Immune system and malignant disease
1 Immune system disorders and transplantation 835
1 Antibody responsive malignancy 860
3 Cytotoxic responsive malignancy 888
3.1 Cytotoxic drug-induced side effects 940
3.1a Hyperuricaemia associated with
4 Hormone responsive malignancy 942
4.1 Hormone responsive breast cancer 952
5 Immunotherapy responsive malignancy 955
6 Photodynamic therapy responsive malignancy 963
7 Targeted therapy responsive malignancy 964
Azathioprine p. 836, ciclosporin p. 838, mercaptopurine
p. 912, and methotrexate p. 913 have a role in the treatment
of inflammatory bowel disease.
Folic acid p. 1025 should be given to reduce the possibility
of methotrexate toxicity [unlicensed indication]. Folic acid is
usually given weekly on a different day to the methotrexate;
alternative regimens may be used in some settings.
Immunosuppressants are used to suppress rejection in organ
transplant recipients and to treat a variety of chronic
inflammatory and autoimmune diseases. Solid organ
transplant patients are maintained on drug regimens, which
may include antiproliferative drugs (azathioprine or
mycophenolate mofetil p. 846), calcineurin inhibitors
(ciclosporin or tacrolimus p. 841), corticosteroids, or
sirolimus p. 840. Choice is dependent on the type of organ,
time after transplantation, and clinical condition of the
patient. Specialist management is required and other
immunomodulators may be used to initiate treatment or to
Impaired immune responsiveness
Modification of tissue reactions caused by corticosteroids
and other immunosuppressants may result in the rapid
spread of infection. Corticosteroids may suppress clinical
signs of infection and allow diseases such as septicaemia or
tuberculosis to reach an advanced stage before being
recognised— important: normal immunoglobulin
administration should be considered as soon as possible
after measles exposure, and varicella–zoster
immunoglobulin (VZIG) is recommended for individuals who
have significant chickenpox (varicella) exposure. Specialist
advice should be sought on the use of live vaccines for those
being treated with immunosuppressive drugs.
Antiproliferative immunosuppressants
Azathioprine is widely used for transplant recipients and it is
also used to treat a number of auto-immune conditions,
usually when corticosteroid therapy alone provides
inadequate control. It is metabolised to mercaptopurine, and
doses should be reduced when allopurinol p. 1121 is given
Mycophenolate mofetil is metabolised to mycophenolic
acid which has a more selective mode of action than
There is evidence that compared with similar regimens
incorporating azathioprine, mycophenolate mofetil reduces
the risk of acute rejection episodes; the risk of opportunistic
infections (particularly due to tissue-invasive
cytomegalovirus) and the occurrence of blood disorders such
Cyclophosphamide p. 894 is less commonly prescribed as
Corticosteroids and other immunosuppressants
Prednisolone p. 678 is widely used in oncology. It has a
marked antitumour effect in acute lymphoblastic leukaemia,
Hodgkin’s disease, and the non-Hodgkin lymphomas. It has
a role in the palliation of symptomatic end-stage malignant
disease when it may enhance appetite and produce a sense of
The corticosteroids are also powerful
immunosuppressants. They are used to prevent organ
transplant rejection, and in high dose to treat rejection
Ciclosporin a calcineurin inhibitor, is a potent
immunosuppressant which is virtually non-myelotoxic but
markedly nephrotoxic. It has an important role in organ and
tissue transplantation, for prevention of graft rejection
following bone marrow, kidney, liver, pancreas, heart, lung,
and heart-lung transplantation, and for prophylaxis and
treatment of graft-versus-host disease.
Tacrolimus is also a calcineurin inhibitor. Although not
chemically related to ciclosporin it has a similar mode of
action and side-effects, but the incidence of neurotoxicity
appears to be greater; cardiomyopathy has also been
reported. Disturbance of glucose metabolism also appears to
Sirolimus is a non-calcineurin inhibiting
immunosuppressant licensed for renal transplantation.
Basiliximab p. 844 is used for prophylaxis of acute
rejection in allogeneic renal transplantation. It is given with
ciclosporin and corticosteroid immunosuppression
regimens; its use should be confined to specialist centres.
BNF 78 Immune system disorders and transplantation 835
Immune system and malignant disease
Belatacept p. 847 is a fusion protein and co-stimulation
blocker that prevents T-cell activation; it is licensed for
prophylaxis of graft rejection in adults undergoing renal
transplantation who are seropositive for the Epstein-Barr
virus. It is used with interleukin-2 receptor antagonist
induction, in combination with corticosteroids and a
Antithymocyte immunoglobulin (rabbit) below is licensed
for the prophylaxis of organ rejection in renal and heart
Tolerability is increased by pretreatment with an
intravenous corticosteroid and antihistamine; an antipyretic
drug such as paracetamol may also be beneficial.
Other drugs used for Immune system disorders and
IMMUNE SERA AND IMMUNOGLOBULINS ›
Prophylaxis of organ rejection in heart allograft recipients
▶ Adult: 1–2.5 mg/kg daily for 3–5 days, to be given over
Prophylaxis of organ rejection in renal allograft recipients
▶ Adult: 1–1.5 mg/kg daily for 3–9 days, to be given over
Treatment of corticosteroid-resistant allograft rejection
▶ Adult: 1.5 mg/kg daily for 7–14 days, to be given over at
DOSES AT EXTREMES OF BODY-WEIGHT
▶ To avoid excessive dosage in obese patients, calculate
dose on the basis of ideal body weight.
l CONTRA-INDICATIONS Infection
l INTERACTIONS → Appendix 1: immunoglobulins
malignancy . sepsis . skin reactions .thrombocytopenia . vomiting
SIDE-EFFECTS, FURTHER INFORMATION Tolerability is
increased by pretreatment with an intravenous
corticosteroid and antihistamine; an antipyretic drug such
as paracetamol may also be beneficial.
l PREGNANCY Manufacturer advises use only if potential
benefit outweighs risk—no information available.
l BREAST FEEDING Manufacturer advises avoid—no
l MONITORING REQUIREMENTS Monitor blood count.
l DIRECTIONS FOR ADMINISTRATION For continuous
intravenous infusion (Thymoglobuline ®) in Glucose 5% or
Sodium chloride 0.9%; reconstitute each vial with 5 mL
water for injections to produce a solution of 5 mg/mL;
gently rotate to dissolve. Dilute requisite dose with
infusion fluid to a total volume of 50–500 mL (usually
50 mL/vial); begin infusion immediately after dilution;
give through an in-line filter (pore size 0.22 micron); not to
be given with unfractionated heparin and hydrocortisone
in glucose infusion—precipitation reported.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Immunosuppressive therapy for kidney transplant in adults
Antithymocyte immunoglobulin (rabbit) is not
recommended as an initial treatment to prevent organ
rejection in adults having a kidney transplant. Patients
whose treatment was started within the NHS before this
guidance was published should have the option to
continue treatment, without change to their funding
arrangements, until they and their NHS clinician consider
www.nice.org.uk/guidance/TA481
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Powder and solvent for solution for infusion
Antithymocyte immunoglobulin (rabbit) 25 mg Thymoglobuline
25mg powder and solvent for solution for infusion vials | 1 vial P £158.77 (Hospital only)
IMMUNOSUPPRESSANTS › ANTIMETABOLITES
l DRUG ACTION Azathioprine is metabolised to
Severe acute Crohn’s disease | Maintenance of remission of
Crohn’s disease | Maintenance of remission of acute
▶ Adult: 2–2.5 mg/kg daily, some patients may respond
Rheumatoid arthritis that has not responded to other
disease-modifying drugs | Severe systemic lupus
erythematosus and other connective tissue disorders |
Polymyositis in cases of corticosteroid resistance
▶ Adult: Initially up to 2.5 mg/kg daily in divided doses,
adjusted according to response, rarely more than
3 mg/kg daily; maintenance 1–3 mg/kg daily, consider
withdrawal if no improvement within 3 months
▶ BY MOUTH, OR BY INTRAVENOUS INJECTION, OR BY
▶ Adult: 1–3 mg/kg daily, adjusted according to response,
consider withdrawal if no improvement within
3 months, oral administration preferable, if not
possible then can be given by intravenous injection
(intravenous solution very irritant) or by intravenous
Suppression of transplant rejection
▶ BY MOUTH, OR BY INTRAVENOUS INJECTION, OR BY
▶ Adult: 1–2.5 mg/kg daily, adjusted according to
response, oral administration preferable, if not
possible then can be given by intravenous injection
(intravenous solution very irritant) or by intravenous
Severe refractory eczema, normal or high TPMT activity
836 Immune system disorders and transplantation BNF 78
Immune system and malignant disease
Severe refractory eczema, intermediate TPMT activity
▶ BY MOUTH, OR BY INTRAVENOUS INJECTION, OR BY
▶ Adult: Initially 0.5–1 mg/kg daily, then increased to
2–2.5 mg/kg daily, dose is increased over 3–4 weeks,
azathioprine is usually started at the same time as the
corticosteroid and allows a lower maintenance dose of
the corticosteroid to be used, oral administration
preferable, if not possible then can be given by
intravenous injection (intravenous solution very
irritant) or by intravenous infusion
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises reduce dose to one-quarter of
the usual dose with concurrent use of allopurinol.
l UNLICENSED USE Azathioprine doses given in BNF for
suppression of transplant rejection and autoimmune
conditions may differ from those in product literature.
Use for severe refractory eczema is unlicensed.
▶ When used for severe refractory eczema absent thiopurine
methyltransferase (TPMT) activity . very low thiopurine
methyltransferase (TPMT) activity
l CAUTIONS Reduce dose in elderly .reduced thiopurine
l INTERACTIONS → Appendix 1: azathioprine
▶ Uncommon Anaemia . hepatic disorders . hypersensitivity . pancreatitis
▶ Rare or very rare Agranulocytosis . alopecia . bone marrow
▶ Frequency not known Nodular regenerative hyperplasia . sinusoidal obstruction syndrome
SIDE-EFFECTS, FURTHER INFORMATION Side-effects may
Hypersensitivity reactions Hypersensitivity reactions
(including malaise, dizziness, vomiting, diarrhoea, fever,
rigors, myalgia, arthralgia, rash, hypotension and renal
dysfunction) call for immediate withdrawal.
Neutropenia and thrombocytopenia Neutropenia is
dose-dependent. Management of neutropenia and
thrombocytopenia requires careful monitoring and dose
Nausea Nausea is common early in the course of
treatment and usually resolves after a few weeks without
an alteration in dose. Moderate nausea can be managed by
using divided daily doses, taking doses after food,
prescribing concurrent antiemetics or temporarily
l ALLERGY AND CROSS-SENSITIVITY Contra-indicated in
hypersensitivity to mercaptopurine.
l PREGNANCY Transplant patients immunosuppressed with
azathioprine should not discontinue it on becoming
pregnant. However, there have been reports of premature
birth and low birth-weight following exposure to
azathioprine, particularly in combination with
corticosteroids. Spontaneous abortion has been reported
following maternal or paternal exposure. Azathioprine is
teratogenic in animal studies. The use of azathioprine
during pregnancy needs to be supervised in specialist
units. Treatment should not generally be initiated during
l BREAST FEEDING Present in milk in low concentration. No
evidence of harm in small studies—use if potential benefit
l HEPATIC IMPAIRMENT Manufacturer advises caution
(impaired metabolism)—monitor liver function and
complete blood count more frequently in those with severe
Dose adjustments Manufacturer advises use doses at lower
end of the dose range in hepatic failure; reduce dose if
hepatic or haematological toxicity occur.
Thiopurine methyltransferase The enzyme thiopurine
methyltransferase (TPMT) metabolises thiopurine drugs
(azathioprine, mercaptopurine, tioguanine); the risk of
myelosuppression is increased in patients with reduced
activity of the enzyme, particularly for the few individuals
in whom TPMT activity is undetectable. Consider
measuring TPMT activity before starting azathioprine,
mercaptopurine, or tioguanine therapy. Patients with
absent TPMT activity should not receive thiopurine drugs;
those with reduced TPMT activity may be treated under
▶ Monitor for toxicity throughout treatment.
▶ Monitor full blood count weekly (more frequently with
higher doses or if severe renal impairment) for first
4 weeks (manufacturer advises weekly monitoring for
8 weeks but evidence of practical value unsatisfactory),
thereafter reduce frequency of monitoring to at least every
▶ Blood tests and monitoring for signs of myelosuppression
are essential in long-term treatment.
l DIRECTIONS FOR ADMINISTRATION
▶ With intravenous use For intravenous injection, give over at
least 1 minute (followed by 50 mL sodium chloride
intravenous infusion). For intravenous infusion (Imuran ®),
give intermittently in Glucose 5% or Sodium Chloride
0.9%. Reconstitute 50 mg with 5–15 mL Water for
Injections; dilute requisite dose to a volume of 20–200 mL
with infusion fluid. Intravenous injection is alkaline and
very irritant, intravenous route should therefore be used
only if oral route not feasible.
Bone marrow suppression Patients and their carers should be
warned to report immediately any signs or symptoms of
bone marrow suppression e.g. inexplicable bruising or
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug. Forms available
from special-order manufacturers include: capsule, oral
CAUTIONARY AND ADVISORY LABELS 21
▶ Azathioprine (Non-proprietary)
▶ Azapress (Ennogen Pharma Ltd)
Azathioprine 50 mg Azapress 50mg tablets | 56 tablet P £2.83
▶ Imuran (Aspen Pharma Trading Ltd)
Azathioprine 25 mg Imuran 25mg tablets | 100 tablet P £10.99
Azathioprine 50 mg Imuran 50mg tablets | 100 tablet P £7.99
BNF 78 Immune system disorders and transplantation 837
Immune system and malignant disease
Powder for solution for injection
▶ Imuran (Aspen Pharma Trading Ltd)
Azathioprine 50 mg Imuran 50mg powder for solution for injection
IMMUNOSUPPRESSANTS › CALCINEURIN
l DRUG ACTION Ciclosporin inhibits production and release
of lymphokines, thereby suppressing cell-mediated
Severe acute ulcerative colitis refractory to corticosteroid
▶ BY CONTINUOUS INTRAVENOUS INFUSION
▶ Adult: 2 mg/kg, to be given over 24 hours, dose
adjusted according to blood-ciclosporin concentration
Severe active rheumatoid arthritis (administered on
▶ Adult: Initially 1.5 mg/kg twice daily, increased if
necessary up to 2.5 mg/kg twice daily after 6 weeks,
dose increases should be made gradually, for
maintenance treatment, titrate dose individually to the
lowest effective dose according to tolerability,
treatment may be required for up to 12 weeks
Severe active rheumatoid arthritis [in combination with
low-dose methotrexate, when methotrexate
monotherapy has been ineffective] (administered on
▶ Adult: Initially 1.25 mg/kg twice daily, increased if
necessary up to 2.5 mg/kg twice daily after 6 weeks,
dose increases should be made gradually, for
maintenance treatment, titrate dose individually to the
lowest effective dose according to tolerability,
treatment may be required for up to 12 weeks
Short-term treatment of severe atopic dermatitis where
conventional therapy ineffective or inappropriate
(administered on expert advice)
▶ Adult: Initially 1.25 mg/kg twice daily (max. per dose
2.5 mg/kg twice daily) usual maximum duration of
8 weeks but may be used for longer under specialist
supervision, if good initial response not achieved
within 2 weeks, increase dose rapidly up to maximum
Short-term treatment of very severe atopic dermatitis
where conventional therapy ineffective or inappropriate
(administered on expert advice)
▶ Adult: 2.5 mg/kg twice daily usual maximum duration
of 8 weeks but may be used for longer under specialist
Severe psoriasis where conventional therapy ineffective
or inappropriate (administered on expert advice)
▶ Adult: Initially 1.25 mg/kg twice daily (max. per dose
2.5 mg/kg twice daily), increased gradually to
maximum if no improvement within 1 month, initial
dose of 2.5 mg/kg twice daily justified if condition
requires rapid improvement; discontinue if inadequate
response after 3 months at the optimum dose; max.
duration of treatment usually 1 year unless other
Organ transplantation (used alone)
▶ Adult: 10–15 mg/kg, to be administered 4–12 hours
before transplantation, followed by 10–15 mg/kg daily
for 1–2 weeks postoperatively, then maintenance
2–6 mg/kg daily, reduce dose gradually to
maintenance. Dose should be adjusted according to
blood-ciclosporin concentration and renal function;
dose is lower if given concomitantly with other
immunosuppressant therapy (e.g. corticosteroids); if
necessary one-third corresponding oral dose can be
given by intravenous infusion over 2–6 hours
Bone-marrow transplantation | Prevention and treatment
▶ INITIALLY BY INTRAVENOUS INFUSION
▶ Adult: 3–5 mg/kg daily, to be administered over
2–6 hours from day before transplantation to 2 weeks
postoperatively, alternatively (by mouth) initially
12.5–15 mg/kg daily, then (by mouth) 12.5 mg/kg daily
for 3-6 months and then tailed off (may take up to a
▶ Adult: 5 mg/kg daily in 2 divided doses, for
maintenance reduce to lowest effective dose according
to proteinuria and serum creatinine measurements;
discontinue after 3 months if no improvement in
glomerulonephritis or glomerulosclerosis (after
6 months in membranous glomerulonephritis)
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ With oral use Manufacturer advises increase dose by 50%
or switch to intravenous administration with concurrent
l UNLICENSED USE Not licensed for use in severe acute
ulcerative colitis refractory to corticosteroid treatment.
MHRA/CHM ADVICE: CICLOSPORIN MUST BE PRESCRIBED AND
DISPENSED BY BRAND NAME (DECEMBER 2009)
Patients should be stabilised on a particular brand of oral
ciclosporin because switching between formulations
without close monitoring may lead to clinically
important changes in blood-ciclosporin concentration.
l CONTRA-INDICATIONS Abnormal baseline renal function
non-transplant indications). uncontrolled infections (in
l CAUTIONS Elderly—monitor renal function . hyperuricaemia . in atopic dermatitis, active herpes
simplex infections—allow infection to clear before starting
(if they occur during treatment withdraw if severe). in
atopic dermatitis, Staphylococcus aureus skin infections—
not absolute contra-indication providing controlled (but
avoid erythromycin unless no other alternative). in
psoriasis treat, patients with malignant or pre-malignant
conditions of skin only after appropriate treatment (and if
no other option). in uveitis, Behcet’s syndrome (monitor
neurological status). lymphoproliferative disorders
(discontinue treatment). malignancy
▶ Malignancy In psoriasis, exclude malignancies (including
those of skin and cervix) before starting (biopsy any
lesions not typical of psoriasis) and treat patients with
malignant or pre-malignant conditions of skin only after
appropriate treatment (and if no other option);
discontinue if lymphoproliferative disorder develops.
l INTERACTIONS → Appendix 1: ciclosporin
838 Immune system disorders and transplantation BNF 78
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