila Mohammed AL Gharasi
Leukaemia

 Leukemia is a group of blood cancers that usually begin in the bone

marrow and result in high numbers of abnormal blood cells.These
blood cells are not fully developed and are called blasts or leukemia cells
General classification:

Clinically and pathologically, leukemia is subdivided into a variety of large

groups.

1- Acute leukemia is characterized by a rapid increase in the number of

immature blood cells.
The crowding that results from such cells makes the bone marrow unable
to produce healthy blood cells resulting in low hemoglobin and
low platelets.
General classification:

2- Chronic leukemia
characterized by the excessive buildup of relatively mature, but still
abnormal, white blood cells. Typically taking months or years to progress,
the cells are produced at a much higher rate than normal, resulting in
many abnormal white blood cells. Whereas acute leukemia must be
treated immediately, chronic forms are sometimes monitored for some
time before treatment to ensure maximum effectiveness of therapy.

 Acute forms of leukemia are the most common forms of leukemia in

children.

 Chronic leukemia mostly occurs in older people, but can occur in any
age group.
Effects of Leukemia on the Body

• The first effect of leukemia is metastatic growth of leukemic cells in

abnormal areas of the body.

• Leukemic cells from the bone marrow may reproduce so greatly that
they invade the surrounding bone, causing pain and, eventually, a
tendency for bones to fracture easily.

• Almost all leukemias eventually spread to the spleen, lymph nodes, liver,
and other vascular regions, regardless of whether the origin of the
leukemia is in the bone marrow or the lymph nodes.
• Effects of Leukemia on the Body

• Common effects in leukemia are the development of infection,

anemia, and a bleeding tendency caused by thrombocytopenia
(lack of platelets).

• These effects result mainly from displacement of the normal bone

marrow and lymphoid cells by the nonfunctional leukemic cells.
Classification of Leukaemia according to type of white blood cell
affected

1. Lymphocytic leukemia. This type of leukemia affects the lymphoid

cells (lymphocytes), which form lymphoid or lymphatic tissue

The lymphocytic leukemias are caused by cancerous production of

lymphoid cells (that involving T and B lymphocytes ), usually beginning in a
lymph node or other lymphocytic tissue and spreading to other areas
of the body.
2. Myelogenous leukemia. This type of leukemia affects the myeloid
cells. Myeloid cells give rise to red blood cells, white blood cells and
platelet-producing cells

The myelogenous leukemia, begins by cancerous production of

young myelogenous cells in the bone marrow (produces partially
differentiated cells, resulting neutrophilic leukemia, eosinophilic
leukemia, basophilic leukemia, or monocytic leukemia) and then
spreads throughout the body so that white blood cells are produced in
many extra-medullary tissues—especially in the lymph nodes, spleen, and
liver.
Specific types:

1. Acute lymphoblastic leukemia (ALL) is the most common type of

leukemia in young children. It also affects adults, especially those< 65
2. Chronic lymphocytic leukemia (CLL) most often affects adults over
the 55. sometimes occurs in younger adults, never affects children.
2/3 of patients are men. The 5-year survival rate is 85%.
It is incurable, but there are many effective treatments.
3. Acute myelogenous leukemia (AML) occurs more commonly in adults
and more common in men than women. It is treated with
chemotherapy. The five-year survival rate is 20
4. Chronic myelogenous leukemia (CML) occurs mainly in adults; a very
small number of children also develop this disease. It is treated
with imatinib . The five-year survival rate is 90%.
5. Hairy cell leukemia
(HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but
does not fit neatly into this category. About 80% of affected people are adult men.
No cases in children
Risk factors of Leukaemia
 Previous cancer treatment. People who've had certain types of
chemotherapy and radiation therapy for other cancers have an
increased risk of developing certain types of leukemia.

 Genetic disorders. Genetic abnormalities seem to play a role in the

development of leukemia. Certain genetic disorders, such as Down
syndrome, are associated with an increased risk of leukemia.

 Exposure to certain chemicals. Exposure to certain chemicals,

such as benzene — which is found in gasoline and is used by the
chemical industry — is linked to an increased risk of leukemia.

 Smoking. Smoking cigarettes increases the risk of AML

 Family history of leukemia. If members of your family have been

diagnosed with leukemia, your risk of the disease may be increased.
Symptoms of Leukaemia
Leukemia symptoms vary, depending on the type of leukemia.
Common leukemia signs and symptoms include:
 Fever or chills
 Persistent fatigue, weakness
 Frequent or severe infections
 Losing weight without trying
 Swollen lymph nodes, enlarged liver or spleen
 Easy bleeding or bruising
 Recurrent nose bleeds
Excessive sweating, especially at night
 Bone pain or tenderness
Acute myeloid leukemia

 Acute leukaemia is normally defined as the presence of

over20 - 30% of blast cells in the bone marrow at clinical
presentation.

 However, it can be diagnosed with less than 20% blasts if specific

leukaemia‐associated cytogenetic or molecular genetic abnormalities
are present

 The lineage of the blast cells is defined by microscopic

examination (morphology) , immunophenotypic (flow cytometry) ,
cytogenetic and molecular analysis .

 This will define whether the blasts are of myeloid or lymphoid lineage
and also localize the stage of cellular differentiation .

 The typical ‘myeloid immunophenotype’ is CD13, CD33+ and TdT− .

 Special antibodies are helpful in the diagnosis of the rare undifferentiated, erythroid or
megakaryoblastic subtypes (Table 13.2).

 Cytogenetic and molecular analysis is essential and is usually performed on marrow

cells, although blood may be used if the blast cell count is particularly high.

 Cytochemistry can be useful in determining the blast cell lineage but is no longer
performed in centres where the newer and more definitive tests are available.
Acute myeloid leukaemia

Pathogenesis
The AML genome contains an average of about 10 mutations within
protein‐coding genes, amongst the smallest number of any adult cancer..
The mutations usually occur on only one of the two alleles for the gene and
may be ‘loss of function’ or ‘gain of function’.
The wide variety of cytogenetic abnormalities and molecular mutations are
such that each case usually has a unique pattern of mutations.

Incidence
Acute myeloid leukaemia (AML) is the most common form of acute
leukaemia in adults and becomes increasingly common with age, with a
median onset of 65 years.
It forms only a minor fraction (10–15%) of the leukaemias in childhood.
Cytogenetic abnormalities and response to initial treatment have a major
influence on prognosis .
Classification of AML

o AML is classified according to the World Health Organization (2008)

scheme. There is an increasing focus on the genetic abnormalities
within the malignant cells and it is likely that ultimately almost all AML
cases will be classified by specific genetic subtype.

o Currently this is not possible but many genetic subtypes have been
determined. Approximately 60% of tumours exhibit karyotypic
abnormalities on cytogenetic analysis and many cases with a normal
karyotype carry mutations .

o Six main groups of AML are recognized

Classification of AML
1 AML with recurrent genetic abnormalities
Encompasses subtypes with specific chromosomal translocations or gene
mutations.
The detection of these abnormalities defines the tumour as AML and so the
diagnostic criteria for this subgroup in that the bone marrow blast cell count
does not need to exceed 20% in order to make a diagnosis.
In general these disorders have a good prognosis.

2 AML with myelodysplasia‐related changes.

In this group the AML is associated with microscopic features of dysplasia in
at least 50% of cells in at least two lineages.
The clinical outcome of these patients is impaired in relation to the first
subgroup.
3 Therapy‐related myeloid neoplasms(t‐AML)
arise in patients who have been previously treated with drugs such as
etoposide or alkylating agents.
They commonly exhibit mutations in the MLL gene and the clinical response
is usually poor.
Classification of AML

4 AML, not otherwise specified.

This group is defined by the absence of cytogenetic abnormalities and
comprises around 30% of all cases. Mutations in the NPM1 and FLT3 genes
are more frequent in those with normal
cytogenetics.
5 Myeloid sarcoma
is rare but refers to a disease that resembles a solid tumour but is composed
of myeloid blast
cells.
6 Myeloid proliferations related to Down’s syndrome.
Children with Down’s syndrome have a greatly increased risk of acute
leukaemia.
Two myeloid variants are recognized:
(i) transient abnormal myelopoiesis in which there is a selflimiting
leucocytosis; and (ii) AML.
The French-American-British (FAB) classification

o system provides terminology that is still sometimes used, and it remains a

valuable diagnostic tool in areas without access to genetic testing
this system has largely become neglected in favor of the WHO
classification, which correlates more strongly with treatment outcomes.

o AML of types M0 to M2 may be called acute myeloblastic leukemia.

o Classification is done by examining the appearance of the malignant

cells with light microscopy and/or by using cytogenetics to
characterize any underlying chromosomal abnormalities.

o The subtypes have varying prognoses and responses to therapy.

o Six FAB subtypes (M1 through to M6) were initially proposed in 1976,
although later revisions added M7 in 1985, and M0 in 1987
 Type Name

M0 acute myeloblastic leukemia, minimally differentiated

M1 acute myeloblastic leukemia, without maturation

M2 acute myeloblastic leukemia, with granulocytic maturation

M3 promyelocytic, or acute promyelocytic leukemia (APL)

M4 acute myelomonocytic leukemia

M4eo myelomonocytic together with bone marrow eosinophilia

M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b)

M6 acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b)

M7 acute megakaryoblastic leukemia

Treatment

 First-line treatment of AML consists primarily of chemotherapy,

and is divided into two phases: induction and consolidation.

 The goal of induction therapy is to achieve a complete remission by

reducing the number of leukemic cells to an undetectable level.

 The goal of consolidation therapy is to eliminate any residual undetectable

disease and achieve a cure.

 Hematopoietic stem cell transplantation

is usually considered if induction chemotherapy fails or after a person
relapses, although transplantation is also sometimes used as front-line
therapy for people with high-risk disease.

 Efforts to use tyrosine kinase inhibitors in AML continue.

I- Induction chemotherapy

The goal of the induction phase is to reach a complete remission. Complete

remission does not mean the disease has been cured; rather, it signifies
no

disease can be detected with available diagnostic methods.All subtypes except

acute promyelocytic leukemia are usually given induction chemotherapy

with

cytarabine and an anthracycline such as daunorubicin or

idarubicin.This

induction chemotherapy regimen is known as ("3+7").

Response to this treatment varies with age, with people aged less than 60

years having better remission rates between 60% and 80%, while older people
Acute promyelocytic leukemia is treated with all-trans-retinoic
acid

(ATRA) and either arsenic trioxide (ATO) monotherapy or an

anthracycline.

A syndrme similar to disseminated intravascular coagulation can

develop

during the initial few days of treatment or at the time the leukemia is

diagnosed, and treatment can be complicated by a differentiation

syndrome characterised by fever, fluid overload and low oxygen levels.

Acute promyelocytic leukemia is considered curable.

II-Consolidation

o Even after complete remission is achieved, leukemic cells likely remain in

numbers too small to be detected with current diagnostic techniques.

o If no consolidation therapy or further postremission is given, almost all

people with AML will eventually relapse.

o This generally involves cytarabine, with the doses administered being

higher in younger patients, who are less likely to develop toxicity related
to this treatment.
Stem cell transplantation

Stem cell transplantation from a donor, called allogenic stem cell

transplantation,

o It is usually pursued if the prognosis is not considered favourable, a

person can tolerate a transplant and has a suitable donor.

o The basis of allogenic stem cell transplantation is on a graft versus

leukemia effect whereby graft cells stimulate an immune response
against leukemia cells.

o Unfortunately this is accompanied by immune responses against other

host organs, called a graft versus host disease
Supportive treatment

o Support is necessary throughout treatment because of problems

associated with AML and also arising from treatment.

o Blood transfusions, including of red blood cells and platelets, are

necessary to maintain health levels, preventing complications

o AML leads to an increased risk of infections, particularly drug-resistant

strains of bacteria and fungi

o Antibiotics and antifungals can be used both to treat and to prevent

these

infections.
In pregnancy
o AML is rare in pregnancy, affecting about 1 in 75,000 to 100,000
pregnant women.
o It is diagnosed and treated similarly to AML in non pregnancy, with a
recommendation that it is treated urgently.

o First trimester pregnancy is considered unlikely to be viable; pregnancy

during weeks 24 – 36 requires consideration of the benefits of
chemotherapy to the mother against the risks to the foetus; and there
is a recommendation to consider delaying chemotherapy in very late
pregnancy (> 36 weeks).
Acute lymphoblastic leukaemia (ALL)

is caused by an accumulation of lymphoblasts in the bone marrow

It is the most common malignancy of childhood.

Incidence and pathogenesis

o The incidence of ALL is highest at 3–7 years, with 75% of cases

o occurring before the age of 6.

o There is a secondary rise after the age of 40 years. Eighty‐five per cent
of cases are of B‐cell lineage and have an equal sex incidence;

o there is a male predominance for the 15% of T‐cell ALL (T‐ALL).

o The pathogenesis is varied. A proportion of cases of childhood ALL
are

initiated by genetic mutations that occur during development

in utero

o Studies in identical twins have shown that both may be born with the

same chromosomal abnormality

o One twin may develop ALL early (e.g. at age 4) because of a second

transforming event affecting the copy numbers of several genes including

those in B‐cell development

o The other remains well or develops ALL later.

Classification
o Acute lymphoblastic leukaemia, B cell or T cell, is subclassified by WHO (2008) according
to the underlying genetic defect.

o Within B‐ALL there are several specific genetic subtypes such as those with the t(9;22) or

t(12;21) translocations,

o The subtype is an important guide to the optimal treatment protocol and to prognosis.

o In TALL an abnormal karyotype is found in 50–70% of cases

Clinical features

Bone marrow failure

Anaemia (pallor, lethargy and dyspnoea);
Neutropenia (fever, malaise, features of mouth, throat,
skin, respiratory, perianal or other infections);
Thrombocytopenia (spontaneous bruises, purpura, bleeding
gums and menorrhagia).

Organ infiltration
This causes tender bones, lymphadenopathy moderate splenomegaly,
hepatomegaly and meningeal syndrome
(headache, nausea and vomiting, blurring of vision
and diplopia).
Clinical features

Organ infiltration

o Fundal examination may reveal papilloedema and sometimes haemorrhage.

o Many patients have a fever which usually resolves after starting

chemotherapy.

o Less common manifestations include testicular swelling or signs of

mediastinal compression in T‐ALL

o If lymph node or solid extranodal masses predominate with <20% blasts in

the marrow, the disease is called lymphoblastic lymphoma but is treated
as ALL.
Investigations

o Haematological investigations reveal a normochromic normocytic

anaemia with thrombocytopenia in most cases.

o The total white cell count may be decreased, normal or increased to 200
× 109/L or more.

o The blood film typically shows a variable numbers of blast cells.

o The bone marrow is hypercellular with >20 – 30% leukaemic blasts.

o The blast cells are characterized by morphology , immunological tests

and cytogenetic analysis .

o Identification of the immunoglobulin or T‐cell receptor (TCR) gene

rearrangement , (aberrant) immunophenotype and molecular genetics of
the tumour cells is important to determine treatment and to detect
minimal residual disease (MRD) during follow‐up.
o Investigations

o Lumbar puncture for cerebrospinal fluid (CSF) examination is not

generally performed as it may promote the spread of tumour cells to the
CNS.

o Initial assessment of the CSF should always be combined with the

concurrent administration of intrathecal chemotherapy.

o Biochemical tests may reveal a raised serum uric acid, serum lactate
dehydrogenase or, less commonly, hypercalcaemia. Liver and renal function
tests are performed as a baseline before treatment begins.

o Radiography may reveal lytic bone lesions and a mediastinal mass caused
by enlargement of the thymus and/or mediastinal lymph nodes
characteristic of T‐ALL
Treatment

This may be conveniently divided into supportive and specific

treatment.

General supportive therapy

Blood product support and prevention of tumour lysis
syndrome.
Hyperuricemia
Hyperphosphatemia
Hyperkalemia (high potassium)
Hypocalcemia

The risk of tumour lysis syndrome is highest in children with a high white
cell count, T‐cell disease or concurrent renal impairment at presentation.
Any episode of fever must be treated promptly
Specific therapy of ALL

o Specific therapy of ALL is with chemotherapy and sometimes

radiotherapy .
o treatment protocols are extremely complex.

o There are several phases in a treatment course, which usually has four
components .

o The factors that guide treatment include age, gender and white cell count
at presentation.

o The initial response to therapy is also important, as slow clearance of

blood or marrow blasts after a week or two of induction therapy or
persistence of MRD is associated
o with a relatively high risk of relapse.

o The disease is associated with chromosomal translocation involving the

MLL gene in 80% of cases and is treated by unique protocols.
Remission induction

o At presentation, the patient with acute leukaemia has a very high

tumour burden and is at great risk from the complications of
bone marrow failure and leukaemic infiltration.

o The aim of remission induction is to rapidly kill most of the tumour

cells and get the patient into remission.

o This is defined as less than 5% blasts in the bone marrow, normal

peripheral blood count and no other symptoms or signs of the disease.

o Steroids (dexamethasone or prednisolone), vincristine and asparaginase

are the drugs usually used and they are very effective – achieving
remission in over 95% of children and in 80–90% of adults (in whom
daunorubicin is also usually added).
(consolidation)chemotherapy

o These courses use high doses of multidrug chemotherapy in order to

eliminate the disease or reduce the tumour burden to very low
levels.

o The doses of chemotherapy are near the limit of patient tolerability .

o Typical protocols involve the use of vincristine, cyclophosphamide,

cytosine arabinoside, daunorubicin, etoposide or mercaptopurine given as
blocks in different combinations.
o The numbers of blocks given in children depends on the child’s risk
category and varies between one and three.
Central nervous system‐directed therapy

o Few of the drugs given systemically are able to reach the CSF and
specific treatment is required to prevent or treat central nervous
system (CNS) disease.

o Intrathecal methotrexate is usually used.

o CNS relapses still occur and present with headache, vomiting,
papilloedema and blast cells in the CSF.

o Treatment is with intrathecal methotrexate, cytosine arabinoside and

hydrocortisone,with or without cranial irradiation and systemic
chemotherapy because bone marrow disease is usually also present.
Maintenance

o This is given with daily oral mercaptopurine and once‐weekly oral

methotrexate.
o Intravenous vincristine with a short course (5 days) of oral
dexamethasone is added at monthly or 3‐monthly (in adults) intervals.

o Maintenance may in some protocols begin soon after remission

induction and is interrupted by the periods of intensive chemotherapy.

o In typical regimens intensive chemotherapy finishes around 38 weeks

and then maintenance begins again and lasts until week 112 in or 164
weeks.
Thank you