Conditioning regimens: basic principles

The combination of drugs and radiotherapy that is administered before stem cell infusion is
termed the conditioning or preparative regimen.
In the setting of allogeneic SCT, the conditioning regimen serves two purposes: host
immunosuppression to prevent graft rejection and myeloablation in order to achieve tumour
eradication.
they are associated with significant toxicity, which precludes their use in patients older than
50–55 years old (45–50 years for recipients of VUD transplants).
The recent demonstration that durable donor engraftment can be reliably achieved using a
non-myeloablative preparative regimen, coupled with increased awareness of the potency of
the GvL reaction, has led to the development of a range of reduced intensity conditioning
(RIC) regimens. These protocols are associated with a markedly reduced TRM than that
which would be observed using a myeloablative regimen. As a result, allogeneic
transplantation can now be safely performed in many patients in whom it would previously
have been contra-indicated on the grounds of age or comorbidity.
In autologous SCT when there is no alloreactive response, myeloablative conditioning
regimens are better tolerated, allowing autografting to be safely performed in patients up to
the age of 70.
Myeloablative conditioning regimens in allogeneic stem cell transplantation
The two commonest myeloablative conditioning regimens used in allogeneic SCT utilize
combinations of cyclophosphamide (Cy) and either TBI or busulphan (Bu).
Cyclophosphamide/total body irradiation (Cy/TBI)
Cyclophosphamide is an alkylating agent which, when administered in the doses routinely
used in myeloablative conditioning regimens, has both immunosuppressive and anti-
leukaemic properties. It is a prodrug that must be metabolized by the P450 system in the
liver to produce metabolically active derivatives, principally phosphoramide mustard, which
exert their cytotoxic activity through the production of interstrand DNA links.
The two major complications of cyclophosphamide at the doses employed in allogeneic
transplantation are haemorrhagic cystitis and cardiac toxicity. The former results from the
toxic effects of a cyclophosphamide metabolite, acrolein, upon the uroepithelium and can be
reduced by the use of the thiol sodium 2-mercaptoethanesulphonate (Mesna); the latter is
very rare at doses of cyclophosphamide below 150 mg/kg.
TBI also has immunosuppressive and anti-leukaemic properties when administered in
myeloablative doses (typically 12–14 Gy). The degree of immunosuppression produced by
TBI-containing regimens is related to the total dose of irradiation delivered. The use of
higher TBI doses is therefore an effective method of optimizing engraftment in settings such
as TCD or unrelated donor transplantation when the risk of graft failure might otherwise be
increased.

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Haematological malignancies are highly radiosensitive and the risk of disease relapse can be
reduced if a higher dose of TBI is used.
Early complications associated with the use of TBI include nausea, vomiting, diarrhea and
parotitis, which can usually be managed symptomatically. More seriously, TBI increases the
risk of both pneumonitis and venoocclusive disease (VOD) of the liver.
Long-term complications include cataract formation, hypothyroidism, infertility and, in
children, growth retardation. Radiobiological principles predict that the toxicity of TBI can
be reduced by either decreasing the overall dose of radiation administered or, as is now
common, by giving it in a fractionated form over a number of days.
Busulphan/cyclophosphamide (Bu/Cy)
Bu/Cy is a myeloablative preparative regimen which has the advantage of not requiring the
presence of irradiation facilities on site. Busulphan is an oral alkylating agent with potent
activity against leukaemic progenitors and is widely used in both allogeneic and autologous
transplantation.
Major complications associated with the use of high-dose busulphan are VOD, infertility and
pulmonary and CNS toxicity. Seizures, a complication associated with the administration of
high dose of busulphan, can be prevented by the use of prophylactic phenytoin or
diazepamIn
In non-malignant disorders such as aplastic anaemia, cyclophosphamide alone can be used as
a conditioning regimen and is sufficiently immunosuppressive to permit engraftment of
allogeneic stem cells, provided that an adequate stem cell inoculums is transplanted.
Strategies for graft-versus-host disease prophylaxis
The commonest method of GvHD prophylaxis utilizes post-transplant immunosuppression in
the form of intravenous cyclosporin and methotrexate. Cyclosporin decrease T-cell
activation by inhibiting the calcineurin-dependent secretion of IL-2. Increasing the intensity
of immunosuppression reduces the risk of GvHD but is also associated with a higher rate of
disease relapse consequent upon a decreased GvL effect.
Depletion of T cells from the donor stem cell inoculums is also an effective form of GvHD
prophylaxis. TCD can be achieved ex vivo by manipulating the stem cell inoculum or in vivo
by administration of T cell-depleting antibodies such as anti-thymocyte globulin (ATG).
Although a highly effective method of GvHD prophylaxis, TCD is associated with an
increased risk of relapse and graft failure, and delays immune reconstitution increasing the
risk of post-transplant infections such as CMV. It is therefore difficult to show any overall
benefit of TCD on patient survival.
Alternative approaches that allow the selective depletion of T cell subsets (CD4+ or CD8+)
are being explored and are of interest in terms of defining approaches that may permit
dissociation of GvHD and GvL.
Clearly, the form of GvHD prophylaxis used for any particular patient should be selected
with their individual risk of both GvHD and relapse in mind. Thus, it may be desirable to
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avoid the use of TCD in patients with advanced leukaemia in whom the risk of relapse is
high. In contrast, patients with a low risk of disease recurrence may benefit from more
intensive GvHD prophylaxis.
It should also be remembered that patients receiving a TCD graft require a more intensely
immunosuppressive conditioning regimen in order to overcome the increased risk of graft
rejection.
Conditioning regimens in autologous stem cell transplantation
Conditioning regimens in autologous SCT are designed with dose intensification in mind,
and are limited mainly by considerations of extramedullary toxicity. High-dose melphalan is
the standard conditioning regimen in myeloma autografts.
BEAM (BCNU , etoposide , cytosine arabinoside and melphalan is widely used in patients
with lymphoma.
Both Bu/Cy and Cy/TBI are effective preparative regimens for patients with acute
leukaemia.
A number of other drug combinations incorporating melphalan, busulphan and thiotepa are
used in solid tumours.
The major extramedullary toxicities of these regimens are mucositis and gastrointestinal
toxicity.