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REVIEW
URRENT
C
OPINION
Treatment for relapsed acute myeloid leukemia:
what is new?
Yishai Ofran a,b and Jacob M. Rowe a,b
Purpose of review
Despite enormous progress in the understanding of leukemia pathophysiology and novel transplantation
protocols, the prognosis following acute myeloid leukemia (AML) relapse is still uniformly poor. In the
current review, advances in risk stratification, protocols involving novel agents and allogeneic stem cell
transplantation (ASCT) will be discussed in light of the vision of personalized therapy.
Recent findings
The role of ASCT in relapsed/refractory AML is well established and has been recently confirmed as
mandatory for cure. Retrospective observations of different large cohorts categorized patients with early
relapse, poor cytogenetics or fms-like tyrosine kinase receptor-3 internal tandem duplication mutation as the
most challenging population. Multiple novel agents have been studied with various promising results;
however, these agents can only serve as a bridge to transplantation. If ASCT is not an option, therapy
should focus on prolongation of patient’s life at its best possible quality. Accumulated molecular data open
new horizons for personalizing therapy and assigning each patient to the drug or protocol from which the
patient will benefit most.
Summary
Relapsed/refractory AML is a heterogeneous disease and no uniform protocol will provide cure to all
patients. Molecular tests may contribute to future personalizing therapy resulting in improved outcome.
Meanwhile, novel and more effective induction and postremission protocols are warranted to lower the
relapse rate.
Keywords
allogeneic transplantation, complete remission 2, intensive chemotherapy, minimal residual disease,
relapsed/refractory acute myeloid leukemia
INTRODUCTION
For acute myeloid leukemia (AML) patients who
enter complete remission, maintaining remission
is an imperative. The probability of relapse depends
on the leukemia’s molecular profile, patient’s age
and the type of postremission therapy administered.
Moreover, with current intensive protocols, up to
20–30% of young and 40–50% of older AML
patients will experience primary induction failure.
Despite enormous progress in the understanding of
leukemia pathophysiology, the prognosis following
relapse is still uniformly poor and novel approaches
are desired for the treatment of relapse.
Molecular and genetic methods enable the
detection of scant leukemic cells reappearing in a
morphologically normal bone marrow. The current
review will discuss up-to-date therapies and how
to interpret results of molecular tests in relapsed/
refractory AML.
GOALS OF THERAPY AND PROGNOSTIC
FACTORS IN RELAPSING ACUTE MYELOID
LEUKEMIA
Only about 10% of patients survive after a relapse in
AML [1,2]. For those select patients who have
survived the relapse and responded to intensive
reinduction therapy, AML may be curable by
allogeneic stem cell transplantation (ASCT). However, physicians are often reluctant to administer
a
Department of Hematology and Bone Marrow Transplantation, Rambam
Healthcare Campus and bBruce Rappaport Faculty of Medicine,
Technion-Israel Institute of Technology, Haifa, Israel
Correspondence to Yishai Ofran, MD, Department of Hematology and
Bone Marrow Transplantation, Rambam Medical Center, Haifa 31096,
Israel. Tel: +972 4 8542541; fax: +972 4 8542343; e-mail: y_ofran@
rambam.health.gov.il
Curr Opin Hematol 2012, 19:89–94
DOI:10.1097/MOH.0b013e32834ff4e1
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Myeloid disease
KEY POINTS
Allogeneic stem cell transplantation (ASCT) is essential
for achievement of long-term survival in relapsed or
refractory acute myeloid leukemia (AML).
HLA-matched related or unrelated donors are
preferable, although haploidentical donors or umbilical
cords may also serve as sources for an
allogeneic transplant.
Early relapse, unfavorable cytogenetics, fms-like
tyrosine kinase receptor-3 internal tandem duplication
mutation, but not old age, predict poor outcome.
When ASCT is not an option, controlling the disease
and prolonging a reasonable quality of life should be
the goal of therapy.
Personalizing therapy in AML is about to change
fundamental perspectives. No longer will the ‘best
protocol in relapse’ be searched. Instead, protocols
should match a patient’s specific condition and include
drugs targeting specific biological and genetic factors.
Providing data such that the tailored protocol is really
the best for a patient will be a challenge.
60 years of age did as well with intensive chemotherapy. This must be very carefully considered, as
the more common practice of many clinicians is to
be aggressive with intensive chemotherapy for
patients in their 50s, while hesitating in administering the same protocols to patients 10–15 years older.
As in newly diagnosed AML [7,8], the data for
relapsed AML suggest that although outcome of
elderly patients is generally worse, some do benefit
from intensive chemotherapy.
Chevallier et al. [5 ] went a step further and
created a prognostic score and validated it in a
different group of 111 patients. The score that contains only three adverse factors (early relapse, FLT3
mutation and poor cytogenetics) discriminates well
between patients with 0–1 and those with 2–3
adverse factors. The 2-year overall survival (OS)
following intensive chemotherapy was in the range
of 23–58% for low-score and 0–12% for high-score
patients. This scoring scale encourages prescribing
intensive chemotherapy for patients with low scores
but should be carefully interpreted when treating
relapsing patients with high scores. In the abovementioned Japanese study [4 ], achievement of
second remission and salvage ASCT emerged as
the most important factors predicting longer
OS. In the validation French cohort, patients with
high-score relapse had a grave prognosis following
intensive chemotherapy. However, the portion of
patients who achieved second remission and proceeded for ASCT was not reported and might
be low, as the validation cohort came from the
LAM (lamivudine)-2001 trial [5 ], which included
patients with no matched siblings.
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aggressive therapy due to the unavoidable therapyassociated neutropenia and thrombocytopenia,
especially in older patients. Nevertheless, susceptibility to infection and bleeding is often related to
the nature of the disease per se. Of note is the fact
that intensive chemotherapy goes together with
and does not contraindicate palliative therapy [3];
alleviating suffering and symptoms is fundamental
in any protocol, regardless of its curative intentions.
Prognostic factors predicting outcome following
intensive chemotherapy for relapsed AML have
been recently reported by two large retrospective
studies of 1015 Japanese patients [4 ] and 138
patients from France and Israel [5 ]. An equivalent
overall survival rate of 30% at 3 years and 36% at
2 years was reported. Patients were treated with
cytarabine and anthracycline combinations and
with addition of gemtuzumab ozogamicin in
the French study. Early relapse (<1 year after complete remission 1) and unfavorable cytogenetics
were poor prognostic markers in both series. The
presence of fms-like tyrosine kinase receptor-3
(FLT3) mutation was evaluated only in the French
study and was found to independently predict for a
poor prognosis. Importantly, contrary to previous
works [1,6], age was not a significant prognostic
marker in both series. Those previous publications
included patients younger than 60 years of age and
within this group, younger patients did better.
Recent works enrolled patients of all ages and
demonstrated that patients younger or older than
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THE ROLE OF SECOND REMISSION
Complete remission is fundamental for cure in
first-line therapy of AML [9 ]. Failure to achieve
a second remission in relapsed AML was recently
demonstrated to be associated with reduced OS
(hazard ratio of 3.23) in a large retrospective study
[4 ]. Most clinicians agree that intensive chemotherapy aiming at second remission is appropriate
in patients with good performance status, late
relapse, no adverse cytogenetic or genetic markers
and significant bone marrow blast counts [10,11].
For patients with early relapse, especially if poor
cytogenetics or FLT3 mutation are present, chances
to enter second remission with intensive chemotherapy are as low as 20% [12 ]. Moreover,
with different reinduction protocols the 30-day
mortality rate is as high as 20% [4 ,13–15]. Therefore, in patients with high-score relapse, intensive
chemotherapy targeting second remission may be
considered futile.
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Treatment for relapsed acute myeloid leukemia Ofran and Rowe
What should be offered to patients in whom an
attempt to reach second remission is not considered? If cure is aspired, ASCT must be considered
mandatory. Otherwise, the goal of therapy may be
prolonging life of the best quality possible.
BONE MARROW TRANSPLANTATION IN
PATIENTS NOT IN COMPLETE REMISSION
Conditioning protocols and donor selection in
relapsed AML have been recently reviewed [16]. We
will herein focus on patient selection for ASCT in the
challenging clinical setting of relapsed AML when
second remission has not been achieved. Scoring
predicting transplantation success was developed
in a retrospective survey of 1673 patients who underwent a myeloablative ASCT for AML in relapse.
Patients with a very low score were demonstrated
to experience a 3-year OS of up to 42% and those with
a very high score had a dismal prognosis with only 6%
alive at 3 years [17 ]. Unfortunately, the high score
refers to the same group of patients in whom attempts
to reinduce second remission are likely to fail.
Patients with a short complete remission 1, poor
cytogenetics, low performance status and/or circulating blasts present a major clinical challenge. These
patients have a low OS rate when proceeding directly
to ASCT, but chances to improve it by inducing
second remission are also scarce and the impact of
significant toxicity associated with induction regimens should not be underestimated. An interesting
strategy of cytoreductive chemotherapy, followed by
reduced-intensity conditioning (RIC) and prophylactic transfusion of donor lymphocytes in refractory
and early relapse patients was created [18]. This
German protocol known as the FLAMSA (fludarabine, Ara-C, amsacrine)-RIC protocol was reported
in a prospective multicenter study involving 103
patients. The study recruited patients with early
relapse and primary induction failure. The median
survival of 16.4 months and the 4-year estimated OS
of 32% are promising. The concept of the FLAMSARIC protocol inspired similar other sequential cytoreduction followed by RIC transplantation protocols
with encouraging results [19–21]. This approach
requires an HLA-matched donor available just when
relapse is diagnosed. Therefore, for AML patients in
complete remission 1 even if allogeneic transplantation is not scheduled, a search for a matched donor
should be initiated to enable sequential transplantation in case of early relapse.
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PATIENTS NOT CANDIDATES FOR
ALLOGENEIC TRANSPLANTATION
If no matched donor is available, cure may be
accomplished by double umbilical cord or
haploidentical ASCT, but with a very low success
rate if transplanted not in remission [22 ], similar to
the data when using matched unrelated donors [23].
Select patients may be cured with intensive chemotherapy followed by an autologous transplant [24].
In chemorefractory relapses when a matched donor
is not available or the patient is unfit for ASCT,
therapy should target prolongation of life instead
of curing the disease. The ultimate objective of
getting patients into remission should, therefore,
be replaced by controlling leukemia and intensive
chemotherapy by continuous chronic therapy with
minimal side effects. For some patients such therapy
will buy time until a suitable donor is available
(bridge to transplantation). In other ‘unfit’ elderly
patients, therapy that will yield significant prolongation of life of an acceptable quality will be
favored.
Hydroxyurea, 6-mercaptopurine and low-dose
Ara-C are old drugs with proven ability to control
leukemia for a limited period of time. Novel agents
and strategies in relapsed AML have been reviewed
by Litzow [25]. Herein we will update those agents
that have been shown to be effective in controlling
leukemia in recent years and discuss benefits and
drawbacks of each agent.
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NOVEL AGENTS AND THEIR ROLE IN
RELAPSED/REFRACTORY ACUTE
MYELOID LEUKEMIA
Clofarabine is a novel purine nucleoside analogue
structurally similar to fludarabine and cladribine,
developed with the aim of avoiding the neurotoxicity that limits the maximal tolerated dose
of old-generation purine analogues. The role of
clofarabine as intensive chemotherapy has been
evaluated in several successful phase I/II studies
[26 ,27]. A phase III study (ECOG-E2906) comparing clofarabine with traditional 7þ3 (daunorubicin and cytarabine) as induction in newly
diagnosed older patients with AML is currently
recruiting. The efficacy of single-agent low-dose
clofarabine or combined with other drugs in controlling relapsed or refractory leukemia has been
evaluated [28], but so far with no significant breakthrough.
Mutation in FLT3 is well known to be a poor
prognostic marker in newly diagnosed and relapsed
AML [5 ]. Specific inhibitors of FLT3 such as sorafenib, lestaurtinib (CEP-701) and quizartinib (AC220)
have been studied in relapsed or refractory AML. The
largest trial was a phase III randomized trial of
salvage chemotherapy with or without lestaurtinib,
which failed to demonstrate a general benefit from
the addition of lestaurtinib [29]. However, the target
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Myeloid disease
inhibition of FLT3 was achieved in only 58% of
patients receiving lestaurtinib, although good inhibition did correlate with longer OS. Sorafenib was
demonstrated to slow down disease progress in
relapse but cannot induce second remission [30].
Quizartinib (AC220) is probably the most effective
FLT3 inhibitor and results of large-scale trials in
relapsed AML are still pending [31]. However,
interim analysis of a phase I/II study has demonstrated that quizartinib provides clinically meaningful reductions in marrow blasts and successfully
bridges to ASCT in a substantial proportion of
patients [31].
Mammalian target of rapamycin (mTOR) was
identified in vitro as an attractive target for therapy.
Furthermore, gene expression analysis pointed to
the AKT/mTOR signaling pathway as involved in
Ara-C responsiveness [32]. Preliminary encouraging
results were reported with deforolimus, sirolimus or
everolimus [33–35], alone or in combination with
other drugs, but confirmation in large-scale studies
is warranted.
Hypomethylating agents are active in high-risk
meylodysplastic syndrome but to a lesser degree in
highly proliferative AML. 5-Azacitidine was shown
in one study to prolong OS in elderly AML patients
with low proliferative disease [36 ], and hence has
drawn attention as an agent that may control low
proliferative relapses. Indeed, a small retrospective
study of 26 patients demonstrated that absence of
peripheral blood blasts is the strongest predictor for
OS in patients relapsing after ASCT. Interestingly,
bone marrow blast counts of more than 20% failed
to predict response in both this and other trials [37].
Responses, however, were observed in the minority
of relapsing patients and were of short duration. If
given with first signs of molecular relapse, azacitidine may delay relapse and allow some patients to
proceed to ASCT [38].
Lenalinomide is an immunomodulatory agent
with known activity in multiple myeloma. Highdose lenalinomide induced second remission in five
of 31 (16%) patients, all of them with low proliferative relapse [39]. Trials combining lenalinomide
with chemotherapy or hypomethylation agents
are ongoing.
X-linked inhibitor of apoptosis protein (XIAP)
inhibits caspases 3 and 9 and is overexpressed and
promotes chemoresistance in AML. AEG-35156 is
an antisense oligonucleotide that targets XIAP.
AEG-35156 at a dose of 350 mg/m2 was well tolerated and effectively knocked down XIAP expression.
Combination of XIAP with chemotherapy yielded
complete remission/CRp in 91% of patients who
had been refractory to a previous induction chemotherapy [40].
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Immune therapy for AML has been reviewed
elsewhere [41]. We will herein discuss recent studies
highlighting the immune therapy potential in
relapsed AML. Vaccination with Wilm’s tumor
(WT)1 antigen-targeted dendritic cells induced complete remission 1 in two chemorefractory patients
who achieved only partial response with induction
protocol [42 ]. Adoptive transfer of T cells directed
against different recipient minor antigens induced
remission in seven AML patients relapsing after
ASCT [43 ]. Most interesting is a study on infusion
of HLA-mismatched stem cells that improves complete remission 1 and OS rates in elderly patients
probably through an immune modulation mechanism [44 ].
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RESPONDING TO MOLECULAR
RELAPSING ACUTE MYELOID LEUKEMIA
With no consolidation therapy, all AML patients
in complete remission 1 eventually relapse [45],
suggesting that at least during the first months of
therapy, undetectable minimal residual disease
(MRD) exists in all patients. Traditional definition
of chemorefractory AML requires the morphologic
presence of 5% blasts in a bone marrow smear
after recovering from conventional induction or
reappearance of blasts in less than a year after
achieving complete remission 1 [46]. New sensitive
molecular techniques allow detection of sparse
malignant cells or DNA, but does detection of
MRD always predict for refractory disease? Two
debates should be addressed to create an updated
clinically meaningful definition of refractory AML.
First, how long after induction are molecular
signs of MRD permissible? Rapidity of MRD eradication is a good prognostic marker in acute lymphoblastic leukemia [47]. In AML, rapid clearance of
blasts and early reduction of WT1 transcripts from
peripheral blood [48,49] predict for a good prognosis. The clinical challenge is how to consider
patients who delayed but eventually attained complete remission. The presence of bone marrow blasts
at day 14 of induction is definitely a surrogate
marker for refractory AML. If reinduction was
delayed until day 21 [50], prognosis is poor. Yet,
with immediate reinduction, some patients will be
rescued and OS for those who eventually attain
complete remission is equal to those patients who
obtained complete remission with single induction
[51 ].
The second debate is whether any level of MRD
justifies reinduction and ASCT [52 ]. The common
wisdom is that leukemic cells should be completely
eradicated. So, responding to any sign of molecular
relapse should give patients a better chance for cure
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Treatment for relapsed acute myeloid leukemia Ofran and Rowe
and a longer survival. This assumption probably will
never be confirmed in prospective randomized trials
because the ‘watch and wait’ approach ignoring
molecular relapse may be considered unethical. A
recent observation highlighted the contribution of a
patient’s own immune system to preventing relapse
probably through its capacity to eradicate undetectable MRD. In 143 adult patients with AML in complete remission 1, adenine-adenine polymorphism
in the cytotoxic T-lymphocyte antigen 4 (CTLA4)
gene was associated with higher incidence of leukemic relapse than the adenine-guanine polymorphism (56.4 vs. 35.6%, P ¼ 0.004, respectively).
This was translated to a lower overall survival at
3 years (39.4 vs. 68.4%, P ¼ 0.004) [53 ]. One can
speculate that some patients may be cured even if
not all leukemic cells have been eradicated by
chemotherapy.
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CONCLUSION
Despite multiple novel agents available, prognosis
of patients with relapsed AML remains poor. Progress in understanding molecular pathophysiology
of AML may hold the key for future treatment
approaches promoting proper assignment of
patients to the most beneficial therapy. Advances
in pharmacogenetics may in the future help identify
such patients. This may direct clinical research into
smaller trials focusing on genetically discriminated
subgroups [32,54]. The above-mentioned CTLA4
polymorphism is an example of a potential path
for personalizing therapy in AML. Immunotherapies
may turn out to be more beneficial for patients with
active CTLA4 polymorphism. Specific small molecules such as FLT3 inhibitors are only indicated in
FLT3-positive AML and are most effective if significant FLT3 inhibition is achieved. Azacitidine is more
likely to control disease in Ten-Eleven translocation 2 gene-mutated AML [55 ]. The personalized
approach is promising but will bring about new
challenges for treating physicians. Clinicians will
have to switch their perspective from a general ‘best
available’ protocol to sophisticated integration of
multiple parameters. A meticulous workup will be
mandatory to select the best protocol matching
patient’s condition, biological and genetic factors,
and considering patient’s wishes within a realistic
context.
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Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 19 Number 2 March 2012
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