Page 190 - Essential Haematology

176 / Chapter 12 Haematological malignancy: management

combination with cytosine arabinoside as intrath- therapeutic regimens used in the treatment of lym-
ecal prophylaxis of CNS disease in patients with phoid malignancy and myeloma.
ALL, acute myeloid leukaemia (AML) or high All - trans retinoic acid (ATRA) is a vitamin A

grade non - Hodgkin lymphoma. High systemic derivative that acts as a differentiation agent in acute
doses may also prenetrate the CNS. Folinic acid promyelocytic leukaemia (APML). Tumour cells in
(formyl THF) is able to overcome the activity of APML are arrested at the promyelocyte stage as a
methotrexate and is sometimes administered to result of transcriptional repression resulting from
‘ rescue ’ normal cells after high - dose methotrexate the PML - RARA fusion protein (see p. 182 ). ATRA
therapy. relieves this block and may lead to a brisk neu-
3 Pyrimidine analogues include cytosine arabino- trophila within a few days of treatment with other

‘

side (cytarabine; ara - C) which is an analogue of side - effects known as the ATRA ’ or differentiation ’
‘
′
2 - deoxycytidine and is incorporated into DNA (see p. 183 ).
where it inhibits DNA polymerase and blocks Demethylation agents (e.g. azacytidine, decit-
replication. abine) act to increase transcription by reducing
4 Purine analogues include fl udarabine (which methylation on cytosine resides within DNA.
inhibits DNA synthesis in a manner similar to Interferon - α is an antiviral and antimitotic sub-
ara - C), mercaptopurine, azathioprine, benda- stance produced in response to viral infection and

mustine, clofarabine and pentostatin . inflammation. It has proven useful in chronic
myeloid leukaemia, myeloma and myeloprolifera-
Cytotoxic antibiotic drugs include the anthra-
tive diseases.
cyclines such as doxorubicin, hydroxodaunorubicin,
Monoclonal antibodies are highly eff ective

epirubicin and mitozantrone. These are able to
against B - cell malignancies. Rituximab binds to
intercalate into DNA and then bind strongly to
CD20 on B cells and appears to mediate cell death,
topoisomerases which are critical for relieving tor-
primarily through direct induction of apoptosis and
sional stress in replicating DNA by nicking and
opsonization (see p. 265 ). Alemtuzumab binds to
resealing DNA strands. If topoisomerase activity is
CD52 and is highly effi cient at fi xing complement
blocked, DNA replication cannot take place.
which lyzes the target B and T cells. Lumiliximab
Bleomycin is a metal chelating antibiotic that
is an anti - CD23 in trial for treatment of chronic
generates superoxide radicals within cells that
lymphocytic leukaemia. Antibodies may also carry
degrade preformed DNA. It is active on non - cycling ®
attached toxins (e.g. Mylotarg ), (anti - CD33) or
cells. ®
radioactive isotopes (e.g. Zevalin ).
Plant derivatives include the vinca alkaloids
Bortezomid is a proteasome inhibitor widely
such as vincristine which is derived from the peri-
used in the treatment of myeloma and some
winkle plant. It binds to tubulin and prevents its
lymphomas.
polymerization to microtubules. This blocks cell

Asparaginase is an enzyme derived from bacte-
division in metaphase. Etoposide inhibits topi-
ria that breaks down the amino acid asparagine
somerase action.
within the circulation. ALL cells lack asparagine
synthase and thus need a supply of exogenous
asparagine for protein synthesis. Intramuscular
Other a gents
asparaginase is an important agent in the treatment
Imatinib, dasatinib and nilotinib bind to the of ALL, although hypersensitivity reactions are

BCR - ABL1 fusion protein. They block binding not uncommon and blood clotting may be
of adenosine triphosphate (ATP) and thus prevent disturbed.
the tyrosine kinase from phosphorylating substrate Platinum derivatives (e.g. cisplatin) are used in
proteins leading to apoptosis of the cell (see Fig. combinations for treating lymphoma.
14.4 ). Arsenic is useful in treatment of acute promy-
Corticosteroids have a potent lymphocytotoxic elocytic leukaemia. It induces diff erentiation and
activity and have an important role in many chemo- apoptosis.