Acute leukaemia

Leukaemias are malignant disorders of the white 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.

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 mutated haematopoietic stem and

progenitor cells, with limited accompanying differentiation, 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 progenitor cells (B cells and T cells). Myeloid refers to
the other lineages: that is, precursors of red cells, granulocytes, monocytes and
platelets.

The diagnosis of leukaemia is usually suspected from an abnormal blood count,

often including a raised white count, and is confirmed by examination of the bone
marrow. This includes the morphology of the abnormal cells, analysis of cell
surface markers (immunophenotyping), 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, increasingly
allowing therapy to be tailored to the patient’s disease.

Mutations in haematopoietic stem cells produce leukaemic stem cells. Proliferation

of these cells that do not mature leads to an accumulation of primitive cells that
take up more and more marrow space at the expense of the normal haematopoietic
cells. Eventually, this proliferation spills into the blood. Acute myeloid leukaemia
(AML) is about four times more common than acute lymphoblastic leukaemia
(ALL) in adults. In children, the proportions are reversed, the lymphoblastic
variety being more common.
WHO classification of Acute Leukemia

Acute myeloid leukaemia (AML) with recurrent genetic abnormalities

 AML with t(8;21)(q22;q22.1), gene product RUNX1-RUNX1T1
 AML with inv(16)(p13.1;q22), gene product CBFB-MYHL1
 Acute promyelocytic leukaemia t(15;17), gene product PML-RARA
 AML with t(9;11)(p21.3;q23.3), gene product MLLT3-KMT2A
 AML with t(6;9)(p23;q34), gene product DEK-NUP214
 AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), gene products GATA2,
MECOM
 AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), gene product RBM15-
MKL1
 AML with mutated NPM1
 AML with biallelic mutations of CEBPA

Acute myeloid leukaemia with myelodysplasia-related changes

 e.g. Following a myelodysplastic syndrome

Therapy-related myeloid neoplasms

 e.g. Alkylating agent or topoisomerase II inhibitor

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Acute myeloid leukaemia not otherwise specified

 e.g. AML with or without differentiation, acute myelomonocytic leukaemia,
erythroleukaemia, megakaryoblastic leukaemia.
Acute lymphoblastic leukaemia (ALL)
 B-lymphoblastic leukaemia/lymphoma
 T-lymphoblastic leukaemia/lymphoma
Risk Factors of Leukaemia

Ionising radiation
 After atomic bombing of Japanese cities (myeloid leukaemia)
 Radiotherapy
 Diagnostic X-rays of the fetus in pregnancy

Cytotoxic drugs
 Especially alkylating agents and topoisomerase II inhibitors (therapy-related
myeloid malignancies), usually after a latent period of several years with alkylating
agents and a few months to 2 years with topoisomerase II inhibitors
 Industrial exposure to benzene

Retroviruses
 Adult T-cell leukaemia/lymphoma (ATLL) caused by human T-cell
lymphotropic virus 1(HTLV-1), most prevalent in Japan, the Caribbean and some
areas of Central and South America and Africa

Genetic
 Identical twin of patients with leukaemia
 Down syndrome and certain other genetic disorders

Immunological
 Immune deficiency states (e.g. hypogammaglobulinaemia)

Leukemoid Reaction:Increase in WBC (>50,000 cell/microlitre) which is a

physiological response to stress or infection. It often describes presence of
immature cells eg myeloblast, RBC with nuclei in peripheral blood.

Myelodysplastic syndromes (MDSs) constitute a group of clonal haematopoietic

disorders with the common features of ineffective blood cell production and a
tendency to progress to AML. As such, they are pre-leukaemic and represent
genetic steps in the development of leukaemia. MDS presents with consequences
of bone marrow failure (anaemia, recurrent infections or bleeding), usually in older
people (median age at diagnosis is 73 years).. The blood film is characterised by
cytopenias and abnormal-looking (dysplastic) blood cells, including macrocytic red
cells and hypogranular neutrophils with nuclear hyper- or hyposegmentation. The
bone marrow is hypercellular, with dysplastic changes in at least 10% of cells of
one or more cell lines. Blast cells may be increased but do not reach the 20% level
that indicates acute leukaemia.

The clinical features are usually those of bone marrow failure (anaemia, bleeding
or infection).

Investigations
Blood examination usually shows anaemia with a normal or raised MCV. The
leucocyte count may vary from as low as 1 × 109/L to as high as 500 × 109/L or
more. In the majority of patients, the count is below 100 × 109/L. Severe
thrombocytopenia is usual but not invariable. Frequently, blast cells are seen in the
blood film, but sometimes the blast cells may be infrequent or absent.

A bone marrow examination will confirm the diagnosis. The bone marrow is
usually hypercellular, with replacement of normal elements by leukaemic blast
cells in varying degrees (but more than 20% of the cells). The presence of Auer
rods in the cytoplasm of blast cells indicates a myeloblastic type of leukaemia.

Management
If a decision to embark on specific therapy has been taken, the patient should be
prepared as recommended: Preparation for specific therapy in acute leukaemia
 Existing infections identified and treated (e.g. urinary tract infection, oral
candidiasis, dental, gingival and skin infections)
 Screen for COVID-19
 Anaemia corrected by red cell concentrate transfusion
 Thrombocytopenic bleeding controlled by platelet transfusions
 If possible, central venous catheter (e.g. Hickman line) inserted to facilitate
access to the circulation for delivery of chemotherapy, fluids, blood products
and other supportive drugs
 Tumour lysis risk assessed and prevention started: fluids with allopurinol or
rasburicase
 Therapeutic regimen carefully explained to the patient and informed consent
obtained
 Consideration of entry into clinical trial

It is unwise to attempt aggressive management of acute leukaemia unless adequate

supportive therapy can be provided.
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.
 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 that relapses during treatment or soon after the end of treatment,
including after HSCT, 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.

Specific therapy

Acute myeloid leukaemia (AML):

There are currently three phases of specific treatment for AML:

Remission induction.
 In this phase, a fraction of the tumour is killed by combinations of
chemotherapy drugs. The standard of care for remission induction in AML is
daunorubicin with cytosine arabinoside given for 7–10 days in two cycles.
Patients with a good or standard risk karyotype, including normal karyotype,
benefit from the addition of the antibody-drug conjugate gemtuzumab
ozagomicin which targets CD33 on the AML cell and delivers the DNA
damaging drug calicheamicin directly into the cell, while AML with the
FLT3-ITD mutation benefits from the addition of theFLT3 inhibitor
midostaurin.

 The patient goes through a period of severe bone marrow hypoplasia lasting
3–4 weeks and requires intensive support and inpatient care from a specially
trained multidisciplinary team. The aim is to achieve remission, a state in
which the blood counts return to normal and the marrow blast count is less
than 5%.

Remission consolidation.
  If remission has been achieved, residual disease is attacked by therapy
during the consolidation phase. This consists of a number of courses of
chemotherapy, most commonly 1–2 courses of high-dose cytosine
arabinoside, again resulting in periods of marrow hypoplasia.

 In poor-prognosis AML, defined by poor risk cytogenetic/molecular genetic

abnormalities or persistent MRD, this may include allogeneic HSCT.

Remission maintenance.
 Maintenance therapy has only recently become an effective tool for some
patients with AML compared to its long-established role in ALL.

 Patients not undergoing allogeneic HSCT with FLT3 mutated AML receive
one year of maintenance with midostaurin and other patients may benefit
from azacitidine.

Relapsed AML carries a poor prognosis. Increasingly, this is preempted by

monitoring MRD and intervening before haematological relapse occurs. However,
the aim is to attempt to achieve further remission and deliver an allogeneic HSCT,
if possible.

Acute promyelocytic leukaemia (APML)

 A subtype of AML is characterised by a tendency to severe bleeding,
including into the CNS, because of enhanced fibrinolysis and DIC induced
by the procoagulant proteins in the malignant cells, e.g. tPA and uPA.
APML carries the best prognosis of all AML if the patient survives the
initial bleeding risk.

 Furthermore, low risk cases can be treated with a non-chemotherapy

regimen of differentiation therapy with all-trans-retinoic acid (ATRA) and
arsenic trioxide (ATO).

 Higher-risk patients are treated with ATRA and anthracycline-based

chemotherapy.

The prognosis is excellent with 90% cure rate for patients receiving treatment.
However, the early death rate from bleeding remains problematic and intensive
supportive care and immediate introduction of ATRA therapy is vital to prevent
this.
Acute lymphoblastic leukaemia (ALL): This is predominantly a disease of
childhood with a mean age of 2–4 years. However, it also occurs in adulthood
where it is more difficult to treat and carries a poorer prognosis. Once again there
are three phases of therapy with treatment tailor-made to risk groups based on
genetic abnormaliites and levels of MRD:

Remission induction –
 As with AML the aim is to achieve remission using a combination of
chemotherapy drugs given over a 4-week period. The drugs commonly used
are dexamethasone, vincristine, anthracyclines, methotrexate,
mercaptopurine and asparaginase. Induction therapy in ALL is often less
damaging and better tolerated than AML, however, the high dosage of
steroids coupled with neutropenia carries a high risk of infections, including
fungal infections. Adult patients are more likely to have a poor-risk genetic
abnormality.

 Once again, old and frail patients tolerate treatment much less well and
treatment is modified accordingly. Adolescent and young adult patients
require special support and have been shown to do better with children’s
protocols than adult protocols.

Remission consolidation –
 The consolidation phase builds on the remission by further decreasing the
leukaemic burden. The intensity of consolidation depends on the level of
MRD at the end of remission induction and includes blocks of chemotherapy
drugs.

 Allogeneic HSCT is used as consolidation for fit adults with ALL and a
suitable donor, but rarely in children unless they relapse.

Remission maintenance –
 If the patient is still in remission after the consolidation phase for ALL, a
period of maintenance therapy is given, with the individual as an outpatient
and treatment consisting of a repeating cycle of drug administration. This
may extend for up to 3 years if relapse does not occur.

 In ALL prophylactic treatment to the central nervous system is required, as

this is a sanctuary site where standard therapy does not penetrate. This
usually consists of a combination of cranial irradiation, intrathecal
chemotherapy and high-dose methotrexate, which crosses the blood–brain
 barrier. Such therapy is integrated into the induction, remission and
consolidation phases of therapy.

Drugs commonly used in the treatment of acute leukaemia

Phase Acute lymphoblastic Acute myeloid leukaemia

leukaemia
Induction Vincristine (IV) Daunorubicin (IV)
Prednisolone (oral) Cytarabine (IV)
L-Asparaginase (IM) Etoposide (IV and oral)
Daunorubicin (IV) Gentuzumab ozogamicin (IV)
Methotrexate (intrathecal) All-trans retinoic acid (ATRA)
Imatinib (oral)* (oral)
Arsenic trioxide (ATO) (IV)
Consolidation Daunorubicin (IV) Cytarabine (IV)
Cytarabine (IV) Amsacrine (IV)
Etoposide (IV) Mitoxantrone (IV)
Methotrexate (IV)
Imatinib (oral)*
Maintenance Prednisolone (oral)
Vincristine (IV)
Mercaptopurine (oral)
Methotrexate (oral)
Imatinib (oral)*
Relapse Fludarabine (IV) Fludarabine (IV)
Cytarabine (IV) Cytarabine (IV)
Idarubicin (IV) Arsenic trioxide (ATO) (IV)
Idarubicin (IV)
*If Philadelphia chromosome-positive. (IM = intramuscular; IV = intravenous)

Supportive therapy
Aggressive and potentially curative therapy, which involves periods of severe bone
marrow failure, would not be possible without appropriate supportive care. The
following problems commonly arise.

Anaemia Anaemia is treated with red cell concentrate transfusions.

Bleeding Thrombocytopenic bleeding requires platelet transfusions, unless the
bleeding is trivial. Recent trials have confirmed that in acute leukaemia
prophylactic platelet transfusion should be given to maintain the platelet count
above 10 × 109/L. Coagulation abnormalities occur and need accurate diagnosis
and treatment, especially in APML.

Infection
 So-called neutropenic sepsis is a major complication of acute leukaemia and
its treatment. UK NICE guidelines define neutropenic sepsis as fever
(>38°C) lasting over 1 hour in a neutropenic patient (neutrophils <0.5 ×
109/l) or with other signs or symptoms of significant sepsis. Parenteral
broad-spectrum antibiotic therapy is essential. Empirical therapy is given
according to the perceived severity of the sepsis illness and local
bacteriological resistance patterns. Increasingly, low-risk cases of
neutropenic sepsis are treated with single antibiotics, e.g.
piperacillin/tazobactam. Higher-risk cases are managed with regimens such
as a combination of an aminoglycoside (e.g. gentamicin) and a broad-
spectrum penicillin (e.g. piperacillin/tazobactam) or a single-agent beta-
lactam (e.g. meropenem). The organisms most commonly associated with
severe neutropenic sepsis are Gram-positive bacteria, such as
Staphylococcus aureus and Staphylococcus epidermidis, which are present
on the skin and gain entry via cannulae and central lines. Gram-negative
infections often 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 initially empirical antibiotic therapy.
Gram-positive infection may require vancomycin or teicoplanin therapy.

 If fever has not resolved after 3–5 days and there is evidence for a
disseminated fungal infection on CT scans or sensitive blood tests,
empirical antifungal therapy (e.g. a liposomal amphotericin B preparation,
voriconazole or caspofungin) is added.
 Patients with ALL are susceptible to infection with Pneumocystis jirovecii,
which causes a severe pneumonia. Prophylaxis with co-trimoxazole is given
during chemotherapy. Diagnosis may require either induced sputum,
bronchoalveolar lavage or open lung biopsy. 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. Prophylaxis against other systemic fungal infections
including Aspergillus, for example itraconazole or posaconazole, is usual
practice during high-risk intensive chemotherapy. This is often used along
with sensitive markers of early fungal infection to guide treatment initiation
(a ‘pre-emptive approach’). For systemic fungal infection with Candida or
aspergillosis, intravenous liposomal amphotericin, caspofungin or
voriconazole is required for up to 3 weeks. In systemic Candida infection
intravenous catheters should be removed.

 Reactivation of herpes simplex infection occurs frequently around the lips

and nose during ablative therapy for acute leukaemia, and is treated with
aciclovir. This may also be prescribed prophylactically to patients with a
history of cold sores or elevated antibody titres to herpes simplex. 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.

 The value of isolation facilities, such as laminar flow rooms, is debatable

but may contribute to staff awareness of careful reverse barrier nursing
practice. The isolation can be psychologically stressful for the patient.

Metabolic problems Frequent monitoring of fluid balance and renal, hepatic and
haemostatic function is necessary. Patients are often severely anorexic and
diarrhoea is common as a consequence of the side-effects of therapy; they may find
drinking difficult and hence require intravenous fluids and electrolytes. Renal
toxicity occurs with some antibiotics (e.g. aminoglycosides) and antifungal agents
(amphotericin). Cellular breakdown during induction therapy (tumour lysis
syndrome; releases intracellular ions and nucleic acid breakdown products, causing
hyperkalaemia, hyperuricaemia, hyperphosphataemia and hypocalcaemia. This
may lead to renal failure. Allopurinol and intravenous hydration are given to try to
prevent this. In patients at high risk of tumour lysis syndrome, e.g. acute leukaemia
with a white cell count of more than 100 × 109/L, prophylactic rasburicase (a
recombinant urate oxidase enzyme) is used. Occasionally, dialysis may be
required.

Psychological problems Psychological support is a key aspect of care. Patients

should be kept informed, and their questions answered and fears allayed as far as
possible.
Prognosis

 Without treatment, the median survival of patients with acute leukaemia is

about 5 weeks.

 This may be extended to a number of months with supportive treatment.

 Patients who achieve remission with specific therapy have a better outlook.
Around 80% of adult patients under 60 years of age with ALL or AML
achieve remission, although remission rates are lower for older patients.
However, the relapse rate continues to be high.

 The level of detectable leukaemia cells after induction therapy, called

measurable residual disease (MRD), can be a powerful prognostic tool and is
now used routinely in some forms of acute leukaemia (e.g. ALL and AML
with NPM1 mutation) to determine subsequent consolidation therapy.

 Advances in treatment have led to steady improvement in survival from

acute leukaemia. Some 90% of children with ALL are cured and about 50%
of adults aged less than 60 years are cured from AML. As discussed above,
APML has a 90% cure rate.

 Prognosis remains poor in most other groups of patients with acute

leukaemias, especially in old age. Current trials aim to improve survival,
especially in standard and poor-risk disease, with strategies that include
better use of allogeneic HSCT, better ability to predict relapse using MRD
and new targeted therapies.

Outcomes in adult acute leukaemia

Disease/risk Risk factors 5-year overall

survival
Acute myeloid leukaemia (AML)
Good risk Promyelocytic leukaemia t(15;17) 90%
t(8;21) 65%
inv(16) or t(16;16) 70%
Poor risk Cytogenetic abnormalities 21%
5, 7, del
5q, abn(3q), complex (>5)

Intermediate risk AML with none of the above 48%

Acute lymphoblastic leukaemia (ALL)

Poor risk Philadelphia chromosome 20%
High white count >100 × 109/L
Abnormal short arm of
chromosome
11 t(1;19)
Standard ALL with none of the above 37%