H e m a t o lo g y E d u c a t io n - European Hematology Association

16 th Congress of the European Hematology Association
who underwent either RIC or SMC HSCT, showed no
adverse effect of age on outcomes but at multi-variate
analysis, both use of RIC and advanced disease stage
(defined as >5% bone marrow blasts) at HSCT resulted
in significantly increased relapse rates. Advanced disease
stage at transplantation and use of an unrelated
donor were significantly associated with increased
NRM; most importantly, advanced disease stage at
transplantation alone was the major independent variable
associated with an inferior OS at 4 years. Other
groups have previously demonstrated the adverse outcome
associated with HSCT in the RIC setting, where
patients are not in CR at transplantation. 13,40,41
There are no prospective randomized controlled trials
to determine the potential benefit of treatment with
intensive induction chemotherapy prior to HSCT and
data are derived mainly from small, single institution
studies. Existing data are usually retrospective and gathered
mainly from the setting of SMC HSCT and from
small, single institution studies. Scott et al. found no
benefit with respect to outcomes post SMC HSCT for
patients with advanced MDS who did receive induction
chemotherapy (IC) versus those who did not. 42 In their
analysis, 18 of 33 patients who received IC pre-HSCT
achieved complete remission and of these, 5 patients
relapsed prior to transplantation. Ninety-two patients
who did not undergo IC showed a relapse-free survival
(RFS) of 26% at 3 years (13% for those who did undergo
induction chemotherapy) and the difference was not
significant, possibly due to the small sample size.
Oran et al. reported on 30 high-risk MDS patients, of
whom 23 patients received IC followed by RIC HSCT,
along with 82 AML patients. 43 In this small retrospective
study, more than 50% of MDS patients had chemorefractory
disease. OS estimates at 2 years were 66% for
patients in CR at HSCT, 40% in the presence of active
disease but no circulating blasts, and 23% in patients
with blasts detectable in the peripheral blood at the
time of HSCT; 2 year cumulative rates of relapse in the
same groups were 15%, 20%, and 46%, although follow-up
was short (median 29.4 months). A high NRM
was seen in those with active disease: 25–30% at 100
days and 35–65% at 2 years. At uni-variate analysis, the
presence of circulating blasts was the sole factor significantly
associated with disease progression – HR was 3.7
compared with those in CR (95% CI 1.4-9.8, p=0.01).
The lack of randomization between pre-HSCT IC
treatment or no therapy renders such retrospective
analyses difficult to interpret and biases are likely to
operate. Certain patients will have been selected to
undergo IC for particular reasons (for example, the perception
of more aggressive disease) and as such, those
patients who have chemo-sensitive disease may be
“selected out” preferentially prior to HSCT. The
response to IC needs to be sufficiently durable to persist
until HSCT: such patients with advanced MDS are at
high risk of relapse during the intervening period
between remission induction and HSCT. Additionally,
conventional IC carries the risk of death during treatment
or causing toxicity, which may then prohibit the
HSCT procedure.
For this reason, newer agents shown to be effective in
treating MDS have been employed to de-bulk disease
prior to HSCT without causing significant toxicity. 5-
Azacytidine is one such agent used in this manner. A
retrospective study of 54 patients with intermediatehigh
risk MDS or CMML who underwent sibling or
unrelated donor HSCT included 30 patients who had
received a median of 4 courses of 5-Azacytidine pre-
HSCT and 24 who received no chemotherapy or induction
chemotherapy. CR was only achieved in 4 of 30
patients who received 5-Azacytidine with PR in 10; 6 of
these 30 patients progressed to AML and of these, 4
patients received standard induction therapy. At 2-years
post transplant, the cumulative incidence of relapse was
31% in those who received 5-Azacytidine and 36% in
those who did not. Thus, treatment with 5-Azacytidine
was not demonstrated in this study to significantly
affect remission rates, relapse rates or OS but has not as
yet been evaluated prospectively. Decitabine has also
shown feasibility as a pre-HSCT induction therapy but
in a small study, with no clear evidence of improvement
in outcomes following HSCT. 44 Many unanswered
questions remain. For example, for those patients who
do respond to hypomethylating agents prior to HSCT,
when is the optimal timing for HSCT – at the time of
best response or when no longer responding/disease
progresses? Data from prospective trials is required.
Management of relapse
Despite the feasibility of HSCT even in older patients
with MDS, the principal concern for transplant physicians
and patients alike is the persistent potential for
relapse. There is very little reported data to enable evidence-based
decision-making regarding treatment of
relapsed MDS post HSCT. Many of the larger retrospective
multi-centre studies will report DFS and RFS but the
details of therapy given to relapsing patients may be
lacking. The two key issues of management of mixed
chimerism and hematological relapse are discussed here.
Mixed donor/recipient chimerism
Donor and recipient chimerism may be closely followed
to enable early identification of falling donor T
cell chimerism and to guide withdrawal of immunosuppression
along with the timing of administration of
donor leucocyte infusion (DLI), although there is a
paucity of data published in this area. Delayed attainment
of donor chimerism is a recognized feature particularly
of T-cell-depleted RIC transplants 45-47 and DLI can
be given to improve low donor chimerism. We have
previously reported, in a prospective study from our
institution, on 10 patients (out of 75, all of whom underwent
RIC HSCT for MDS, with a uniform fludarabine,
busulphan, and alemtuzumab (FBC) containing regimen)
and were treated with escalating doses of DLI for
mixed chimerism after day 100. In 9 of 10 patients, full
donor chimerism (FDC) was achieved. 46 This data was
subsequently updated and identified 28 of 110 patients
who had undergone FBC conditioned RIC HSCT for
MDS and demonstrated falling donor chimerism. These
patients received a median of two doses of DLI (5x10 5
CD3/kg and 1x10 6 CD3/kg) and 17 of 28 subsequently
attained FDC. Ten of 28 patients developed graft-versus-host
disease (GvHD); 2 of those 10 patients succumbed
to GvHD and 1 to relapsed disease despite
| 240 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)