Portada Simposios - Supplements - Haematologica

136 Haematologica (ed. esp.), volumen 85, supl. 2, octubre 2000
VIRAL INFECTIONS
IN ALLOGENEIC STEM CELL
TRANSPLANT RECIPIENTS
P. LJUNGMAN, MD, PH.D.
Dept. of Hematology. Huddinge University Hospital.
Karolinska Institutet. S-14186 Stockholm, Sweden.
Viral infections are important as causes of morbidity
and mortality after allogeneic bone marrow
transplantation. The main explanation for this tendency
is that T-cell mediated immune responses is
the main factor for controlling viruses in the immune
competent state and these responses are severely
depressed in allogeneic bone marrow transplant recipients.
Specific antibodies are important for preventing
infections with exogenous viruses. Thus,
also the gradual loss of specific antibodies occurring
in many allogeneic bone marrow transplant
patients will also increase the risk for reinfections
with viruses previously encountered in life. This review
will cover some recent aspects of infections
with CMV, Human herpesvirus 6, respiratory viruses,
and adenovirus in allogeneic stem cell transplant
recipients.
Cytomegalovirus (CMV)
CMV has been one of the most feared infectious
complications to allogeneic bone marrow transplantation.
Patients who are CMV seronegative before
transplantation should if possible be transplanted
from a CMV negative donor 1 . This is often not possible
since only a limited number of donors are available
and time to find a donor is frequently critical,
but in for example patients who are to undergo an
unrelated transplantation for CML, it should be
considered to use CMV serostatus as a donor selection
criterion.
Since the prognosis of therapy of established CMV
disease is still poor, preventive measures against disease
is very important. These can be divided into
either prevention of reactivation (prophylaxis) or
prevention of development of disease after CMV reactivation
(preemptive therapy). The first preventive
measure that was studied was the use of iv immune
globulin. Several randomized trials have been performed
giving diverging results. Bass et al summarized
these trials in a meta-analysis showing a slight but
significant reduction in CMV disease and pneumonia
2 . However, due to the high cost of high dose iv
Ig and the modest effect, it has been replaced in
most transplant centers by prophylactic strategies
through antiviral agents. Two large studies of aciclovir
prophylaxis have been performed and both
show a reduction of CMV infection and an improvement
in survival 3,4 . The survival benefit of these studies
is probably not only mediated through a reduction
in CMV disease, however, and breakthroughs of
CMV disease are not infrequent. Today also valaciclovir
could be considered since it has shown efficacy
against CMV in renal transplant patients 5 . If
these agents are to be used as CMV prophylaxis they
must be combined with a strategy of preemptive therapy.
Ganciclovir have been tested in two randomized
trials both showing a strong reduction in CMV
disease but no effect on survival 6,7 . There are two
possible reasons for the lack of survival benefit. First
these studies were performed before the widespread
use of growth factors such as G-CSF and ganciclovir
induced neutropenia was a problem in both studies.
An alternative possibility to give prophylaxis to all
patients with varying risks for CMV disease is the
use of early or preemptive therapy based on early detection
of CMV. Einsele et al showed recently in a
randomized trial that the use of a PCR-based diagnostic
technique reduced the incidence of CMV disease
and CMV associated mortality compared to rapid
isolation 8 . Ljungman et al showed that PCR based
preemptive therapy was an independent factor
for reduction of CMV disease, CMV associated mortality,
and overall transplant related mortality 9 . Boeckh
et al showed in a randomized study that antigenemia
based preemptive therapy could be used
with similar efficacy in preventing CMV disease as
ganciclovir prophylaxis 10 . Ganciclovir prophylaxis
was more effective in preventing CMV disease during
the time it was given (the first 100 days after bone
marrow transplantation) while the risk for late CMV
disease was higher in the ganciclovir prophylaxis
group equalizing the risk for CMV disease and survival
at 180 days after transplantation.
Either ganciclovir or foscarnet can be used for preemptive
therapy. Ganciclovir has been used in most
published studies. In one small study, there was no
difference between foscarnet and ganciclovir 11 . A larger
randomized trial by the European Group for
Blood and Marrow Transplantation (EBMT) recently
presented in abstract form found no difference in efficacy
while there was less neutropenia in the foscarnet
arm but no difference in renal toxicity 12 . Cidofovir
(HPMPC) is a new compound that has advantages
since it is highly effective against CMV and only
needs to be given once weekly. However, it is associated
with significant renal toxicity. It has been used
in some patients and preliminary experience have
been presented at meetings showing a good effectiveness
but a risk for renal toxicity of approximately
20 % (Ljungman et al; ASH 1999). Further studies are
needed to define the role for cidofovir in allogeneic
stem cell transplant patients. Several new antiviral
compounds are in early clinical development.
Despite that major advances have been reached
in CMV management several problems still exist including
the increased incidence of CMV disease with
delayed onset. Lack of specific immunity to CMV
both regarding cytotoxic T-cell (CTL) responses and
helper T-cell responses to CMV has been associated
with a high risk for CMV disease. A series of studies