REVIEW

CURRENT
OPINION Progress in the problem of relapsed or refractory
acute myeloid leukemia
Alice S. Mims a and William Blum b

Purpose of review
The majority of patients with acute myeloid leukemia (AML) die from disease recurrence and historically,
treatment options in both the relapsed and refractory settings of this disease have been limited. However,
new insights into the molecular characterization and biology of relapsed and refractory AML have led to
novel therapeutics and improvement in outcomes in these settings. The current understanding of
mechanisms of disease resistance and status of treatment options both currently available and under
exploration in relapsed and refractory AML are summarized in this review.
Recent findings
The rapid approval of multiple therapeutic agents since 2017 has led to improvement in selected
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populations such as isocitrate dehydrogenase and fms-like tyrosine kinase 3-mutated relapsed and
refractory AML with agents such as enasidenib, ivosidenib, and gilteritinib. Despite these advancements,
the only current curative approach remains allogeneic transplantation and only for those minority of
patients that are candidates. However, encouraging results are being seen with a multitude of novel small
molecular inhibitors and immunotherapeutic approaches currently in clinical trials both as single agents and
combination strategies in both upfront and relapsed/refractory AML.
Summary
Continued advancements in the knowledge of various mechanisms of relapse and resistance in AML are
ongoing, leading to the realization that diverse treatment strategies are needed to both prevent and
manage relapsed and refractory disease.
Keywords
acute myeloid leukemia, clonal architecture, immunotherapy agents, relapsed/refractory, small molecule
inhibitors

INTRODUCTION AML is defined as the inability to achieve complete

Acute myeloid leukemia (AML) is a devastating
diagnosis that is curative only in the minority of
patients. Current standard treatment results in 5-
year overall survival (OS) for 35–40% of younger
patients (<60 years) and 5–15% of older patients
(60 years) [1,2]. Though chemotherapy has con-
siderable toxicities, the risk of treatment-related
death is actually quite low; most patients die of
leukemia. Allogeneic transplantation (alloHCT)
remains the most effective means to reduce the risk
of relapse. Vasu et al. recently published results from
2551 AML adult patients treated with standard
intensive chemotherapy regimens without alloHCT
& University Comprehensive Cancer Center, Columbus, Ohio and bDepart-
in first remission [3 ]. Results showed 10-year dis-
ease-free survival estimated at only 15% in younger
patients and less than 2% of the older population,
demonstrating the enormity of the problem of AML
relapse with standard chemotherapy alone.
Several terms are commonly used to describe
and define relapse in AML. Primary refractory
remission after two cycles of intensive induction
therapy (reported 25–30% incidence in younger
adults) [4,5] and 30–50% of older adults [6,7]. Early
relapse is defined as disease recurrence within
6 months after achievement of initial complete
remission. Patients with primary refractory disease
or early relapse are predicted to have low response
rates when given salvage chemotherapy and short
OS compared with those patients with later relapse.
This is demonstrated in Table 1 by findings of Walter
a
Division of Hematology, Department of Medicine, The Ohio State
Department of Hematology and Medical Oncology, Emory University
School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA
Correspondence to Alice S. Mims, MD, The Ohio State University 320 W
10th Avenue, Columbus, OH 43210, USA. Tel: +1 614 685 6031;
e-mail: alice.mims@osumc.edu
Curr Opin Hematol 2019, 26:88–95
DOI:10.1097/MOH.0000000000000490

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 Relapsed or refractory acute myeloid leukemia Mims and Blum

Table 1. Predicted median survival after acute myeloid

KEY POINTS
leukemia treatment failure
 Ivosidenib for IDH1m and enasidenib for IDH2m AML Outcome Median survival (95% CI)
have complete remission rates of approximately 20% All patients n ¼ 1026
and in responders, median OS of at least 18 months in
the relapsed/refractory setting. Failed induction 4 (3–5) months

 Gilteritinib shows single-agent ORR of 51% in FLT3-ITD CR 0–3 months 3 (2–5) months
and TKD mutated AML and allowed some patients to CR 3–6 months 3 (2–4) months
bridge to alloHCT. CR 6–9 months 5 (4–7) months

 Understanding the clonal architecture of AML will aid CR 9–12 months 12 (7–18) months
in determining resistance mechanisms and innovative CR 1–2 years 15 (9–28) months
therapeutic strategies to both prevent and treat relapse
and refractory disease. (Abbreviated version from Walter et al.)
CR, complete remission.

and ongoing research in relapsed and refractory

et al. [8] after analyzing 1026 patients with relapsed/
refractory AML. Also faring very poorly are patients
who relapse after alloHCT, with estimated 3-year OS
of 12% or less if relapse occurs within 2 years of
alloHCT [9]. Regardless of the timeframe or setting,
there is no consensus standard of care treatment
regimen for patients with relapsed/refractory dis-
ease. Historically, treatment options have been lim-
ited to intensive chemotherapy regimens or more
palliative approaches with hypomethylating agents
(HMA), low-dose cytarabine (LDAC), or supportive
care/comfort measures [1]. However, since 2017,
there have been four agents approved by the Federal
Drug Administration (FDA) for patients with
relapsed/refractory AML, and many other agents
currently in clinical trials are showing promise.
Herein, we discuss the progress in clinical care
AML.
LESSONS LEARNED FROM STUDIES IN
CLONAL ARCHITECTURE
The ideal approach to relapsed/refractory AML is to
prevent occurrence in the first place. Knowledge
gained from studies of clonal architecture of AML
may help to develop superior therapeutic strategies
at diagnosis and beyond to increase the likelihood of
cure. Ding et al. performed seminal work with
whole-genome sequencing of primary AML tumor
samples for eight patients at both diagnosis and
relapse [10]. The authors discovered two major
mutational patterns: the founding clone gained
mutations that evolved at time of relapse, and a
subclone of the founding clone gained additional

FIGURE 1. Schematic of clonal architecture at diagnosis and two subsequent relapses in an AML patient. A FISH plot
representing clonal evolution of a patient throughout the disease course. Diagnosis, first relapse pre-allogeneic transplant, and
second relapse post-allogeneic transplant are depicted. The dominant subclone at both post-chemotherapy relapse and post-
transplantation relapse was derived from a small subclone that was detected at presentation (in red), which evolved with new
mutations of unknown significance after each therapy. AML, acute myeloid leukemia. Reprinted with permission from NEJM.

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Myeloid disease
mutations and expanded at relapse (similar to that
observed in Fig. 1). In either scenario, the initial
choice of chemotherapy failed to eradicate the
founding clone; in both scenarios, it is possible that
chemotherapy itself contributed to the expansion or
emergence of clones with the new mutations [10].
Whether new mutations emerge, or were present at
diagnosis but below detectable thresholds, remain an
important question. Similarly, there is heterogeneity
among patients, of course, on this question. In a
mouse model of AML, Shlush et al. further analyzed
both diagnosis and relapse AML patient samples
through whole-genome sequencing and transcrip-
&&
tional profiling [11 ]. They similarly showed that
the origin cell at relapse can vary among patients
with some arising from a more primitive leukemic
stem cell or a more committed leukemia cell clone
that has retained the stem cell transcriptional pro-
gram. Their findings highlight that successful thera-
pies to prevent relapse should not only target the
dominant leukemic clone but also must effectively
target putative leukemic stem cells. At relapse, based
on the origin cell, patients may need different thera-
peutic strategies. Christopher et al. investigated
another potential mechanism of relapse, this time
in the post-alloHCT setting. The authors again exam-
ined paired diagnostic and relapse AML patient sam-
&&
ples [12 ]. By performing both exome and RNA
sequencing, they determined that in patients who
relapsed after alloHCT, downregulation of major
histocompatibility complex class II genes was
observed in AML cells along with dysregulation of
other pathways that impact immune function. Resid-
ual leukemic cells evolved to downregulate major
histocompatibility complex class II genes (involved
in antigen presentation), thus reducing graft-versus-
leukemia activity. Together, all of these different
articles highlight the complexity of AML and the
many different resistance and escape mechanisms
that leukemic cells employ to survive. As we continue
to learn more about the biology of the disease both at
diagnosis and at relapse, hopefully individualized
therapeutic strategies can be implemented to elimi-
nate risk of recurrence.
CURRENT TREATMENT STRATEGIES
Intensive chemotherapy
For relapsed AML patients who are considered can-
didates for intensive therapy, treatment selection
decisions have historically been based on duration
of prior remission. A simple rule of thumb is the
shorter the remission duration, the lower the likeli-
hood of achieving subsequent remission. Said in
another way, patients who respond the best to prior
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therapy are more likely to respond to subsequent
therapy. As reported by Keating et al. [13], if AML
first complete remission duration was greater than
1 year the likelihood of second complete remission
was 60%, versus 19% for those patients with first
complete remission less than 1 year. These data from
the 1980s unfortunately still largely applies today,
with some modest improvements in supportive
care. However, promising new results with molecu-
larly targeted therapies (which will be discussed in
the next section) have substantially improved out-
comes for patients with targetable mutations.
Without targeted therapy, for patients who have
first complete remission lasting over 1 year, rein-
duction with the same induction regimen used for
initial remission can be considered [14]. Typically,
high dose cytarabine-based salvage regimens have
been recommended for first-line salvage treatment
for primary refractory or early relapse disease. There
are a variety of combination chemotherapy regi-
mens [i.e., mitoxantrone, etoposide, and cytarabine,
fludarabine, cytarabine, and granulocyte colony-
stimulating factor), CLAG-M (cladribine, cytara-
bine, granulocyte colony-stimulating factor, and
mitoxantrone)] that have been used in this setting
with estimated response rates of approximately 40–
50% [15–18]. Clearly, there is selection bias in these
individual reports, as older or infirm patients who
would be unlikely to respond to such therapies are
(appropriately) unlikely to receive them.
There is evidence to support the use of alloHCT in
carefully selected patients with primary refractory or
relapsed AML, with reported success rates of 20% or
less [19]. Most centers agree on a role for myeloabla-
tive alloHCT for fit younger patients with primary
refractory AML. In contrast, though there is no con-
sensus, the low likelihood of cure for patients with
relapsed AML who are transplanted not in remission
suggests that such patients (especially those with
proliferative disease and circulating blasts) may be
better served with alternative treatment approaches.
The goal would be to achieve second complete remis-
sion first rather than proceeding directly to alloHCT
with active leukemia. Useful predictive models for
alloHCT in patients not in remission help transplant
decision-making by providing risk/benefit estimates
based on clinical and disease-specific factors. One
such method is the Duval score which showed the
importance of five pre-transplant factors in regards to
survival after alloHCT. Adverse factors are first com-
plete remission duration of less than 6 months, pres-
ence of circulating blasts, donor other than a human
leukocyte antigen (HLA)-identical sibling, Karnofsky
or Lansky score less than 90, and poor-risk cytoge-
netics. A predictive score of 0 has OS of 42% at 3 years
versus 10% for a score at least 3 [20].
Volume 26  Number 2  March 2019
 Relapsed or refractory acute myeloid leukemia Mims and Blum
New approaches designed to improve outcomes
with intensive chemotherapy include combination
with small molecule inhibitors, immunotherapies,
or other targeted therapeutics and will be discussed
in subsequent sections.
Nonintensive chemotherapy
Nonintensive chemotherapy including HMAs such
as azacitidine and decitabine, or LDAC has also been
used in relapsed/refractory AML. HMA therapy
given in the salvage setting led to poor complete
remission rates between 15–20% with median OS of
approximately 6–9 months [1,21,22]. LDAC after
intensive chemotherapy had complete remission
rates of less than 10% and median post-relapse
survival of 5–6 months [23]. Clearly, none of these
treatment strategies is ideal, and all are typically
considered to be of palliative intent. Two drugs were
recently FDA approved in the upfront setting in
combination with lower intensity treatment for
older patients not candidates for intensive therapy:
venetoclax or glasdegib, respectively. Whether the
addition of either drug to similar regimens in the
relapsed setting will prove similarly efficacious
remains to be determined.
Small molecule inhibitors
Small molecule inhibitors including drugs targeting
specific molecular aberrations are new to the arsenal
of AML therapy. These agents are appealing because
of decreased toxicity compared to intensive
chemotherapy, the ability to bridge some patients
to transplant, increased duration of remissions, and
hematological improvements leading to improve-
ment of quality of life. Both isocitrate dehydrogenase
(IDH1 or IDH2) and FMS-like tyrosine kinase 3 (FLT3)
inhibitors have been recently approved in AML.
Isocitrate dehydrogenase inhibitors
IDH1 and 2 are critical enzymes involved in the citric
acid cycle. The two major isoforms that are targets in
AML therapeutics include IDH1 which is located in
the cytoplasm and IDH2 located in the mitochon-
dria. Both IDH1 and IDH2 catalyze the conversion of
isocitrate to a-ketoglutarate under normal circum-
stances. Somatic mutations in IDH1 and IDH2 result
in converting isocitrate to the oncometabolite 2-
hydroxyglutarate which leads to impairment of nor-
mal hematopoietic differentiation through induc-
tion of epigenetic dysregulation [24–27]. The
incidence of IDH mutations in AML is 5–10% for
IDH1 and 10–15% for IDH2. Inhibitors targeting the
abnormal enzyme from mutated IDH2 (enasidenib)
and IDH1 (ivosidenib) are oral agents and have
recently been FDA approved in the setting of
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relapsed/refractory disease. Both agents may cause
a differentiation syndrome with capillary leak and
leukocytosis, at an incidence of approximately 10%.
This requires careful monitoring during treatment.
Importantly, both drugs were approved following
completion of first-in-human, non-randomized clin-
ical trials in relapsed/refractory AML.
The phase 1/2 study of enasidenib included 109
relapsed/refractory IDH2 mutated AML patients at the
recommended phase 2 dosing schedule of 100 mg
daily. The overall response rate (ORR) was 38.5%
which included responses of complete remission,
complete remission with incomplete count recovery
(CRi), partial remission, and morphological leukemia
free state. The complete remission rate was 20.2% with
an additional 6.4% of patients achieving CRi. The time
to complete remission was 3.7 months with median
duration of response (DoR) of 8.8 months. The median
OS in patients with relapsed/refractory AML was 9.3
months with estimated 1 year OS of 39%. For those
patients who achieved a complete remission, the
&&
median OS was 19.7 months [28 ].
For ivosidenib, the phase 1 dose escalation and
expansion clinical study included 125 patients with
relapsed/refractory IDH1-mutated AML treated at
the clinical efficacy dose of 500 mg daily. Of these
125 patients, the ORR was 41.6% defined as in the
enasidenib study with a 21.6% complete remission
rate and 8.8% complete remission with partial
hematologic recovery (CRh). CRh is defined as bone
marrow myeloblasts of less than 5% combined with
both absolute neutrophil count more than 500/ml
and platelet count more than 50 000/ml. The median
time to complete remission and CRh was 2.7
months with median DoR of 8.2 months. All
patients who achieved complete remission or CRh
had responses occurring within 6 months of starting
ivosidenib. The median OS was 8.8 months and not
reached at data cut-off at 18 months for patients
with complete remission or CRh [29 ].
&&
With these exciting single-agent findings, IDH
inhibitors are now being explored in upfront and
relapsed/refractory settings in combination with
HMA or intensive treatment as well as in the
post-transplant setting as maintenance therapy
(NCT03683433, NCT02577406, NCT03515512,
NCT03728335). New IDH1 inhibitors such as FT-
2102 and IDH305 are currently in clinical trials
(NCT02719574 and NCT02381886).
FMS-like tyrosine kinase 3 inhibitors
FLT3 is mutated in approximately 30% of AML
patients with the majority being FLT3 internal tandem
duplications (ITD) and less frequently FLT3 tyrosine
kinase domain (TKD). Midostaurin was the first FLT3
inhibitor FDA approved for FLT3-mutated AML but
www.co-hematology.com 91
Myeloid disease
only in the setting of upfront treatment in combina-
tion with intensive chemotherapy [30]. Midostaurin
has not shown significant single agent activity and not
felt to be beneficial in the relapsed/refractory setting,
at least not as monotherapy [31]. Sorafenib, a multi-
targeted kinase inhibitor, has shown activity in the
relapsed/refractory FLT3 mutated AML setting and has
been used off-label both as a single agent and in
combination with HMA therapy. This is based on
reported monotherapy complete remission rates of
6–48% [32,33] and complete remission rates in com-
bination with HMA of 16–80% in small series of
patients [34,35].
Gilteritinib was recently FDA-approved as mono-
therapy for relapsed/refractory AML with activity in
both FLT3-ITD and TKD-mutated disease. In the phase
1/2 study, 169 patients with FLT3-mutated AML were
treated at dose of 80 mg/day or above, a dose where
90% of FLT3 phosphorylation inhibition was observed
by day 8 of treatment. Of these patients, the ORR of
52% included rates of complete remission at 11%, CRi
at 30%, and partial remission at 11%. DoR was
20 weeks and OS at 31 weeks with 19% of patients
&&
able to bridge to alloHCT [36 ]. These findings led to
the approval of this agent in November 2018. Two
other second-generation FLT3 inhibitors are also
showing promise in the relapsed/refractory setting,
quizartinib and crenolanib. Quizartinib has shown a
composite complete remission rate of 44–54% in
FLT3-ITD relapsed/refractory AML (does not target
FLT3-TKD). However, responses averaged approxi-
mately 10 weeks, with resistance notably including
&
acquisition of FLT3-TKD mutations [37 ]. Crenolanib
targets FLT3 and platelet-derived growth factor recep-
tor and has shown single agent activity with CRi rates
of approximately 39 and 11% partial remission in 18
relapsed/refractory FLT3-mutated AML patients with-
out prior exposure to other FLT3 inhibitors [38]. All
three second-generation FLT3 inhibitors are also being
explored in combination with induction chemother-
apy and HMA therapy in the upfront and relapsed/
refractory settings (NCT02236013, NCT02668653,
NCT03661307, NCT01892371, NCT02283177,
NCT03250338, NCT02400281). There is also a ran-
domized placebo-controlled trial underway assessing
the role of gilteritinib as maintenance post-transplant
for patients with FLT3-ITD mutations to attempt to
mitigate the risk of relapse (NCT02997202).
Additional small molecule inhibitors
Venetoclax is a highly selective, orally bioavailable
b-cell lymphoma 2 (Bcl-2) BCL2 inhibitor that was
recently FDA approved for newly diagnosed AML in
combination with HMA and LDAC therapy for older
&&
(75 years) or unfit patients [39 ]. For venetoclax
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
and HMA, complete remission and CRi rates were
70% at the 400 mg dose with azacitidine and 74% at
the 400 mg dose with decitabine, with time to
response of 1–2 months. This agent has been stud-
ied as monotherapy in patients with relapsed/refrac-
tory AML, but activity is low. The recent phase 2
monotherapy study allowed patients with either
recently relapsed AML (n ¼ 30) or untreated AML
unfit for intensive chemotherapy (n ¼ 2) with dose
escalation up to 800 mg daily. The complete remis-
sion rate was 6% and CRi rate was 13% with a
median OS of 4.7 months. For responders, the
median leukemia-free survival was 2.3 months
&
[40 ]. Venetoclax is also being explored currently
in the relapsed/refractory setting with multiple
novel–novel combination studies including gilter-
itinib and ivosidenib (NCT03484520,
NCT03441555, NCT03625505, NCT03471260).
TP53-mutated (TP53m) patients fare extremely
poor with conventional intensive chemotherapy.
However, there have been recent data that show
potential benefit from HMA therapy, in particular
the 10-day decitabine approach as shown by Welch
et al. [41]. There is a planned study comparing the 10-
day decitabine approach versus intensive reinduc-
tion chemotherapy for patients with TP53m AML
who fail first induction. A potential target in AML
that includes the TP53m subtype is neural cell devel-
opmentally downregulated 8 (NEDD8)-activating
enzyme which processes NEDD8 for binding to its
target substrates such as Cullin-RING E3 ubiquitin
ligases. Pevonedistat binds to NEDD8 forming an
adduct tightly bound to NEDD8-activating enzyme
which is then unable to process NEDD8, leading to
antiproliferative effects in AML. Treatment appears to
simultaneously induce DNA damage and DNA dam-
age responses with compromised DNA repair sensi-
tizing transformed cells to DNA-damaging agents
[42]. This agent has shown single-agent responses
in AML with an ORR of approximately 10% (two
complete remission and three partial remissions)
[43]; combination with azacitidine in relapsed/refrac-
tory AML showed an ORR of 50% with 20 complete
remissions, two CRi, and seven partial remissions. In
patients with TP53m, the composite complete remis-
sion/partial remission rate was 80% with this combi-
nation [44]. This agent is being studied in
combination with 10-day decitabine in newly diag-
nosed TP53m AML patients [NCT03013998].
IMMUNOTHERAPEUTIC STRATEGIES
Targeting CD33
Gemtuzumab is a humanized CD33 monoclonal
antibody linked to cytotoxic calicheamicin, which
Volume 26  Number 2  March 2019
 Relapsed or refractory acute myeloid leukemia Mims and Blum
underwent voluntary withdrawal from the market
in 2010 because of safety concerns. However, this
agent was reapproved in 2017 after a revamped
dosing schedule in combination with induction
chemotherapy showed improvements in clinical
outcome [45]. In relapsed/refractory AML, a phase
2 study enrolled 57 patients with CD33þ AML in first
relapse, with initial remission durations between 3
and 18 months. Fractionated doses of gemtuzumab
monotherapy were given on days 1, 4, and 7 as this
repeated exposure was thought to enhance internal-
ization of the drug and lead to increased intracellular
accumulation. With single agent dosing, 15 patients
achieved complete remission with median relapse-
free survival of 11.6 months and four patients
achieved CRi with median relapse-free survival of
8.6 months. No episodes of veno-occlusive disease
were seen with seven patients who underwent
alloHCT after treatment [46]. Other CD33-targeted
agents are in study including BI 836858, a fully
human CD33 monoclonal antibody; AMV564,
CD33xC3 bispecific antibody (BiTE); IMGN779, a
CD33 antibody-drug conjugate (ADC); AMG330,
CD3xCD33 BiTE [NCT03207191, NCT03144245,
NCT02674763, NCT02520427]. SGN-CD33A, a
CD33 ADC, was being tested in AML but unfortu-
nately hepatotoxicity including several cases of veno-
occlusive disease was observed. There are no current
plans for future clinical trials in AML for this agent.
Other potential immunotherapy targets
CD123 is the a-subunit of the interleukin-3 receptor
and is more highly expressed in AML than normal
hematopoietic stem cells. There are multiple agents
currently in phase 1/2 clinical trials targeting CD123
in relapsed/refractory AML including IMGN632, a
CD123 ADC coupled via peptide linker to unique
DNA alkylating payload; Flotetuzumab, a
CD123xCD3 BiTE; and Xmab-14045, a second
CD3xCD123 BiTE. Preliminary data for these agents
show promising complete remission/CRi rates rang-
ing from 19 to 25% with final response results
pending [47–49]. There is also a clinical trial under-
way testing chimeric antigen receptor (CAR) T cells
targeting CD123 (NCT03114670).
The success of programmed death-ligand (PD-
L1) and programmed death protein 1 (PD-1) target-
ing in other malignances has raised interest in AML.
Single agent therapy results were disappointing but
now these antibodies are being explored in combi-
nation with HMA therapy and high-dose cytarabine
in the relapsed/refractory population. In combina-
tion with HMA therapy, early complete remission
rates are being reported at 10–43% and at 35% with
high-dose cytarabine combination [50–52]. It is
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likely, however, that the relatively low mutational
burden observed in AML (relative to melanoma and
non-small cell lung cancer) will limit the use of these
agents in AML, at least in combination with cyto-
toxic therapies. Addition of such agents to immu-
nologic targeting approach such as BiTEs will be an
interesting approach for study. There are many
additional other immunotherapeutic agents includ-
ing off the shelf normal donor CAR T cells (targeting
CD123) and natural killer (NK) cell CAR therapy (NK
CARs with activating NK Group 2D receptors for
ligands on leukemic cells) [53].
CONCLUSION
The treatment arsenal for AML grows with the addi-
tion of nonchemotherapeutic strategies such as
small molecular inhibitors and immunotherapeutic
targeting approaches. Although small molecule
inhibitors do not appear to be curative as mono-
therapies, these agents may be able to bridge
patients to transplant or improve quantity along
with quality of life in nontransplant candidates.
Critical to successful treatment of AML will be con-
tinued evolution of our understanding of the clonal
architecture and biology of the disease at diagnosis
through to relapse and hopefully to cure.
Acknowledgements
None.
Financial support and sponsorship
A.S.M. reports consulting with Agios, Astellas, and Abb-
vie.
W.B. reports research funding with Xencor, Immu-
noGen, Boehringer Ingelheim (BI). Consulting with BI,
Astellas, Pfizer, Tolero.
Conflicts of interest
There are no conflicts of interest.
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 Relapsed or refractory acute myeloid leukemia Mims and Blum

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