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

acid. 62 The second was a large multicenter US study
comparing a 10-day schedule of 5-azacitidine with the
carbamate HDAC inhibitor MS-275 (entinostat). In the
preliminary data presented at ASH in 2009 and 2010,
respectively, none of these studies was able to report
superiority with the combination arm. Other studies
with more potent HDAC inhibitors are ongoing.
Another alternative being explored by the MDACC
group is that of intercalating azanucleoside with noncross
reactive agents, such as clofarabine. Clofarabine is
a nucleoside analogue with clinical activity in MDS. 63
Does lenalidomide have a role outside anemia in lower
risk disease?
At the present time, the best results of lenalidomide
are in patients early in the course of the disease with
anemia, a chromosome 5 alteration, minimal transfusion
requirements, and minimal other cytopenias. 7 In these
settings, results with this agent are exceptional, resulting
in transfusion independency in over 60% of patients.
Results of a randomized study comparing lenalidomide
with standard of care were presented at ASH 2009. 64 The
question is whether lenalidomide could have a role in
other settings in MDS. First, the drug has been used in
patients with lower risk disease without alteration of
chromosome 5. On the initial study reported by Raza et
al., transfusion independency was achieved in 26% of
patients. 65 Response duration was 41 weeks. Although
not insignificant, it is not clear whether these results are
better than what could be expected from the use of
growth factor support. To test this concept, a randomized
clinical trial comparing lenalidomide with standard
of care is now ongoing worldwide.
Recently, several studies have evaluated the role of
lenalidomide in higher risk disease. 66 The French group
reported on 47 patients with higher risk disease treated
with standard dose lenalidomide. Seven patients
achieved complete remission. Responses were associated
with presence of isolated chromosome 5 alteration
and platelets over 100x 10 3 Ku/ml. 66 At MDACC, results
have not been of this magnitude (Borthakur et al., in
preparation). Perhaps the activity of lenalidomide could
be improved in higher risk MDS by using higher doses.
The group at Washington University reported on the
safety and activity of lenalidomide at a dose of 50 mg
daily in patients with AML. 67 The conclusion of this
study was that these doses could be tolerated in older
patients with AML and were associated with response
rates of 30%. Finally, the other approach is combinations.
One such combination is to use lenalidomide
with 5-azacitidine. Sekeres et al. initially reported on a
trial of 5-azacitidine and lenalidomide. 68 This study
demonstrated that the combination, using standard
doses of 5-azacitidine and lenalidomide, was safe and
associated with an ORR of 67%. At MDACC, a clinical
trial is evaluating doses of lenalidomide of 50 mg daily
x 10 days after 5 days of standard dose 5-azacitidine.
Preliminary results indicate that this type of schedule is
safe and active in higher risk MDS and AML.
What are the options for patients that do not benefit
or stop benefiting from azanucleosides?
Because the use of azanucleoside is now generalized
in community practice, one problem we are facing is
London, United Kingdom, June 9-12, 2011
that of patients that lose response to either 5-azacitidine
or decitabine. This is a major problem as survival has
been documented to be very poor. 69 In the analysis of
Jabbour et al. of 87 patients that had received decitabine,
median survival was 4.3 months. Most of these patients
were refractory to standard ara-C based therapies. The
mechanisms of resistance to decitabine is not understood
but could be pharmacological. 70 Why patients
acquired secondary resistance is not understood either.
In my opinion, there are ready available interventions
for these patients and therefore, all patients should be
considered for clinical trial. Studies with agents, such as
clofarabine 71 and sapacitabine 72 are ongoing. A phase III
study is evaluating the role of compound ON1910 in
this context.
What is the role of allogeneic stem cell transplantation
in MDS?
Until recently, alloSCT and non-alloSCT therapies
(described above) have been viewed as two different
and almost exclusive interventions. In the analysis of
Cutler et al., 73 it was proposed that patients with lower
risk disease do not benefit in general from early transplantation.
In contrast, patients with higher risk disease
did derive a survival benefit if transplanted early. These
results were obtained in a cohort of patients before
access to other therapies, such as azanucleosides, was
widely available. This data has generated multiple questions:
1) Is there a subset of patients with lower risk disease
that could benefit from early transplantation? 2)
What is the optimal therapy prior to alloSCT? 3) Do we
have to consider the use of maintenance approaches
post alloSCT? 4) Is there a subset of patients that may
not benefit at all from alloSCT?
First, is the realization that only a small fraction of
patients will eventually receive alloSCT. This is due
partly due to the median age of patients, presence of
other comorbidities, and economical and societal issues
that limit access to alloSCT for MDS patients. For
instance, US Medicare (that medically covers patients
over 65 years of age) does not support the use alloSCT
outside the setting a clinical trial. It is possible that in the
near future, the use of true mini-transplant approaches,
cord blood, and even haploidentical approaches could
increase the number of potential candidates with MDS
for alloSCT. In my opinion, this will have to be studied
in MDS specific clinical trials.
Can we identify a subset of patients with lower risk
disease that could benefit from early alloSCT? The
question could be answered by identifying patients
with lower risk and poor survival. The MDACC lower
risk model indeed allows identification of such a subset
of patients. 6 The main reason why alloSCT was not
shown to improve survival in the analysis of Cutler et al.
was that the inherent early mortality associated with
alloSCT. Therefore, identifying a subset of patients with
estimated poor survival could support the introduction
of “early” transplantation in lower risk MDS. If the
MDACC lower risk model was validated, a trial of early
intervention would be an important study to conduct.
What is the optimal therapy prior to alloSCT? Results
of upfront alloSCT in patients with excess blasts are
questionable. Most clinicians would recommend some
form of “debunking” type of therapy prior to alloSCT.
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