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

Table 1. Meta-analysis of 23 randomized trials of allogeneic
HSCT analysed on a donor no donor analysis. Adapted
from Koreth et al. JAMA 2009, 301, 2349–61; with permission.
One problem in assessing the role of transplantation
in AML, particularly when donor/no donor analyses are
used, is the increasing use of unrelated donors in the no
donor group and the impact of delayed transplant in
CR2 for the donor group. An alternative statistical
method is to use the Mantel-Byar approach. This allows
for time to transplantation by switching patients at time
of allograft in CR1 to the transplantation curve. To illustrate
the use of this method, in the MRC AML12 trial,
when a Mantel-Byar analysis was used to assess the
impact of allogeneic HSCT, transplantation was found
to improve RFS and OS significantly in poor risk
patients, whereas no benefit was seen in this risk group
using a donor/no donor analysis. 6 This was due primarily
due to non-compliance with allograft in the donor
group in CR1 and the impact of unrelated donor HSCT
in CR1 in the no donor group.
Favorable and intermediate risk acute myeloid leukemia
Despite the value of these meta-analyses in guiding
practice, the role of HSCT needs to be reassessed in relation
to the new information that has accrued concerning
the genetic basis of AML and the impact that these have
on prognosis. For example, with cytogenetically normal
AML (CN-AML), prognostic significance has been
shown for mutations in the NPM1, CEBPA, and FLT3
genes alone or in combination in younger adult
patients. 7-11 CN-AML patients harboring internal tandem
duplication (ITD) of the FLT3 gene have an inferior outcome
compared with cases without FLT3-ITD, although
there is evidence that outcome may be more related to
the level of the mutated allele. 7,8,11 In several studies, the
presence of NPM1 mutation in CN-AML has been associated
with higher CR rates and better event-free survival
(EFS). 9,10 CN-AML with biallelic mutations in
CEBPA is another subset that has been associated with
a favorable prognosis. 11,12 These findings have led the
European LeukemiaNet (ELN) to propose a new classification
of AML risk groups, which incorporates this new
prognostic information 13 (Table 2). Clearly the value of
allogeneic HSCT now needs to be reassessed based on
this new classification of AML-related genetic changes.
In this context, a study by the German-Austrian AML
Group (AMLSG) provided evidence that those AML
patients whose molecular genetic profile predicts a
favorable prognosis, such as CN-AML with mutated
NPM1 without FLT3-ITD, may not benefit from allogeneic
HSCT. 14 The adoption of the ELN classification in
future studies will be important in aiding the interpreta-
London, United Kingdom, June 9-12, 2011
Table 2. Standardized reporting for correlation of cytogenetic
and molecular genetic data in AML with clinical data
from ELN AML guidelines. 13
Genetic group Subsets
Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD (normal karyotype)
Mutated CEBPA (normal karyotype)
Intermediate-I Mutated NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 without FLT3-ITD (normal karyotype)
Intermediate-II t(9;11)(p22;q23); MLLT3-MLL
Cytogenetic abnormalities not classified as favorable or adverse
Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); MLL rearranged
-5/ del(5q); -7; abn(17p); complex karyotype
tion of trial results, as previously this has been frequently
confounded by variation in risk group classifications
used by different clinical trial groups.
The role of allogeneic HSCT in the treatment of
FLT3/ITD positive patients is currently an area of some
controversy. These patients were originally included in
the meta-analyses of donor versus no donor trials 4,5 discussed
above, which showed a superior outcome for
allogeneic HSCT in intermediate and poor risk AML.
Three groups have recently reported on outcome after
allogeneic HSCT in FLT3/ITD-positive AML 14-16 and
while all three studies showed a strong reduction of
relapse with hazard ratios of approximately 50%, only
the German study by Schlenk et al. 14 showed significantly
improved survival by donor availability. In summary,
although definitive evidence from prospective trials is
not available, allogeneic HSCT should be considered in
patients who are FLT3-ITD positive, particularly for
those patients not involved in clinical trials of FLT3 inhibition.
Further refinement of the assessment of prognosis in
AML may be possible in the future by minimal residual
disease measurement; for example, by flow cytometry
at the end of consolidation chemotherapy. In a recent
study of patients with good and intermediate risk cytogenetics,
who had evidence of residual disease after
consolidation, predicted a significantly higher relapse
rate (77% vs. 22%) and reduced OS at 4 years compared
with patients with no detectable abnormal cells. 17
Furthermore, patients who had evidence of minimal
residual disease and went on to receive an HSCT had a
reduced risk of relapse and a superior outcome if they
received an allogeneic transplant but this benefit was
not observed in patients who had an autograft. 17 The use
of minimal residual disease detection and its integration
into risk scores, therefore, may inform decision-making
concerning transplantation in patients with good/intermediate
risk disease in the future.
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 43 |