Received: 18 June 2018 Revised: 26 June 2018 Accepted: 10 July 2018

DOI: 10.1002/ajh.25214

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL

MALIGNANCIES: A CONTINUING MEDICAL EDUCATION SERIES

Acute myeloid leukemia: 2019 update on risk-stratification and

management
Elihu H. Estey

Division of Hematology, Clinical Research

Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].

Division, Fred Hutchinson Cancer Research
Center, University of Washington and
Member, Seattle, Washington
Correspondence
Elihu H. Estey, Division of Hematology, Clinical
Research Division, Fred Hutchinson Cancer
Research Center, University of Washington
and Member, Seattle, Washington.
Email: eestey@u.washington.edu
Abstract
Outcome in patients with acute myeloid leukemia (AML) ranges from death within a few days of
beginning treatment (treatment related mortality, TRM) to likely cure. The major reason patients
are not cured is resistance to treatment, often manifested as relapse from remission, rather than,
even in older patients, TRM, whose incidence is decreasing. Knowledge of the pre-treatment
mutation status of various genes has improved our ability to assign initial treatment and, of par-
ticular importance, knowledge of whether patients ostensibly in remission have measurable
residual disease should influence subsequent management. Several new drugs have been
approved by the FDA and we discuss their role in treatment.

1 | DIAGNOSIS
Acute myeloid leukemia (AML) results from accumulation of abnormal
myeloblasts, most commonly in the bone marrow, leading to bone
marrow failure and death. Peripheral blood involvement is frequent,
while infiltration of organs, most ominously the brain and/or lung is
rare and seen most often in patients with high blood blast counts (eg,
>50 000/μL). Granulocytic sarcoma (GS) refers to AML seemingly lim-
ited to sites outside marrow or blood. Because it progresses to mar-
row involvement usually within 1 year, GS should generally be
managed like AML with marrow involvement.1
The 2016 World Health Organization's (WHO) criterion for AML
described below are more important in determining outcome than the
AML-MDS distinction,4 some centers treat patients with >10% blasts
as AML, even if they are considered as excess blasts 2 by the WHO.2
Biologically, patterns of mutations in AML arising after a preceding
hematologic disorder such as myelodysplasia often bear more resem-
blance to those seen in MDS than in primary (de novo) AML. 5,6
2 | DISEASE OVERVIEW
By age 70, about 10% of presumably normal individuals have clonal
mutations in hematopoietic cells.7 Such “age-related clonal hemato-

is at least 20% myeloblasts in marrow (or blood) with myeloid lineage poiesis” (ARCH) predisposes to acquisition of other mutations.6 Some

established by multiparameter flow cytometry (MFC).2 Exceptions to involved in RNA splicing (SRSF2), DNA methylation (DNMT3a, TET2,

the ≥20% criterion are cases of CBF AML (cytogenetic abnormalities t IDH 1/2), chromatin modification (ASXL1), or the cohesion complex

[8;21], inv [16], or t[16;16]), NPM1 mutated AML, or acute promyelo- (STAG2) are associated with development of MDS. Subsequent gain

cytic leukemia; in each the diagnosis of AML is independent of blast of mutations in genes encoding myeloid transcription factors (RUNX1,

%. Occasionally myeloid blasts may have T- or B-cell markers, or sepa-
rate myeloid and lymphoid populations may exist. These cases are
referred to as “mixed phenotype acute leukemia.”2 It is unclear
whether they should be managed as AML, ALL, or both and manage-
ment may depend on the degree to which the myeloid or lymphoid
component predominates. Cases with >20% blasts but which lack
markers are referred to as acute undifferentiated leukemia and often
managed like AML.
The 20% blast cut-off used to distinguish “AML” from “MDS” is
arbitrary. Based on data suggesting the prognostic covariates
CEBPA) or signal transduction proteins (FLT3) leads to development
of AML “secondary” to MDS (s-AML).6 In contrast, patients with pri-
mary (“de novo”) AML often have RUNX1, CEBPA, FLT3, or MLL
mutations but not mutations associated with prior MDS.6 Patients
with AML after receipt of prior chemotherapy (t-AML) can show
either the s-AML or the de novo pattern of mutations; those exhibit-
ing the de novo pattern have the relatively favorable outcome seen in
de novo AML while those showing the secondary pattern fare as simi-
larly poorly as s-AML. 7 Perhaps, 1/3 of patients believed to have de
novo AML based on history will exhibit genetic mutations that are

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95% specific for s-AML; despite a clinical diagnosis of de novo AML,
these patients appear to have a similar outcome as s-AML.7
Mutations present in hematopoietic cells at birth are germline
mutations (ie, present at birth in all cells).8,9 Germline mutations often
involve RUNX1, GATA2, and DDX41 and characterize hereditary
myeloid malignancy syndromes (HHMS). These frequently culminate
in MDS/AML, which, although usually presenting in childhood, can be
seen in adults usually age <40 years but occasionally older. Screening
of families for germline mutations is advisable if a family member is a
potential donor for allogeneic hematopoietic cell transplant (allo-
HCT), or if a patient has a potentially germline mutation (eg, RUNX1,
GATA2, and DDX41), HHMS organ manifestations, or a suggestive
family history 8,9
3 | PRETREATMENT RISK STRATIFICATION
Patients with AML are primarily considered, for example in clinical tri-
als or by practicing hematologists/oncologists, as “younger” or “older.”
Age 60-65 years commonly divides the two groups, with 65-70 year
being median age of patients at diagnosis. Medicare records from
2000 to 2009 indicated only 40% of patients age >65 years with AML
received chemotherapy within 3 months of diagnosis. 10 Patients who
were treated lived longer. 10 While this may have reflected treated
patients simply had better inherent prognoses, the Swedish Acute
Leukemia Registry observed lower death rates in 864 patients aged
70-79 if they resided in regions of the country where a higher propor-
tion of patients received 7 + 3 rather than “best supportive care,”,11;
there were no regional differences in performance status and 7 + 3
was superior regardless of performance status, although other poten-
tially confounding covariates were not be accounted for (nor was
quality of life). About 25% of 1337 patients alive at least 1 year after
being diagnosed between 1997 and 2013 were age >64 years and
25% of these were age >68 in 2014.12 Examining the period
1973-2011, the largest improvements in survival relative to a compa-
rable group from the general population (relative survival ratio)
occurred in patients age <60 until 1997 but thereafter occurred in
patients aged 61-70 although a 65-year old still lost 2/3 s of her/his
projected life expectancy even if diagnosed in 2011, and improve-
ments were not seen in individuals over age 70. 12
There remains a tendency even in fitter older patients to offer
less rather than more “intense” therapy, with the former represented
by the “hypomethylating agents' (HMAs) azacytidine or decitabine.
Dombret at al. asked physicians whether they would choose “best
supportive care” only (BSC), low dose cytarabine (LDAC), or “intense
00
chemotherapy” (IC), that is, conventional “7 + 3 for each of
488 patients age >65 with >30% blasts. 13 Patients were then random-
ized to the preselected “conventional care regimen” (CCR) or azacyti-
dine. Although 75% of patients had performance score (PS) 0-1 and
none PS 3-4, only 18% were preselected to receive IC vs 64% for low
dose cytarabine and 18% for BSC, documenting a predilection for less
intense therapy. Survival with azacytidine was superior to that with
CCR, although statistically essentially due to the comparison between
azacytidine and BSC or LDAC and relatively modest (30% alive at
ESTEY
1 year if given azacytidine rather than BSC, 45% if given azacytidine
rather than LDAC and 55% if given azacytidine rather than 7 + 3
The azacitidine13 and Swedish data 11,12 indicate there is less rea-
son for the therapeutic nihilism previously exhibited toward at least
some older patients,10 although the need for better therapy in these
patients is undeniable. However, it is also undeniable that, as dis-
cussed below, despite our current emphasis on age as the principal
consideration in management of AML, age is not the most important
determinant of either “treatment-related mortality” (TRM)
or resistance to therapy, defined as failure to achieve complete remis-
sion (CR) despite not incurring TRM, or, more commonly, relapse.
3.1 | Factors associated with TRM
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Distinguishing TRM from resistance seems useful because different
strategies might be used in patients at high risk of TRM vs those at
high risk of resistance. Because the time needed to attain CR may vary
according to the characteristics of a patient's AML and its treatment,
there will necessarily be overlap between TRM and resistance. None-
theless death within 28-30 days of beginning induction is a frequently
used criterion for TRM in patients given 7 + 3. There is a sharp reduc-
tion in weekly death rates once 4 weeks have elapsed from start of
such therapy or therapy containing higher doses of cytarabine and
purine analogs such as fludarabine, suggesting patients who die in this
time frame are qualitatively different from those who do not.14 Simi-
larly, suggestive are data that different factors are associated with
TRM thus defined and resistance.
Recent years have seen declines in TRM following the “intensive”
therapy noted in the preceding paragraph. 15 These declines likely
reflecting better supportive care, for example prophylactic use of
posaconazole during induction, may underlie the improvements in sur-
vival noted in the Swedish Registry.16 TRM rates fell from 18% in
SWOG and 16% at MD Anderson (MDA) in 1991-1995 to 3% at
SWOG and 4% at MDA in 2006-2009. This decrease was indepen-
dent of age, PS, and measurements of organ function. Although selec-
tion bias such that older patients who would have received intensive
therapy in the earlier period and often received less intense therapies
(eg, azacytidine) in the more recent period hence would not have been
included in the analysis may have been responsible, this would not
explain the decline in TRM in younger patients.
Because several factors, primarily PS but also creatinine, albumin,
and blood counts, determine risk of TRM multivariate models, includ-
ing some available online, have been developed to predict this out-
come.3 Removing age from these models has only minimal effects on
their predictive ability suggesting age is a surrogate for other TRM
covariates.14 Hence current European Leukemia-Net (ELN) and
National Comprehensive Cancer Network guidelines recommend age
be considered only in the context of other covariates when deciding
to whether to recommend more vs less intensive induction ther-
apy. 17,18 In the case of conventional intense induction regimens, these
covariates would include those primarily associated with resistance
(see below) as the more likely the risk of resistance the less willingness
there would be to accept a given risk of TRM.
Since 2016 version of this update, it is becoming clearer comor-
bidities, site of treatment, cohabitation status, and educational level
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ESTEY
may influence survival, perhaps largely through TRM. In a validation
set of 367 patients Sorror et al. noted the importance of comorbidities
as described in the hematopoietic cell transplantation comorbidity
index (HCT-CI, see below) in forecasting survival rates at 8 weeks
19
after treatment initiation. Examining 7007 patients in the California
Cancer Registry Ho et al. found 25% had been treated at a National
Cancer Institute designated Cancer Center (NCI-CC, defined as a cen-
ter which treated a median of 13 AML patients annually) and 75% at a
non-NCI-CC that treated at least one person with AML annually
(median 2). Sixty-day mortality was 12% at an NCI-CC and 24% at a
non-NCI-CC. Age <65-years, higher socio-economic status, fewer
comorbidities, and public health insurance were associated with treat-
ment in an NCI-CC. However, after accounting for these covariates,
treatment at an NCI-CC remained associated with lower 60-day mor-
tality rates (odds ratio 0.46, 95% CI 0.38-0.57).20 Data from 3243
patients in the Danish National Acute Leukemia Registry (DNLR) sug-
gest patients aged >60 years are more likely to receive intensive
induction and have better survival when cohabitating rather than liv-
ing alone, independent of PS, comorbidities, and cytogenetic risk. 21
Since median follow-up was only about 6 months, it is possible a fair
number of deaths reflected TRM, which is often most common during
initial induction. The same group reported an association between
higher education levels and better survival in 1588 DNLR patients
(median age about 60 years) also independent of PS, comorbidities,
and cytogenetic risk 22; the longer follow-up (median about 1 year)
makes it more difficult to distinguish TRM from resistance.
3.2 | Factors associated with resistance
Experience suggests patients, perhaps because of the negative conno-
tations associated with “chemotherapy,” are often more concerned
FIGURE 1 Distribution of genetic aberrations in AML (see reference 18)
1269
with the possibility of TRM than of resistance. However even in
patients in their 70s and 80s resistance is often the greater problem,
at least in patients reported in the literature. Considering studies con-
ducted before 2000 Appelbaum et al. found that in patients aged
>75 years, rates of not entering CR despite surviving the first 30 days
of induction therapy were similar with those of death by day 3023; the
latter rates are likely to have fallen more than the former in more
recent years.15 Even in patients aged >70 years with performance sta-
tus 2-4 at time of CR, the risk of relapse is threefold that of death in
CR, 24 the distinction between TRM (death in remission) and resistance
perhaps being more objective in patients in remission than in patients
undergoing induction.
Genetics encompassing both classical cytogenetics and the muta-
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tional status of various genes is the most important predictor of resis-
tance18 (Figure 1, Table 1), that is, failure to enter CR despite not
incurring TRM or relapse from remission. Much of the prognostic
import of “de novo” vs “secondary” AML is subsumed by genetics thus
defined.5 The ELN guidelines, updated in 2017, are probably the most
widely-used source for assessing risk of resistance and classify
patients into “favorable,” “intermediate,” and “adverse” groups based
on leukemia cell cytogenetics and mutations18 (Table 2). The single
most adverse factor is a TP53 mutation, commonly associated with
complex cytogenetics, but adding to the negative effect of the latter.
The favorable effect of NPM1 and (bi-allelic) CEBPA mutations are
considered unaffected by cytogenetic status.18 A FLT3 internal tan-
dem duplication (ITD) is regarded as unfavorable only if the ratio of
mutated to normal alleles (allelic ratio, AR) is >0.5. 18
While Harada et al. found the ELN 2017 effectively stratified
Japan Acute Leukemia Study Group patients (n = 197, 90% age < 60),
with the exception of the FLT3 AR cut-point25 Eisfeld et al. found
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1270 ESTEY

TABLE 1 Proposed genomic classification of AML (see reference 29) TABLE 2 2017 ELN risk stratification by genetics (see reference 18)

Frequency in the Risk

*
Study Cohort category Genetic abnormality
(N = 1540) Most Frequently Favorable t(8;21)(q22;q22.1); RUNX1-RUNX1T1
No. of Mutated Genes
Genomic Subgroup patients (%) Gene (%) inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
AML with NPM1 418 (27) NPM1 (100), DNMT3A Mutated NPM1 without FLT3-ITD or with
mutation (54), FLT3 ITD (39), FLT3-ITDlow = allelic r atio < 0.5
NRAS (19), Biallelic mutated CEBPA
TET2 (16), PTPN11 (15)
Intermediate Mutated NPM1 and FLT3 -ITD high = allelic ratio > 0.5
AML with mutated 275 (18) RUNX1 (39), MLLPTD
chromatin, (25), SRSF2 (22), Wild-type NPM1 without FLT3-ITD or with
RNA-splicing genes, DNMT3A (20), FLT3-ITDlow (without adverse-risk genetic lesions)
or both† ASXL1 (17), STAG2 (16), t(9;11)(p21.3;q23.3); MLLT3-KMT2A
NRAS (16), TET2 (15),
FLT3ITD (15) Cytogenetic abnormalities not classified as favorable or
adverse
AML with TP53 199 (13) Complex karyotype
Adverse t(6;9)(p23;q34.1); DEK-NUP214

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mutations, (68), −5/5q (47),
chromosomal −7/7q (44), t(v;11q23.3); KMT2A rearranged
aneuploidy, or both‡ TP53 (44), −17/17p
t(9;22)(q34.1;q11.2); BCR-ABL1
(31), −12/12p (17),
+8/8q (16) inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);
81 (5) inv(16) (100), NRAS (53), GATA2,MECOM(EVI1)
AML with inv(16)
(p13.1q22) or t +8/8q (16), +22 (16), −5 or del(5q); − 7; −17/abn(17p)
(16;16)(p13.1;q22); KIT (15), FLT3TKD (15)
Complex karyotype monosomal karyotype
CBFB–MYH11
Wild-type NPM1 and FLT3 -ITD high†
AML with biallelic 66 (4) CEBPAbiallelic (100),
CEBPA mutations NRAS (30), WT1 (21), Mutated RUNX1
GATA2 (20) Mutated ASXL1
AML with t(15;17) 60 (4) t(15;17) (100), FLT3ITD Mutated TP53
(q22;q12); PML– (35), WT1 (17)
RARA
AML with t(8;21)(q22; 60 (4) t(8;21) (100), KIT (38), “next generation sequencing” (NGS) to assess mutations in 80 cancer
q22); RUNX1– −Y (33), −9q (18)
and/or leukemia related genes. 26 Patients with NPM1 mutation con-
RUNX1T1
stituted a “favorable” group but only if the NPM1 mutation was
AML with MLL fusion 44 (3) t(x;11q23) (100), NRAS
genes; t(x;11)(x; (23) accompanied by a mutation in a variety of other genes; this favorable
q23)§
group had an 81% CR rate, with 3-year survival and disease-free sur-
AML with inv(3) 20 (1) inv(3) (100), −7 (85),
vival rates of 45-46% (Figure 3). Patients in this favorable group were
(q21q26.2) or t(3;3) KRAS (30), NRAS (30),
(q21;q26.2); GATA2, PTPN11 (30), ETV6 (15), uniformly also classified as favorable by ELN 2017 and constituted
MECOM(EVI1) PHF6 (15), SF3B1 (15) about 1/3 of ELN 2017 favorable patients and about 10% of all the
AML with IDH2 R172 18 (1) IDH2R172 (100), authors' patients. Ostronoff et al. have likewise noted patients aged
mutations and no DNMT3A (67), +8/8q
other class-defining (17) >65 years in the ELN favorable group NPM1 mutated/FLT3 normal
lesions have much poorer outcomes than younger adults27 while Patel
ITD
AML with t(6;9)(p23; 15 (1) t(6;9) (100), FLT3 et al. have reported higher NPM1 mutation burden (higher proportion
q34); DEK–NUP214 (80), KRAS (20)
of mutated/normal alleles, that is, “variant allele frequency”) was asso-
AML with driver 166 (11) FLT3ITD (39), DNMT3A
mutations but no (16) ciated with shorter EFS and survival as were DNMT3a mutations in
detected 109 patients with de novo AML and mutated NPM1. 28
class-defining
lesions Although Eisfeld et al. ‘s26 and Patel et al.'s 28 findings await con-

AML with no detected 62 (4)
driver mutations
AML meeting criteria 56 (4)
for ≥2 genomic
subgroups
ELN 2017 was problematic in 423 patients age >60 years with de
26
novo AML treated on several Alliance protocols ; no patients
received a transplant in CR1. ELN favorable risk patients had longer
survival and relapse-free survival than ELN intermediate and adverse
risk patients, but the latter two groups were essentially indistinguish-
able (Figure 2). Moreover, at 3 years, disease(relapse)-free survival in
the “favorable” group was only 25% and survival 30% (Figure 2). To
identify patients who might have better outcomes the authors used
firmation in an independent population, data from Papaemmanuil
et al. also speak to the potential value of examining a broader range of
genes than indicated as prognostic in ELN 2017.29 In particular, after
examining survival in 1540 patients treated on one of three separate
trials of intensive induction  allogeneic HCT and validating findings
using sophisticated statistical techniques, these authors stressed the
importance of gene-gene interactions, and similarly to Eisfeld et al.26
the mutation status of other genes in patients with NPM1 mutations.
Thus, the negative effect of a FLT3 ITD in patients with an NPM1
mutation was much more pronounced in patients with than without a
DNMT3a mutation (Figure 4). Likewise, in patients with an NPM1
mutation presence of a RAS mutation improved survival more in the
presence than the absence of a DNMT3a mutation (Figure 4). Analo-
gously, the adverse effect of an MLL aberration noted in ELN 2017

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ESTEY
The use of MRD assessment in patients ostensibly in CR has plau-
sibly made auto HCT a more viable option. Specifically, patients in the
ELN 2017 intermediate group pretreatment who become MRD nega-
tive after induction therapy might be appropriate candidates for auto
HCT even if fit for allo HCT in the expectation auto might avoid some
of the long-term complications of allo.
6 | THERAPY OF RELAPSED AND
R E F R A C T O R Y ( R / R ) A M L (“ S A L V A G E
THERAPY”)
6.1 | Definitions and assessing prognosis with
standard therapy
Not infrequently AML is considered “primary refractory” if CR is not
observed after a first course of 7 + 3. Examining 1505 adults given
7 + 3 on one of 4 SWOG protocols Othus et al.130 found 48%
achieved CR on course 1 and 9% died, leaving 638 people alive but
not in CR. Although the protocols called for administration of a 2nd
7 + 3, this occurred in only 333 (52%). A similar proportion has been
noted by ECOG. Examining various pretreatment factors, such as age,
performance status, and cytogenetics, and post-treatment factors,
such as results of a “day 14” marrow alone or compared to pretreat-
ment, administration of a second course was associated only with
treatment at a “non-academic” SWOG center. The CR rate on a 2nd
7 + 3 was 43% with a TRM rate of 10%. None of the covariates noted
above nor the day a second course began influenced 2nd course CR
rate. Although patients in CR only after two courses had shorter RFS
and survival, this reflected older age and cytogenetics, rather than
courses to CR. These data prompted ELN to define refractory AML as
having failed two courses of 7 + 3,18 although the relation between
number of courses to CR and subsequent outcomes is not definitively
established. Whether patients whose AML has failed to respond to a
first 7 + 3 would be better served by a second 7 + 3 rather than
change to alternative therapy can only answered via a randomized
trial. However, the data suggest the minimum acceptable CR rate for
studies investigating new therapies in AML refractory to a first 7 + 3
should be 40%-45% rather than the typical 25%-30%; use of the latter
results in people continuing to receive the new therapy when it is
already known likely to be worse than a second 7 + 3. Whether no
CR after two courses should also be the criterion for primary refrac-
tory AML after therapy with high-dose cytarabine-containing regi-
mens is less clear 131
It can be difficult to distinguish relapse of the original AML from a
“new” AML brought on for example by chemotherapy, with the latter
suggested by findings of a substantively new cytogenetic or muta-
tional profile. The proportion of relapsed AMLs that truly represent
“new” disease is unknown and depends on what is meant by
“substantively.”
The fundamental decision to be made with salvage therapy, as
with initial therapy, is the choice between standard (eg, FLAG or
FLAG-ida) and investigational re-induction therapies. Again, since the
results with the latter are, by definition, unknown the decision must
rest on degree of dissatisfaction with the former. Probably the
1285
principal factor most consistently associated with response to salvage
therapy has been duration of prior CR. Although various cut-points
have been used to define lower vs shorter CR1 durations, it is likely
the shorter the CR1 duration, assigning primary refractory patients a
CR1 duration of zero, the poorer the outcome.132 Several systems
which combine CR1 duration with other factors are available for
assessing prognosis. 133 A convenient one, derived from 667 adults
aged <60 in first relapse, remains Breems, et al.134 (Table 6) Survival
probabilities at 1-year were 70% in the best group, (46% at 5 years),
which however constituted only 9% of patients, with a mean CR1
duration of 17 months), and were 46% in the intermediate group
(25% of patients, mean CR1 duration 16 months) and 16% in the
worst group (2/3 s of patients, mean CR1 duration 7 months)
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(Supporting Information Figure 8). CR rates were 85%,60%, and 34%
respectively among patients in the “favorable”, intermediate, and
adverse groups who received treatment. Although reasons underlying
initial therapeutic choices were difficult to ascertain and therapy-
specific CR rates were accordingly not provided, these results suggest
patients in the worst group (alternatively those with CR1 durations
<1 year) are unlikely to benefit from standard intensive therapy (eg,
FLAG-ida), thus becoming candidates for “clinical trials.” In contrast
standard therapy might be more appropriate in the best and interme-
diate groups. In general, however repetition at relapse of the same
induction and post-remission therapy used initially leads to worse
results. This is consistent with the notion that induction chemother-
apy exerts selective pressure such that new potentially resistant leu-
kemic clones emerge as do non-leukemic clones harboring similar
mutations as seen in age-related clonal hematopoiesis. 135 This sug-
gests that even should 2nd CR be attained with standard induction,
post-remission therapy should optimally include allo HCT, particularly
if this has not been done before; indeed, regardless of prognostic
group patients lived longer if in CR2 they received allo HCT, although,
as usual, various selection biases may have affected the decision to
perform allo HCT.134 The recommendation for investigational therapy
TABLE 6 Prognostic scoring system for AML in first relapse
“favorable” group 1-6 points, intermediate group 7-9 points, adverse
group 10-14 points (see reference 134)
Factor Points
CR1 duration
≥18 mo 0
7-18 mo 3
≤6 months 5
Cytogenetics at diagnosis
t(16;16) or inv16 0
t(8;21) 3
Other 5
Age at relapse
≤35 y 0
36-45 y 1
>45 y 2
SCT before first relapse
No 0
Yes 2
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ESTEY
FIGURE 2 Assessment of ELN 2017 risk stratification system in patients aged 60 or above (see reference 26)
depended on the presence of a mutation in the tyrosine kinase
domain of the FLT3 gene and although ELN 2017 regarded mutations
in IDH2 or in DNMT3a as having no prognostic effect, prognosis
became considerably worse when both IDH2 and DNMT3a mutations
were present (Figure 4). It cannot be overemphasized that the prog-
nostic effect of a given mutation almost always depends on what
other mutations are present.
The ongoing replacement of single gene assays by NGS to assess
a panel of genes, and possibly in the future by exome sequencing and
genome wide assays30 will facilitate development of more sophisti-
cated prognostic systems than ELN 2017; for example, the seemingly
straightforward entity of CBF AML is mutationally complex and this
complexity has prognostic implications. 31,32
AML is conventionally
regarded as an indication for immediate treatment, raising the ques-
tion of whether treatment can be delayed even the usually 2-7 days
needed to receive NGS results and potentially using them to decide
on therapy. Both Sekeres et al. (in older patients) 33
and Bertoli et al. in
younger and older patients including those with WBC >50 000/μL) 34
concluded delay of therapy had no effect on outcome after account-
ing for other prognostic covariates; the deleterious effect on outcome
in younger patients in Sekeres et al. was relatively small and has to be
considered in context of potential benefit. Median time from diagnosis
to beginning therapy, that is, delay, was only 4-8 days and the effect
of potential selection bias cannot be quantified. Although a trial ran-
domizing patients to immediate treatment vs waiting until NGS results
are available is likely impossible, it seems any potential harm resulting
from delay might well be less than the harm in immediately beginning
a therapy that is unlikely to be effective, for example, 7 + 3 in subjects
with TP53 mutations.
It is useful to distinguish between a prognostic and a predictive
covariate. The former refers to a covariate such as PS 3-4 or a TP53
mutation35 that likely applies regardless of specific treatment (eg,
7 + 3 or azacitidine), the latter to a covariate that is therapy specific.
Many models regard treatment as a single entity and do not examine
whether the effect of a covariate differs according to treatment, rec-
ognizing most of the prognostic effect of various mutations has been
worked out in subjects given intensive therapy Experience to date
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suggests however the same factors that influence response to one
treatment do so with another. For example, the presence of complex
cytogenetics, TP53 mutations, or high AR FLT3 ITDs are associated
with relapse with both allogeneic HCT and treatment without
allogeneic HCT.
Although many prognostic systems focus on survival as the out-
come of interest, survival is likely confounded by treatment given
after an initial treatment fails more so than shorter term outcomes
such as event-free survival.36 The relative limited prognostic ability of
even sophisticated models cannot be overemphasized. For example,
Papaemmanuil et al developed a model incorporating cytogenetic,
genomic, and clinical data (the latter including age, performance sta-
tus, blood counts, treatment protocol, and year of treatment) and
evaluated how often the model correctly predicted which one of a
pair of patients had longer survival.29 Iterative repetitions over many
pairs indicated the model's concordance with survival was only 71%
with genomic features accounting for about 2/3 s of the explained
variation and clinical, demographic, and treatment factors for 1/3.
Various other models perform similarly. 37 However, it is likely incor-
poration of post-treatment data with the pretreatment data discussed
above will improve prognostic accuracy; we will return to this topic
after a discussion of induction therapy.
4 | INITIAL INDUCTION THERAPY
4.1 | Goal of induction therapy
A case can be made this should be CR without measurable residual
disease (MRD). After accounting for de novo vs secondary disease,
cytogenetics, age, blood counts, and the longer time needed to
achieve CR than other responses (“survival by response bias”), Othus
et al. noted a survival advantage for CR rather than CR with incom-
plete count recovery (CRi) in 261 patents aged <60 years given 7 + 3
or more intense therapy and in 133 patients (median age 73) given
azacytidine + gemtuzumab ozogamicin (GO) on SWOG studies. The
effect of CR was on survival was similar with azacitidine as with more
intense regimens.38 Examining rates of death at 6 month intervals in
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1272
FIGURE 3 Modification of ELN 2017 risk stratification in patients aged 60 or above (see reference 26)
patients treated with 7 + 3 or more intense regimens since 2005,
Othus et al. noted these were constant during years 1-2 after treat-
ment began but fell by half in year 3, leading them to define “poten-
tially cured” patients as those alive 2-3 years after treatment began,
although subsequent death rates in those alive at these times were
still considerably higher than expected for an age-matched normal
population.39 The primary predictor of being alive at 3 years was
achievement of CR by day 100.39 Many clinicians also believe “quality
of life” is better in people who achieve CR because they are likely to
receive fewer transfusions and spend less time in hospital than people
who achieve CRi or hematologic improvement, although this seems an
important area for further investigation. ELN 2017 distinguished CR
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without MRD as superior to CR because of the former's associations
with better long-term outcome,18 as discussed below.
4.2 | Candidates for clinical trials of new induction
therapy
It should be stressed there are some patients in whom the risk of
TRM is not commensurate with the benefit of achievement of CR 
MRD and some in whom the likelihood of achievement of CR  MRD
with conventional therapy is so low that even a relatively low risk of
TRM would be difficult to justify. As indicated above, age alone should
not be the sole or even principal means to identify such patients18 in
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FIGURE 4 Interactions between different mutations affecting prognosis (see reference 29)
contrast to covariates such as PS 3-4 or comorbidities for high risk of
TRM or such as ELN 2017 adverse risk for low probability of entering
(and staying) in CR. Both groups are prime candidates for clinical trials,
the former with “less intense” therapies, although patients at high risk
of TRM with conventional therapies are often excluded from such tri-
als. 40
Patients with ELN 2017 adverse risk might plausibly receive
conventional induction with 7 + 3 with the goal of allogeneic HCT in
CR1. However, in some such patients, particularly those with complex
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cytogenetics, a monosomal karyotype, or a TP53 mutation, the proba-
bility of CR with 7 + 3 is so slight that investigational therapies are
advisable once AML is diagnosed. Given the importance of CR with-
out MRD in determining post induction outcome, it is likely that as
rates of CR without MRD (rather than merely of CR) become more
widely known, other groups in whom this rate is <50% will become
prima facie candidates for clinical trials of new induction therapies.
Even today National Comprehensive Cancer Network guidelines
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1274
recommend consideration of trials for all patients.17 Indeed, survival in
the great majority of patients with the exception of ELN favorable
patients age <60-65 is such that clinical trials should spring to mind
for all but such patients once AML is diagnosed.
4.3 | Intensity of induction therapy
Several studies have noted superior survival, or at least similar survival
with less toxicity/inconvenience, with conventional lower intensity
regimens (eg, azacytidine or decitabine) than with higher intensity reg-
imens (eg, those containing “high-dose” cytarabine [HDAC], defined
as individual doses at least 1 g/m2).41,42 In contrast in a multicenter
study Sorror et al.43 reported longer 2 year survival rates in those of
1295 patients given more intense (typically 7 + 3 or HDAC- contain-
ing) rather than more intense (typically azacitdine) induction regimens,
even if patients were aged 70-79 years and regardless of AML com-
19
posite model or treatment-related mortality model 14 scores43; as
expected the proportion of patients given more intense therapy varied
by age: 96% if 50-59 (n = 264), 81% if 60-69 (n = 421), 41% if age
70-79 (n = 242), and 20% if age 80-92 (n = 62).However, the differ-
ences in survival have been slight (eg, 7 vs 5 months median in Boddu
et al.41 ) and even when larger (eg, 53% vs 32% and 37% vs 12% at
2 years in those with AML- CM scores 4-6 and 7-9, respectively, in
Sorror et al.43) have nonetheless been clearly unsatisfactory in the
worst prognosis patients (22% vs 11% if AML-CM score ≥10). All
these studies have been historically controlled, problematic given limi-
tations in evaluating the likelihood of response if patients given a cur-
rent therapy had received a historical one instead.37 Although
randomized, the Dombret at al. azacytidine vs CCR trial noted above
enrolled relatively few patients in the 7 + 3 vs azacytidine arm.13 An
ongoing EORTC trial (NCT02172872, “inDACtion”) is randomizing
patients aged ≥60 years with PS 0-2 and normal kidney/liver function
between standard 7 + 3 induction and 10-day decitabine followed by
allogeneic HCT in responding patients; estimated completion date is
December, 2019. While is seems clear TP53 mutations and a monoso-
mal karyotype, if not adverse cytogenetics per se, predict poor out-
come with both azacytidine and more intense therapies13,18,35 it is
less clear if other genetic features can distinguish patients more likely
to do better with one of these than the other44; for example, it has
been reported patients with NPM1 mutations have shorter remissions
after therapy with azacitidine or decitabine.45 Suggestively, after
accounting for prognostic covariates, failure to respond to azacytidine
remains highly associated with failure to respond to 7 + 3,46 suggest-
ing these two therapies have much in common and more important
than assessing which is better may be efforts to improve either
or both.
Regarding 7 + 3 vs more intensive therapy, a German randomized
comparison involving 3375 adults found equivalent EFS and RFS with
47
7 + 3 and high-dose cytarabine-containing therapy. More recently,
Garcia-Manero et al. in SWOG1203 randomized 738 adults aged
<60 years among 7 + 3 (daunorubicin dose 90 mg/m2 daily X3) idaru-
bicin + HDAC (cytarabine dose 1.5 g/m2 daily X 4, IA) and IA + vori-
nostat (IAV).48 CR rates were 75-80% with each arm. Although
remissions were achieved more often after course 1 with IA, and the
proportion of individuals with intermediate and adverse cytogenetics
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receiving HCT in CR1 was similar (about 48% among arms), there
were no differences in EFS, DFS, or survival (Supporting Information
Figure 1A). The same was true considering NPM1, CEBPA, FLT3 ITD
status, or cytogenetic status with the exception that favorable-risk
patients appeared to have better EFS, RFS, and survival with 7 + 3
(Supporting Information Figure 1B). However, patients given IA or IAV
received less cytarabine once in CR than patients given 7 + 3, and it is
plausible results might have been different had fludarabine + HDAC +
idarubicin (FLAG-ida) rather than 7 + 3 been used, given results from
a large randomized NCRI study in the UK that found reduced relapse
rates with FLAG-ida than with 10 days of standard cytarabine + dau-
norubicin.49 However, there were no differences in survival possibly
because of higher treatment-related mortality rate in CR in the FLAG-
ida arm. Further complicating the issue is the very realistic possibility
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a given result may not be generally applicable. For example, although
a 1205 patient randomized NCRI trial found no difference, other than
more TRM in the higher dose arm, between 7 + 3 using daunorubicin
doses of 90 mg/m 2 vs the usual 60 mg/m2 each daily X 3,50 patients
with FLT3 ITD (n = 200) had less relapse leading to longer survival if
given 90 mg/m.51 Likewise, a HOVON trial randomizing 795 evaluable
adults age <65 between 7 + 3 as cycle 1 followed by amsacrine (simi-
lar to idarubicin or daunorubicin) + HDAC as cycle 2 each
clofarabine (a purine analog similar to fludarabine except with
greater single agent activity at tolerable doses) found longer EFS and
survival with addition of clofarabine but only in the ELN 2010
intermediate-1 group (EFS at 4-years 40% vs 26%, P = .002 and in
subjects who were NPM1 mutated but FLT3 wild type (EFS at 4-years
40% vs 18%, P < .001).52
Given these data, it is difficult to be dogmatic about intensity of
induction therapy, with the possible exception that regimens similar in
intensity to 7 + 3 or FLAG-ida be used rather than azacytidine or deci-
tabine in people at low risk of TRM. At the author's center, we have
used G-CLAM (in which, because of its greater single agent activity)
cladribine replaces the fludarabine of FLAG-ida) provided patients
have a low TRM score regardless of age. However, although results
with GCLAM seem, in the absence of randomization, at least similar to
7 + 3, the rate of CR without MRD is only 71%. 53 Hence, we are
interested in combining GCLAM with potentially less toxic agents that
might improve efficacy. Whether this becomes reality is probably
more important than the intensity of induction therapy. Addition of
some agents to 7 + 3 or FLAG-ida has already improved outcome,
making these agents an integral part of induction therapy, as
described below and as reviewed in Wei and Tiong.54
4.4 | Midostaurin and FLT3 inhibition
FLT 3 ITDs occur in about 25% of patients aged <60 years and in
about 15% of older patients.55 Mutations in the tyrosine kinase
domain of the gene occur in an additional 5%-10%. Midostaurin is an
oral multitargeted tyrosine kinase inhibitor active in patients with a
FLT3 mutation. Stone et. al. screened 3277 adults aged <60 for a
FLT3 mutation, found 896 to be FLT3 “positive,” of whom 717 were
randomized to 7 + 3  midostaurin; results of testing were reported
to investigators within 48 hours of specimen receipt in a central labo-
ratory. 56 Midostaurin or placebo was given at 50 mg twice daily on
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FIGURE 5 Survival after 7 + 3 + either midostaurin or placebo (see
reference 56)
days 8-21 during induction and “consolidation” (4 cycles of cytarabine
at the commonly used 3 g/m 2 BID on days 1, 3, and 5), and was used
alone as “maintenance” at the same dose for 1 year. Although CR
rates were similar in both groups (59% midostaurin and 54% placebo),
survival, the primary endpoint, was longer with midostaurin (median
follow-up 59 months in the 359 patients still alive). This largely
reflected a lower relapse rate, as also evidenced by longer EFS with
midostaurin. Midostaurin was superior regardless of ITD allelic ratio
(<vs > 0.7) or whether the FLT3 mutation was an ITD or a TKD
(Figure 5). Similar proportions in each arm received HCT at any time
(55%-59%) or in CR1 (23%-28%) and results were unaffected if cen-
soring was done at HCT, although survival was superior with midos-
taurin if HCT was done in CR1 but not later. Although the
contribution of “maintenance” to the results has yet to be
57
demonstrated, and the greater effect of midostaurin on survival, but
not EFS, in men than women remains unexplained, 56 the Stone
et al. study clearly indicate addition of midostaurin to 7 + 3 is now
standard therapy for adults aged <60 with newly diagnosed AML and
a FLT3 aberration. On April 28, 2017, the FDA approved midostaurin
for all patients with a FLT3 aberration regardless of age, despite a lack
of randomized data in older patients. NCRI data suggest in patients
with a FLT3 ITD and a low probability of TRM daunorubicin doses of
90, rather than 60 mg/m2 daily × 3 be used in 7 + 3 together with
51
midostaurin, although this remains speculative.
Midostaurin inhibits kinases other than FLT3. Hence it is plausible
these drugs will also be effective in people with no FLT3 aberrations,
and studies investigating this possibility are in progress. As an exam-
ple, Röllig et al. have reported addition of sorafenib, often thought of
as a “FLT3 inhibitor” but actually a multikinase inhibitor (although not
1275
active against FLT3 TKDs) improved EFS, although not survival, when
compared to 7 + 3 in a randomized trial in adults age <60, but had no
benefit in older adults. 58,59 The effect on EFS was the same in
patients with or without an ITD; patients with FLT3 TKDs were not
treated. Future comparisons of chemotherapy + either midostaurin or
more potent, specific FLT3 inhibitors in patients with FLT3 aberra-
tions may shed light on the importance of targeting multiple, rather
than a single, aberration.
Among these more potent, specific inhibitors are crenolanib, qui-
zartinib, and gilteritinib.60 These are likely to be combined with che-
motherapy and compared to chemotherapy + midostaurin. These
drugs also are relatively active vs the FLT3 D835 TKD mutation,
which often appears when resistance to earlier FLT3 inhibitors
develop, 61 perhaps suggesting combinations of newer inhibitors and
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midostaurin. Treatment with FLT3 inhibitors also appears to unmask a
dependence on glutaminolysis, suggesting incorporation of glutamin-
ase inhibitors to overcome development of resistance.62
4.5 | Gemtuzumab ozogamicin and CD33 inhibition
The cell surface antigen CD33 is commonly expressed on the AML cell
surface (including possibly in some cases AML “stem cells”) 63 as well
as on normal myeloid cells but not on other normal cells, with the
exception of sinusoidal cells in the liver. GO consists of an antibody to
CD33 combined with the toxin caleacheamicin. Used alone GO is
highly effective against acute promyelocytic leukemia (APL) presum-
ably because of the heavy expression of CD33 in APL.64 It is much
less effective as a single agent in other AML with CR and CRi rates of
only 13% each in relapsed disease.65 Hence, as with FLT3 inhibitors,
attention has focused on combinations of GO with chemotherapy.
Hills et al. performed an individual-patient meta-analysis of five rele-
vant trials (UK NCRI 2, French Goelams group, French Alfa group and
US SWOG group 1 each) combining GO with 7 + 3 or FLAG-ida and
using data from 3325 adults, median age 58.66 There was no intertrial
heterogeneity, considering various endpoints. Although CR rates were
similar GO, significant reductions in risk of relapse with GO contrib-
uted to a survival benefit at 5 years confined to those with “favorable”
cytogenetics 55% vs 76% (95% confidence interval 0.31-0.73 for
reduction in risk of death) and with intermediate cytogenetics (34% vs
39%, HR 0.75-0.95). Administration of 3 mg/m 2 GO on days 1, 4, and
7 of chemotherapy was associated with the least toxicity and equal
benefit. Based on these data on September 1, 2017, the FDA
approved GO for adults with CD33 positive AML, and it should rou-
tinely be combined with 7 + 3 or FLAG-ida in those with ELN favor-
able or intermediate risk assuming an acceptable risk of TRM, as was
the case in the studies noted above. Amadori et al compared GO used
alone vs “best supportive care ‘only in patients over age 75, age 61-75
with performance status 3-4, or who declined’ intensive chemother-
apy”, finding a statistically significant (P = .005) but medically less sig-
nificant survival advantage for GO (medians of 5.9 vs 3.6 months) and
a CR + CRi rate of 27% (30/111).67
In an effort to better stratify patients likely to respond to GO + che-
motherapy Olombel et al. reported in 200 patients EFS and RFS were lon-
ger with GO than chemotherapy without GO only in those with high CD
33 expression (at least 70%) independent of cytogenetics and NPM1/
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FLT3 status.68 In contrast, Khan et al., examining 1583 younger and older
patients, found no relation between CD33 expression and outcome fol-
lowing GO in patients with “favorable (CBF)” cytogenetics, but a sugges-
tion in other cytogenetic groups that those in the lowest quartile of
2 69
CD33 expression might benefit from 6, rather than 3, mg/m GO dose.
CD33 single nucleotide polymorphisms (SNPs) regulate the
expression of CD33 isoforms. Certain SNPs denoted as TT result in a
lack of exon 2, resulting in absence of the CD33 IgV domain, which is
the antibody-binding site for GO, as well as diagnostic immunopheno-
70
typic panels. Lamba et al. found only children with the CC SNP (51%
of 816 children) which encodes a full exon 2 benefitted from addition
of GO to chemotherapy regardless of cytogenetics or CD33 expres-
71
sion. However, this finding has not been confirmed by the UK
NCRI72 : material for SNP determination was available in 536/2063
adults entered on their chemotherapy GO trials. The proportion of
patients with the CC SNP (47%) was similar to that in Lamba et al. and
as in Lamba et al. CD33 expression was lowest with the TT. However,
although the favorable cytogenetic group had the expected longer
survival when given chemotherapy + GO, SNP had no influence on
outcome. Similar results have been reported in adults by SWOG
(Othus personal communication). Currently we do not yet appear
ready to assign adults to receive GO on a basis other than cytogenet-
ics, especially considering likely differences in quantifying CD33
expression except if done in large specialized centers.
Development of improved anti-CD33 antibodies is being investi-
gated. For example, it might be advantageous to design an antibody in
which the CD33- anti CD33 binding site is closer to the cell surface as
experimental data suggest such proximity would enhance the efficacy
of CD3/CD33 bi-specific T-cell engagers (BiTEs), analogous to
CD3/CD19 BiTEs in ALL, or CD33 directed chimeric antigen receptor
(CAR) T-cells.73
4.6 | CPX 351 (“Vyxeos”)
CPX 351 is a liposomal formulation of cytarabine and daunorubicin at
a fixed 5:1 M ratio of cytarabine/daunorubicin that was determined
as optimum in preclinical testing. The liposomal encapsulation leads to
prolonged exposure to the two drugs.74 Lancet et al. randomized
309 patients aged 60-75 and PS 0-2, with either (a) prior cytotoxic
therapy, (b) antecedent MDS or CMML (receipt of azacytidine or
daunorubicin), or (c) WHO-defined MDS-like cytogenetic abnormali-
ties to either 7 + 3 (60 mg/m 2 daunorubicin daily × 3) or CPX-351.
CPX was associated with higher CR + CRi rates (48% vs 33%) and,
with a minimum follow-up of 13 months, longer EFS (HR = 0.74,
P = .02) and survival (HR = 0.69, P = .05, with medians of 10 vs
6 months). Sixty-day mortality was 21% with 7 + 3 and 13% with
75
CPX and toxicity was similar. About 34% of CPX and 25% of 7 + 3
patients received HCT; the transplanted CPX patients were older but
more often in CR than the transplanted 7 + 3 patients. A landmark
76
analysis suggested better post HCT survival in the CPX group
(Supporting Information Figure 2). Although this may have simply
reflected the higher proportion of CPX than 7 + 3 patients in CR/CRi,
it is plausible a higher proportion of CPX patients had no MRD in CR
or CRi There are also suggestions CPX may be particularly effective vs
7 + 3 in people with FLT3 ITD. Conversely, a multivariate analysis
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identified such conventional covariates as poorer PS and adverse
cytogenetics as associated with poorer rates of CR, EFS, and sur-
vival.77 Likewise, given the frequency with which people with second-
ary AML have previously received azacitidine, it is noteworthy the
benefit of CPX vs 7 + 3 appears limited to patients who have not
received azacitidine. Nonetheless the totality of evidence from the
phase 3 trial prompted the FDA on August 3, 2017 to approve CPX
351 for patients with therapy-related AML (t-AML) or AML with
MDS-related changes2 regardless of age even though the trial leading
to approval was conducted only in patients aged 60-75, and, as with
many trials, the proportion of eligible patients who participated in the
randomization (a convenient measure of selection bias) is unclear.40 It
is important to note the adverse prognostic significance of t-AML is
limited to patients who have received cytotoxic chemotherapy, rather
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than only surgery  XRT for a prior malignancy.78 Future directions
might include combinations with FLT3 inhibitors, or given lower
60-day mortality rates in the randomized trial, use at full dose in
patients at high risk of TRM for example, those with PS 3-4 or organ
dysfunction, who were generally not included in the randomized
trial.75 Results of trials of doses of CPX 67% or 33% those used in the
randomized trial in such patients were not better than those in histori-
cal controls.79 It is however clear CPX-351 is a viable option in fit
older patients with ELN intermediate risk18 “secondary AML” as
defined above.
4.7 | Venetoclax
Venetoclax is an oral inhibitor of the anti-apoptotic protein BCL-2
thought to mediate resistance to typical AML therapy. DiNardo
et al. administered the drug at daily doses of 400 800, or 1200 mg
daily together with either decitabine or azacytidine to 145 people
(median age 74, range 65-86) considered unfit for standard therapy
and with intermediate or adverse cytogenetics and noted a 30-day
death rate of 3%, CR rate of 35%, and a CR + CRi rate of 66%80
(Supporting Information Figure 3A).The latter rates were higher with
intermediate cytogenetics CR 41% vs 30%, CR + CRi 75% vs 57%.
Median survival was 18 months, although median time on study was
only 7 months. Similar results were reported with daily venetoclax
(600 mg) + low-dose cytarabine 20 m/m2 daily × 10 in 61 patients,
median age 74, range 66-87) likewise judged unfit for intensive ther-
apy: 30-day mortality rate 3%, CR rate 26%, CR + CRi rate 62%,
median survival about 1 year, with median follow-up about 1 year80
(Supporting Information Figure 3B)
Based on these data the FDA granted “breakthrough” therapy des-
ignation for venetoclax + either azacytidine or decitabine (on January
28, 2016) or + low-dose cytarabine (on July 28, 2017) for patients who
are ineligible for intensive therapy. Several questions remain. First, how
to define “ineligible”? Of note, although the patients in the venetoclax
studies described above were “older,” eligibility required PS 0-2 with
about 75%-80% having PS 0-1, that is, minimally symptomatic. Normal
organ function was presumably also required, recalling ELN 2017 rec-
ommendations that something other than older age is needed to con-
sider someone inappropriate for intensive induction, for example
performance status 3-4, comorbidities, or a high likelihood of resistance
to standard intensive induction.18 Will responsiveness to venetoclax +
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in all patients in the intermediate and, particularly worst, Breems
et al. prognostic groups certainly extends to older patients, who all
else being equal would be expected to do even worse than the
patients analyzed by Breems et al. and to all patients who are receiv-
ing a 2nd re-induction attempt after failing the first.136,137
Table 7 summarizes recommendations for management of R/R
AML. If feasible, allo HCT is favored in CR2 even in cases with long
initial CR1s and in which allo HCT was performed in CR1. A possible
exception may be cases in which allo HCT was done in CR1 but CR
duration was <6 months. Here, unless some very different approach is
taken to 2nd HCT the morbidities of the procedure may not be com-
mensurate with the benefits.
6.2 | Newer approaches
Perusal of clinicaltrials.gov indicates many new therapies are available
for R/R AML. Although this is undoubtedly encouraging, such avail-
ability suggests significant uncertainty as to which therapy is best.
Given interest in venetoclax and CPX-351 in newly diagnosed AML,
thoughts might turn to these in people not previously exposed.
DiNardo et al. treated 43 patients median age 68, 84% of whom were
receiving the drug as 2nd or later salvage, and 91% of whom received
the drug together with azacitidine, decitabine, or “low dose” cytara-
bine.138 Although the objective response rate (ORR: CR+ CRi + mar-
row leukemia free-state) was 21%), the CR rate was only 5%, the CRi
rate 7% and median survival was 3 months. Four of the nine
responses occurred in the eight patients with RUNX1 mutations. Feld-
man et al. noted CR rate of 5/20 at the CPX-351 dose subsequently
used in untreated patients; four of the five had initial CR1 durations
of at least 1 year.139 Despite the small numbers treated and the plau-
sible existence of various selection biases, it is difficult to view results
with venetoclax or CPX351 in R/R AML as materially superior to his-
torical results.
6.2.1 | Enasidenib, ivosidenib, and other targeted
therapies
Mutations in IDH2 occur in about 10% of AML patients and lead to
accumulation of R-2 hydroxyglutarate(HG), leading to DNA and his-
tone hypermethylation and consequent differentiation arrest of AML
TABLE 7 Management of relapsed/refractory AML
Number of prior Breems score (alternatively prior
re-induction attempts CR1 duration)
0 (1st salvage) 1-6 points
(>18 months)
0 (1st salvage) 7-9 points
(12-18 months)
0(1st salvage) 10-14 points
(<12 months)
1 or more (2nd or higher N/A
salvage)
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blasts. Enasidenib inhibits mutant IDH2 protein thus reducing ele-
vated HG levels and promoting differentiation. Stein et al. reported an
objective response rate of 39% (95% CI 28%-44%) among 109 adults
with R/R AML and IDH2 mutations who were given the 100 mg daily
dose used in the expansion cohort of the phase 2 study140 the CR and
CRi rates were 20% and 7%, respectively. In distinct contrast with
chemotherapy, the probability of CR or CRi on a given course
appeared similar until at least the sixth (Supporting Information
Figure 9). The most notable toxicity consistent with the drug's pro-
posed mechanism of action was a differentiation syndrome entirely
reminiscent of that following treatment of APL with all-trans retinoic
acid or arsenic trioxide and thus often accompanied by leukocytosis
and effectively treated with steroids141 ; the differentiation syndrome
tends to resolve, as does hyperbilirubinemia; whether it is associated
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with response is not clear. With a median follow-up of 8 months,
median survival was 9 months. As usual, it was longer in responders
but whether this was totally reflective of time spent in response,
rather than an inherently better prognosis is not clear, and the relation
between various types of “response” and survival time, after account-
ing for guarantee time, also remains to be resolved. Based on these
results, on August 1, 2017, the FDA approved enasidenib for treat-
ment of R/R AML characterized by an IDH2 mutation.
Of note, the median survival following administration of chemo-
therapies such as FLAG to R/R patients with an IDH2 mutations
resembles that seen after enasidenib142 This raises the possibility of
combining “intensive” chemotherapy with enasidenib to avoid devel-
opment of resistance. Examples such as GO or midostaurin suggest
the benefit of “targeted” therapies are likely to be much greater when
combined with chemotherapy than when used alone.87 The same may
apply with other targeted agents that show some, but limited, activity
in R/R AML (eg, the DOT1L inhibitor pinometostat which affects the
MLL rearrangement characteristic of 11q23 translocations,143 or the
IDH1 inhibitor inasidenib, which has been approved by the patients
with IDH1 mutations.144,145 An example of such a trial combines
7 + 3 with enasidenib (if IDH2 mutation) or ivosidenib (if IDH 1 muta-
tion) in newly diagnosed AML.145 Analysis of resistance to enasidenib
indicate that while levels of HG typically remain suppressed at relapse
mutant IDH clones which had persisted at relapse acquire additional
lesions (eg, 7q deletion or various mutations) which re-impose a
Re-induction therapy If CR is achieved
Similar to initial induction therapy, for Allo HCT if feasible; if not, auto HCT if
example, 7 + 3, FLAG  idarubicin, no MRD, or clinical trial
GCLAM (Halpern et al. phase 1/2
trial of GCLAM with dose-escalated
mitoxantrone for newly diagnosed
AML or other high-grade myeloid
neoplasms. Leukemia e-published
April 17,2018
As above or clinical trial As above
Clinical trial (consider allo HCT as part As above
of induction)
Clinical trial (consider allo HCT as part As above
of induction)
/
ESTEY
azacytidine or + low dose cytarabine depend on the same factors asso-
ciated with responsiveness to other therapies, noting the lower
81
response rate in people with TP53 mutations in the Wei et al. study
(Supporting Information Figure 3B) and with adverse cytogenetics in
81
the DiNardo et al. study? Might addition of venetoclax to 7 + 3 or
FLAG-ida improve outcomes in patients at low risk of TRM? Might ven-
toclax be useful in a post-remission setting, for example in people with
MRD after induction and/or “consolidation”? Several of these questions
will be addressed in upcoming trials (see https://www.clinicaltrials.gov/
ct2/results?term=venetoclax+%2B+AML&Search=Search), including
those comparing azacytidine (or decitabine)  venetoclax or low dose
cytarabine  venetoclax. Given the issue of ineligibility noted above a
comparison of venetoclax + azacytidine (or low dose cytarabine) to
7 + 3 might be of academic interest.
4.8 | Ten-day decitabine
Although used to treat AML for many years, decitabine has typically
2
been given for 5 days at a daily dose of 20 mg/m . However, a paper
by Welch et al. reporting a rate of 100% in 21 patients with TP53
mutations, who received 20 mg/m 2 daily × 10 days has received
much attention.82 The CR rate was 19%, the remainder of the
response being varying forms of CRi with <5% marrow blasts by mor-
phology. While reductions in TP53 mutation burden were universal,
they were invariably incomplete, no more frequent in people with
than without blood count recovery, with remission duration similar in
these two groups. Remissions generally lasted less than 1 year and
median survival in TP53 mutated patients was 12.8 months, which
however resembled survival in patients without TP53 mutations; such
similarity was, as the authors note, remarkable.
Although these results have likely prompted considerable use of
the 10-day schedule, it not clear that the results can be generalized.
Efforts are in progress to address this question in a large single-arm
study. A randomized single-center comparison of 5- and 10-days
schedules of decitabine closed because the probability the 10-day
schedule would be superior was low, although the statistical properties
of the design in TP53 mutated patients was not noted (Short N, pre-
sented at Acute Leukemia Forum, Newport Beach CA 2018). Although
there is no obvious harm in administering 10 rather than 5 days of deci-
tabine, perhaps the paper's principal value was demonstration of the
complexity of relapse, with at least in some cases, the dominant clone
at relapse, not the dominant one at diagnosis, suggesting in some cases
treatment can facilitate relapse. The dissociation of CR (vs CRi) from
survival suggests this relation may vary by treatment.
4.9 | Dasatinib
About 25%-35% of cases of CBF AML (ie, AML with t[8;21], inv [16]
or t[16;16]) have mutations in C-KIT [Figure 1], which have been asso-
ciated with shorter remissions. 83 Cases without mutations often have
KIT overexpression, and overexpression is more common in CBF AML
than in other types.83 Dasatinib inhibits not only the BCR-ABL kinase
of CML but also KIT kinase including that encoded by KIT mutations
83
that are resistant to other kinases. The German AMLSG added dasa-
tinib on days 8-21 after beginning 7 + 3, days 6-28 of each of 4 cycles
1277
of post CR high-dose cytarabine, and thereafter alone at 100 mg daily
× 1 year as “maintenance.” 83 Median age was the expected 50 years
and the CR/CRi rate was expectedly high 94% (84/89), 92% in
37 patients with t(8;21), and 96% in 52 with inv 16. However, with
median follow-up of 4 years, 4-year relapse rate is less 33% vs 43%
and 4-year EFS (but not survival) longer (58% vs 48%) with addition of
dasatinib. 83 Toxicity, including pleural effusions in about 8%, was not
undue. At relapse, KIT mutation was lost in 5/9 patients presenting
with these mutations, again speaking to the complexity of relapse.
Alliance has reported similar results, while also finding addition of
dasatinib abrogated the negative impact of KIT mutations.84 Both
AMLSG and Alliance are following up with randomization to intensive
chemotherapy  dasatinib.
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
4.10 | “Beat AML” and targeted therapy
Numerous drugs have been designed to inhibit the “downstream” con-
sequences of the many mutations observed in AML (although only a
few mutations are usually observed in a given patient.85 These conse-
quences might for example be functionally abnormal proteins that ini-
tiate/maintain the disease. Given the heterogeneity of AML numerous
such “targeted agents” are being investigated, midostaurin, and the
IDH2 inhibitor enasidenib, described further below, are prime exam-
ples. The Leukemia and Lymphoma Society is sponsoring a “BEAT
AML” trial designed to examine a variety of these agents.86 The trial
plans to accrue 500 patients aged 60 or above with newly diagnosed
AML. The first aim is to assess the feasibility of enrolling patients,
based on mutation status, within 7 days of procurement of a marrow
sample, which is sent to a central lab. Table 3 indicates the relation
between mutation status and assignment to therapy in BEAT AML.
An issue is the use of the targeted agent alone for, in some cases,
several cycles (Table 3). It has been pointed out agents such as midos-
taurin and GO have only modest activity when used alone but with
considerable incremental benefit upon addition of chemotherapy.87
However, given advances in therapy of infections it is likely rapid
attainment of CR, and a concomitant neutrophil count >1000/μL is
less important than previously. Indeed, it has been noted a majority of
survival time is, currently, not uncommonly spent out of CR (Shaw C
presented at Society of Hematology Oncology [SOHO] meeting,
September, 2017). Hence the risk in receiving a targeted agent alone
for a limited time, as in BEAT AML, is probably quite low.
4.11 | Recommendations for initial induction
therapy
Table 4 considers standard therapy for both ELN favorable or interme-
diate risk disease to encompass GO or midostaurin, the latter for
patients with a FLT3 ITD or TKD. Patients with CBF AML (ELN favor-
able) rarely have FLT3 aberrations (Figure 1) and whether any such
patients should receive both GO and midostaurin is hard to decipher
absent more data; the same is true for the larger group of ELN interme-
diate patients with a FLT3 aberration. A lack of data makes it difficult
to know whether midostaurin should be administered to all patients, as
suggested by the FDA, or only patients aged <60 as in the trial leading
to approval; the same is true for CPX-351 (approved for all but tested
/
1278 ESTEY

TABLE 3 Arms of “BEAT AML” (see reference 86)

Mutation “Targeted” agent Other therapies

None, or RUNX1/RUNX1T1[t(8;21)],or Samalizumab Smalizumab given with 7 + 3 for induction,
used alone for “maintenance”
CBFB/MYH11 (inv 16) (p13;q22)or t (antibody against CD200 which is
(16;16)(p13;q22) correlated with frequency
immunosuppressive T regulatory cells
(Leukemia 2012;26(9) 2146-48))
None, or TET 2, or IDH1, or WT1 BI 836858 BI 838568 given with azacitidine for
induction and “maintenance”
(anti CD33 antibody augments antibody
dependent cellular toxicity after
treatment with decitabine; [Vasu
et al. Blood 2016;127:2879-2889]
IDH2 Enasidenib Add azacitidine if neither CR nor CRi after
5 cycles enasidenib
(IDH2 inhibitor, see below)
MLL Entospletinib Add azacitidine after 1-4 cycles

Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].

entospletinib if no CR/CRi or
SYK (spleen tyrosine kinase) inhibitor
“progressive disease”
J Hematol Oncol 2017; Jul 28;10(1):145.
doi: 10.1186/s13045-017-0512-1.
TP53 Entospletinib Add 2 cycles decitabine after 1 cycle
entospletinib if subsequent induction
SYK inhibitor
needed; at least 1 of the 2 cycles must
give Decitabine × 10 days
NPM1 with no FLT3 ITD Entospletinib Entospletinib given with 7 + 3 if age <75
with PS 0-2 ; if age >75 or PS >2 add
SYK inhibitor
azacitidine if no CR/CRi after 1 cycle
entospletinib
TP53 Pevonedistat Pevonedistat given with azacitidine ×
4 cycles and then for “maintenance”
(inhibitor of the NEDD8-activating enzyme,
combined with azacitidine reported to
improve response rate of latter [ Swords
et al. Blood 2018;131:1415-24]

only in ages 60-75); here, however I have simply followed the FDA's
labeling instructions. Less intensive therapy seems intuitively prefera-
43
ble in patients at higher risk of TRM, but some data question this
resolution awaits a randomized trial as does the role of CPX 351 vs
chemotherapy + GO or + midostaurin in secondary AML. It is plausible
some less intense therapy might be not only less toxic but more effec-
tive than today's more intensive therapy or that CPX351 might have a
role in de novo AML, for example if characterized by FLT3 ITD. These
and other questions can only be answered in clinical trials and given
the unsatisfactory outcomes of even patients at low risk of TRM in the
ELN intermediate group (<50% long term survival) a case can be made
that the first option even in such patients should be a clinical trial. This
and is certainly true in patients at higher risk of TRM, criteria for which
should not be based exclusively on age. A problem of course is that
many patients at higher risk of TRM are currently excluded from trials
based on poor performance status or comorbidities, making it difficult
to generalize the results to people who are not only older but also less
fit.40 Montalban-Bravo et al. have demonstrated the potentially favor-
able benefit/risk ratio of a trial in cases where eligibility criteria are
essentially ineligibility for standard trials. 88

TABLE 4 Recommendations for initial induction therapy

ELN group TRM risk lowa TRM risk higherb

c
“Favorable” 7 + 3 + GO or FLAG-ida + GO Azacytidine (or decitabine) + GO c or clinical
trial
“Intermediate” 7 + 3 + GO or FLAG-ida + GO d,e Azacytidine (or decitabine) + GO d,e or
clinical trial, for example, combinations
Or clinical trial, for example, combinations
involving venetoclax
of 7 + 3 + venetoclax
Adverse Clinical trial, for example, “BEAT AML” or Clinical trial, for example, “BEAT AML” or
combinations involving venetoclax combinations involving venetoclax
+7 + 3 or FLAG-ida; add midostaurin if
add midostaurin if FLT3 ITD positivee
FLT3 ITD or TKD positivee
a
Usually age <70-75 with performance status <2 and no cardiac, hepatic, renal dysfunction, and albumin >3.5
b
Usually age >70 plus performance status 2-4 and/or 1 of above comorbidities
c
Consider midostaurin if FLT3 ITD positive (allelic ratio <0.5)
d
Midostaurin if FLT3 ITD or TKD
e
Consider CPX −351 if secondary AML as described in Ref. 75

/
ESTEY
differentiation block146 again suggesting the importance of combining
several different targeted agents with each other or with chemother-
apy to prevent emergence of resistance.
The successes of immunotherapy in various solid tumors has led
to an upsurge of interest in immunotherapy in AML.147 Because AML
is not notably immunogenic per se immune-modulatory drugs (ipilimu-
mab, nivolumab, and pembrolizumb) are being combined, often with
decitabine or azacitidine; several trials are in progress (reviewed in ref-
erence 148). Azacitidine and/or decitabine have effects that in princi-
ple may be favorable (eg, increased receptor expression on T cells or
antigen presentation sites on AML blasts) or unfavorable (eg,
increased PD-1 or CTLA-4 expression on T-cells leading to T-cell
exhaustion. Eventually this type therapy may have more success when
tested in patients in remission  MRD (see below).
BiTEs are described in the section on gemtuzumab ozogamicin
above.
6.2.2 | Allogeneic HCT
The success of allo HCT is in considerable measure due to immune
effect exerted by donor T- and NK-cells. Allo HCT is the therapy often
viewed as most likely to cure R/R AML. However, because it is typi-
cally not done until CR2 is observed only a small minority of R/R
patients receive it. For example, only 14% of patients in Breems
et al.’s worst prognostic group received HCT as initial salvage therapy
for 1st relapse.134 This has led to interest in an “early transplant”
approach in which patients receive intensive re-induction therapy, fol-
lowed by “obligatory” HCT several weeks after administration of che-
motherapy. Because it is well-known that HCT done in relapse is
much less effective than HCT in CR the idea is to reduce the amount
of disease prior to HCT while still performing HCT without however
requiring achievement of CR. For example, Middeke et al.149 gave
CLARA (clofarabine + ara-C, 1 g/m2 daily × 5) to 84 patients, median
age 61, 43 relapsed after a median CR1 duration of 6 months,
41 refractory to initial therapy. 52% of the patients had <10% marrow
blasts on day 15 and 56 of the 84 patients received HCT. A total of
39 of the 84 had a donor identified prior to enrollment; 32 of these
39 received HCT a median of 29 days after enrollment, as did, at a
median of 37 days, 24 of the 45 without a donor identified at enroll-
ment. The major factor associated with performance of HCT was pre-
enrollment marrow blast % (median 22%, range 5%-92% HCT vs
median 60%, range 17%-90% no HCT. Conditioning was clofarabine
2 2
(30 mg/m days minus 6 to minus 3) + melphalan (140 mg/m on day
minus 2). With a median follow-up of 40 months 3-year survival rate
was 40% (95% CI 31-52%), including 36% for refractory disease, 44%
for relapsed disease, and 45% for initial CR1 duration <6 months
(n = 21). 149 While these results compare very favorably to those
expected without early HCT it remains unclear whether they will
prove generalizable, noting the results largely reflect outcomes in the
75% of patients with HCT CI scores <3.
The possibility of a “bridge to HCT” is often invoked when noting
responses such as CRi or marrow-leukemia free state following single-
agent targeted therapies. However, these responses seem more likely
150
to be associated with MRD than CR Given the association between
1287
pre-HCT MRD and post-HCT relapse it seems natural to question the
value of bridge to HCT when underlaid by these responses.
In any event relapse is the principal cause of failure of HCT. Aza-
citidine may be the most widely used treatment for post HCT relapse.
After administering the drug at the usual 75 mg/m2 daily × 5 or
7 days to 181 patients with morphologic relapse (>5%) blasts after
HCT, Craddock et al. devised a prognostic index based on time from
HCT to relapse (2 points if <6 months, 1-2 if 6-12 months, 0 if
>12 months) and marrow blast % (1 point if > the median 20%, 0 oth-
erwise). 2 year survival rates were 37%, 15% and 3% in people with
scores of 0, 1-2, and 3 who constituted 18%, 28%, and 54% of the
patients, respectively; survival rates were paralleled by CR (CR + PR)
rates of 34% (49%), 14%,(28%), and 8% (17%). 151 Addition of donor
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
lymphocytes infusions (DLI) had no effect, in keeping with older
reports of the typical inefficacy of DLI and withdrawal of immunosup-
pression. 152 As with relapse in general, standard approaches are of lit-
tle use except in people with “long” CR durations, for example,
>1 year, more than justifying referral of patients for clinical trials, for
example, those that might augment the GVL effect.
7 | NEWER SCENARIOS FOR TE STING NEW
AGENTS
Conventionally new agents are tested in relapsed or adverse-risk
newly diagnosed AML. This practice may predispose to discarding
these agents, which however might perform better in less advanced
disease. One possibility is in the setting of MRD. However, enrollment
into many trials of new drugs is restricted to morphological relapse
(>5% blasts). It is plausible response rates to new drugs might be
higher if tested in cases where MRD is the only evidence of disease.
Justification would be the very high predictive value of a positive
MRD test for relapse, particularly in people with ELN 2017 adverse-
risk pretreatment, the usually short (<1 year) interval between appear-
ance of MRD and morphologic relapse, and the generally limited side
effects of “targeted” therapies, resulting in likely favorable/benefit risk
ratios when used to treat MRD. Indeed, it is likely the next few years
will see more use of targeted therapies to treat MRD. These years
may also see the partial replacement of standard morphologic assess-
ment of marrow to detect relapse by MRD-based techniques; it
appears that when MFC testing is negative morphology will inevitably
show <5% blasts, below the threshold for morphologic relapse.153
Treating patients with MRD only AML would allow comparison of
outcomes when the same therapy is used to treat an MRD only
relapse and morphologic relapse. It would also allow testing of the yet
unproven, but eminently plausible, hypothesis that reduction in MRD
would lead to better outcomes. A further step would allow testing of
new drugs in cases that are MRD negative but still at relatively high
risk of relapse based on pretreatment factors.
Finally, we may overestimate how much we know about the tar-
gets of targeted therapy. We noted above the beneficial effect of sor-
afenib, often thought of as a FLT 3 inhibitor, when added to 7 + 3,
seem similar in people regardless of whether they have a FLT3 ITD.58
Hence once a targeted therapy demonstrates activity in patients with
/
ESTEY 1279

TABLE 5 Incorporation of MRD data with pretreatment ELN risk score to determine post-remission therapy

Risk of non-relapse mortality

(NRM) post-HCT
Risk of relapse at 1-2 years justifying allo. HCT (HCT-CI score Possible subsequent treatment if
Pretreatment MRD status after two without allogeneic HCT associated with that risk) excessive risk/benefit ratio with
ELN risk courses therapy ( 94,96–98) (see reference 111) allogeneic HCT
Favorable Positive 40-50% if <20-25% Clinical trial
CBF (≤2)
50-60% if NPM1+/FLT3
negative
Negative 10% (CBF) None Ara-C 1 g/m 2 BID days 1,2,3 ×
3 cycles + GO (or midostaurin if
15-20% if NPM+/FLT3
FLT3 positive)
negative
Intermediate Positive 60-75% <30% Clinical trial
(≤3-4)

Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].

Negative 20% < 10% Clofarabine + ara-C, autologous
HCT,
(<1)
Adverse Positive 90-100% <40-50% Clinical trial
(≤5)
Negative 60% <20-25% (≤2) Autologous HCT, clofarabine +
ara-clinical trial

FIGURE 6 Comparison of outcomes in patients in CR without MRD by MFC, in patients in CR but with MRD by MFC and in patients with
“active disease”(>5% blasts by morphology) (see reference 95)

/
1288
the target it may be potentially valuable to assess outcome in people
without the target. 87
CONFLICT OF INTEREST
Nothing to report.
REFERENCES
1. Lazarevic V, Orsmark-Pietras C, Lilljebjorn H, et al. Isolated myelosar-
coma is characterized by recurrent NFE2 mutations and concurrent
preleukemic clones in the bone marrow. Blood. 2018;131:577-581.
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the
World Health Organization classification of myeloid neoplasms and
acute leukemia. Blood. 2016;127:2391-2405.
3. Walter RB, Othus M, Borthakur G, et al. Prediction of early death fol-
lowing induction therapy for newly diagnosed acute myeloid leuke-
mia with pretreatment risk scores: a novel paradigm for treatment
assignment. J Clin Oncol. 2011;29(33):4417-4424.
4. Estey E, Thall P, Beran M, et al. Effect of diagnosis (refractory anemia
with excess blasts, refractory anemia with excess blasts in transfor-
mation, or acute myeloid leukemia [AML]) on outcome of AML-type
chemotherapy. Blood. 1997;90:2969-2977.
5. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia
ontogeny is defined by distinct somatic mutations. Blood. 2015;125:
1367-1376.
6. Walter MJ. What came first: MDS or AML? Blood. 2015;125:
1357-1358.
7. Shlush LI. Age-related clonal hematopoiesis. Blood. 2018;131:
496-504.
8. University of Chicago Hematopoietic Malignancies Cancer Risk
Team. How I diagnose and manage individuals at risk for inherited
myeloid malignancies. Blood . 2016;128:1800-1813.
9. Godley LA, Shimamura A. Genetic predisposition to hematologic
malignancies: management and surveillance. Blood . 2017;130:
424-432.
10. Medeiros BC, Satram-Hoang S, Hurst D, et al. Big data analysis of
treatment patterns and outcomes among elderly acute myeloid leu-
kemia patients in the United States. Ann Hematol. 2015;94:
1127-1138.
11. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leu-
kemia: real world data on decision to treat and outcomes from the
Swedish acute leukemia registry. Blood. 2009;113:4179-4187.
12. Juliusson G, Abrahamsson J, Lazarevic V, et al. Prevalence and char-
acteristics of survivors from acute myeloid leukemia in Sweden. Leu-
kemia. 2017;31:728-731.
13. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study
of azacitidine vs conventional care regimens in older patients with
newly diagnosed AML with >30% blasts. Blood. 2015;126:291-299.
14. Walter RB, Othus M, Borthakur G, et al. Prediction of early death
after induction therapy for newly diagnosed acute myeloid leukemia
with pretreatment risk scores: a novel paradigm for treatment assign-
ment. J Clin Oncol. 2011;29(33):4417-4423.
15. Othus M, Kantarjian H, Petersdorf S, et al. Declining rates of
treatment-related mortality in patients with newly diagnosed AML
given 'intense' induction regimens: a report from SWOG and MD
Anderson. Leukemia. 2014;28:289-292.
16. Halpern AB, Lyman GH, Walsh TJ, et al. Primary antifungal prophy-
laxis during curative-intent therapy for acute myeloid leukemia.
Blood. 2015;126:2790-2797.
17. O'Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leuke-
mia, version 3.2017, NCCN clinical practice guidelines in oncology.
Journal of the National Comprehensive Cancer Network : JNCCN. 2017;
15:926-957.
18. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of
AML in adults: 2017 ELN recommendations from an international
expert panel. Blood. 2017;129:424-447.
ESTEY
19. Sorror ML, Storer BE, Fathi AT, et al. Development and validation of
a novel acute myeloid leukemia-composite model to estimate risks of
mortality. JAMA Oncol. 2017;3:1675-1682.
20. Ho G, Wun T, Muffly L, et al. Decreased early mortality associated
with the treatment of acute myeloid leukemia at National Cancer
Institute-designated cancer centers in California. Cancer. 2018;124:
1938-1945.
21. stgård LSG, Norgaard M, Medeiros BC, et al. Associations between
cohabitation status, treatment, and outcome in AML patients: a
national population-based study. Blood. 2018 Jun 14;131(24):
2730-2733.
22. stgård LSG, Norgaard M, Medeiros BC, et al. Effects of education
and income on treatment and outcome in patients with acute mye-
loid leukemia in a tax-supported health care system: a National
Population-Based Cohort Study. J Clin Oncol. 2017;35:3678-3687.
23. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid
leukemia. Blood. 2006;107:3481-3485.
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
24. Yanada M, Garcia-Manero G, Borthakur G, et al. Relapse and death
during first remission in acute myeloid leukemia. Haematologica.
2008;93:633-634.
25. Harada Y, Nagata Y, Kihara R, et al. Prognostic analysis according to
the 2017 ELN risk stratification by genetics in adult acute myeloid
leukemia patients treated in the Japan Adult Leukemia Study Group
(JALSG) AML201 study. Leukemia Res. 2018;66:20-27.
26. Eisfeld AK, Kohlschmidt J, Mrozek K, et al. Mutation patterns identify
adult patients with de novo acute myeloid leukemia aged 60 years or
older who respond favorably to standard chemotherapy: an analysis
of alliance studies. Leukemia. 2018;32:1338-1348.
27. Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of
NPM1 mutations in the absence of FLT3-internal tandem duplication
in older patients with acute myeloid leukemia: a SWOG and UK
National Cancer Research Institute/Medical Research Council report.
J Clin Oncol. 2015;33:1157-1164.
28. Patel SS, Kuo FC, Gibson CJ, et al. High NPM1 mutant allele burden
at diagnosis predicts unfavorable outcomes in de novo AML. Blood.
2018 Jun 21;131(25):2816-2825.
29. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classifica-
tion and prognosis in acute myeloid leukemia. N Engl J Med. 2016;
374:2209-2221.
30. Kuo FC, Mar BG, Lindsley RC, et al. The relative utilities of
genome-wide, gene panel, and individual gene sequencing in clinical
practice. Blood. 2017;130:433-439.
31. Duployez N, Marceau-Renaut A, Boissel N, et al. Comprehensive
mutational profiling of core binding factor acute myeloid leukemia.
Blood. 2016;127:2451-2459.
32. Itzykson R, Duployez N, Fasan A, et al. Clonal interference of signal-
ing mutations holds prognostic relevance in core binding factor acute
myeloid leukemia. Blood . 2018 Jul 12;132(2):187-196.
33. Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis to
treatment initiation predicts survival in younger, but not older, acute
myeloid leukemia patients. Blood. 2009;113:28-36.
34. Bertoli S, Berard E, Huguet F, et al. Time from diagnosis to intensive
chemotherapy initiation does not adversely impact the outcome of
patients with acute myeloid leukemia. Blood. 2013;121:2618-2626.
35. Takahashi K, Patel K, Bueso-Ramos C, et al. Clinical implications of
TP53 mutations in myelodysplastic syndromes treated with hypo-
methylating agents. Oncotarget . 2016;7:14172-14187.
36. Estey E, Othus M, Lee SJ, et al. New drug approvals in acute myeloid
leukemia: what's the best end point? Leukemia. 2016;30:521-525.
37. Estey E, Gale RP. How good are we at predicting the fate of someone
with acute myeloid leukaemia? Leukemia. 2017;31:1255-1258.
38. Othus M, Sekeres MA, Nand S, et al. Complete remissions (CRs) with
Azacitidine regimens compared to Crs with 7+3 induction chemo-
therapy and the effect on overall survival. Blood. 2016;128:
1613-1613.
39. Othus M, Garcia-Manero G, Godwin J, et al. Associations between
complete remissions (CRs) with 7+3 induction chemotherapy for
acute myeloid leukemia and 2-3 year survival ("potential cure") over
the past four decades: analysis of SWOG trial data. Blood. 2017;130:
1301-1301.
/
1280
5 | POST-REMISSION THERAPY
5.1 | Risk stratification: Importance of post-
treatment MRD
Once remission (CR or CRi) is observed physicians must decide
whether to proceed to hematopoietic cell transplant (HCT, typically
allogeneic in the U.S. and either allogeneic or autologous elsewhere)
to prevent relapse (up to Ref. 88, Table 5 and Figure 6). In general, the
risk of NRM is greater with HCT (particularly allogenic), while the risk
of relapse is less with HCT (particularly allogeneic). Quantifying each
risk with HCT vs non HCT approaches is critical in deciding between
them. For example, a plausible >10% improvement in relapse-free sur-
vival after allo HCT has been proposed to justify the potential long-
term risks of allo HCT, for example, chronic graft-vs-host disease and
development of malignancies due to immunosuppressive therapy.
Essentially all patients in the ELN 2017 adverse risk category, most in
the intermediate risk, and almost none in the “favorable” risk catego-
ries would meet this criterion. If it is decided the risk of relapse is rela-
tively low based on ELN 2017 without HCT, the most commonly used
post remission therapy is probably “high-dose” cytarabine, often given
as 3 g/m2 every 12 hours on days 1, 3, and 5. However, a German-
Austrian AML Study Group found administration of this dose on days
1, 2, and 3 to 392 patients was associated with a median 4-day reduc-
tion in time to ANC >500 from start of chemotherapy and with fewer
platelet transfusions than in 176 historical patients given the 1, 3, and
5 schedule.89 Cytarabine doses of 1 g/m2 twice daily for 3-4 days for
three courses after CR is achieved are very probably as effective as
higher doses and/or more courses irrespective of cytogenetic group.90
Furthermore, after randomizing 221 adults age 18-59 in the interme-
diate or adverse ELN 2010 groups, but seemingly without a donor for
HCT, between cytarabine in the usual 3 g/m2 schedule and cytarabine
2 2
1 g/m daily X5 plus clofarabine 30 mg/m daily X5 (CLARA) both
preceded by G-CSF, Thomas et al. reported a lower incidence of
relapse (34% vs 46% at 2 years P = .025) accompanied by longer RFS
(but not survival) with CLARA regardless of risk group, raising the
question whether CLARA should constitute standard post-remission
91
therapy in such patients.
However, basing post-remission therapy exclusively on risk of
relapse determined by pretreatment information is problematic, since,
as discussed above, in these instances we likely overestimate our abil-
37
ity to forecast prognosis. It is intuitive knowledge gained after treat-
ment begins might increase this ability. Means to this end might for
example include assessment of disease status 2-3 weeks post treat-
ment. However, most attention has focused on the presence of mea-
surable residual disease (MRD) even though conventional criteria for
CR are met. Although criteria for CR are often considered to include
only neutrophil and platelet count >1000/μL and >100 000/μL,
respectively, Danish investigators have noted the association between
continued receipt of red cell transfusions at time of CR and increased
risk of relapse.92
MRD is assessed using MFC or molecular means. The 2018 ELN
MRD guidelines provide technical details.93 Using at least 8-colors to
detect abnormal antigen patterns MFC can detect one abnormal cell
among 10 000 normal ones (sensitivity 10[−4]) and using “different
ESTEY
from normal” methodology is applicable in almost all cases. Molecular
techniques can be divided into real-time PCR and next generation
sequencing (NGS) . PCR provides sensitivity of 10(−4) to 10(−6) but is
limited to the 40%-50% of patients with the fusion transcripts
RUNX1-RUNX1T1 (characteristic of t[8;21]), CBFB-MYH11 [inv 16]
or t[16;16]) or with an NPM1 mutation.93 In contrast, NGS can, theo-
retically, be applied to all leukemia specific genetic aberrations. How-
ever, some genes are not suitable for MRD detection either because,
although positive at diagnosis, may be negative at morphologic relapse
(eg, FLT3) or because they are associated with age-related clonal
hematopoiesis7 and, as such, may have arisen before development of
AML. At least with molecular methods, peripheral blood is usually
10-fold less sensitive than marrow, although blood can be sampled
more frequently, which in principle might increase its sensitivity.
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
MRD has been assessed upon achievement of CR (after 1 or
2 induction cycles), after completion of “consolidation” therapy, or
subsequently.93 Which of these is optimal, or whether it is preferable
to assess MRD at different times, focusing on an increase or decrease
rather than a single result, is unsettled.93 Likewise, the criterion for a
positive test (eg, >0% or >0.01% by MFC) is unclear, as is whether
patients who are MRD negative but have only CRi (ie, incomplete
count recovery) have the same prognosis as patients who are in CR
but are MRD positive. MRD testing lacks standardization (although
the same can be said of morphologic evaluation). Nonetheless, despite
these issues MRD detection has unambiguously been shown to have
a high positive predictive value for subsequent morphologic relapse,
which typically occurs within 12 months of detection of MRD. Ter-
wijn et al.94 showed higher rates of relapse at 1 year in patients who
remained MFC- positive after 2 cycles of therapy regardless of whether
cytogenetics were “favorable” (40% vs 5%), “intermediate” (60% vs 20%),
or “adverse” (100% vs 50%). The unfavorable effect of MRD by MFC
remains after allogeneic HCT; thus Araki et al.95 have reported risk of
relapse following HCT in people who have <5% morphologic blasts but
are MFC positive pre-HCT is closer to that seen in people receiving HCT
with >5% blasts (“active AML”) than to people who are MFC negative pre
HCT (Figure 6). Regarding PCR, Ivey at al. demonstrated the 15% of
patients with intermediate-risk AML and pretreatment NPM mutations
who were in presumed CR but remained NPM positive in blood after
2 cycles of induction therapy had an 86% cumulative incidence of
relapse vs 34% for NPM negative patients96 (Figure 7). Multivariate anal-
ysis indicated persistent NPM positivity in blood was the sole predictor
of relapse and had similar effects in people with or without FLT3 muta-
tions (Figure 7). Likewise, less than 3 log reduction in PCR transcripts for
RUNX1-RUNX1T1 or CBFB-MYH11 after high-dose cytarabine “consol-
idation” was associated with a 3-year cumulative incidence of relapse of
54% vs 22% for patients with the presumably favorable CBF AML and
reduction in transcripts was the only factor identified with relapse in mul-
tivariate analysis, including pretreatment KIT mutations.97
Attention has more recently turned to assessment of post-
treatment persistence of a variety of mutations assessed using NGS.
Jongen-Lavrenic et al.98 found one or more mutations amenable to
NGS testing in 430 of 482 adults age <66 years (average 2.9 muta-
tions per patient). Testing in these 430 was done in remission (CR or
CRi) within 21 days to 4 months after receipt of a second course of
therapy, with mutations found to persist in 51% of patients. These
/
ESTEY
40. Estey E, Gale R, Sekeres M. New drug approvals in acute myeloid leu-
kemia: uses and abuses. Leukemia. 2018 Jun 6. https://doi.org/10.
1038/s41375-018-0168-z In press.
41. Boddu PC, Kantarjian HM, Ravandi F, et al. Characteristics and out-
comes of older patients with secondary acute myeloid leukemia
according to treatment approach. Cancer. 2017;123:3050-3060.
42. Quintas-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic ther-
apy is associated with similar survival compared with intensive che-
motherapy in older patients with newly diagnosed acute myeloid
leukemia. Blood. 2012;120:4840-4845.
43. Sorror M, Storer B, Elsawy M, et al. Intensive versus non-intensive
induction therapy for patients (pts) with newly diagnosed acute mye-
loid leukemia (AML) using two different novel prognostic models.
Blood. 2016;128:216.
44. Desoutter J, Gay J, Berthon C, et al. Molecular prognostic factors in
acute myeloid leukemia receiving first-line therapy with azacitidine.
Leukemia. 2016;30:1416-1418.
45. Prata PH, Bally C, Prebet T, et al. NPM1 mutation is not associated
with prolonged complete remission in acute myeloid leukemia
patients treated with hypomethylating agents. Haematologica. 2018
May 10. https://doi.org/10.3324/haematol.2018.189886 In press.
46. Bello C, Yu D, Komrokji RS, et al. Outcomes after induction chemo-
therapy in patients with acute myeloid leukemia arising from myelo-
dysplastic syndrome. Cancer. 2011;117:1463-1469.
47. Krug U, Berdel WE, Gale RP, et al. Increasing intensity of therapies
assigned at diagnosis does not improve survival of adults with acute
myeloid leukemia. Leukemia . 2016;30:1230-1236.
48. Garcia-Manero G, Othus M, Pagel J, et al. A randomized phase III
study of standard Cytarabine plus Daunorubicin (7+3) therapy versus
Idarubicin with high dose Cytarabine (IA) with or without Vorinostat
(IA+V) in younger patients with previously untreated acute myeloid
leukemia. Blood. 2016;128:901.
49. Burnett AK, Russell NH, Hills RK, et al. Optimization of chemother-
apy for younger patients with acute myeloid leukemia: results of the
medical research council AML15 trial. J Clin Oncol. 2013;31:
3360-3368.
50. Burnett AK, Russell NH, Hills RK, et al. A randomized comparison of
daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from
the UK NCRI AML17 trial in 1206 patients. Blood. 2015;125:
3878-3885.
51. Burnett AK, Russell NH, Hills RK. Higher daunorubicin exposure ben-
efits FLT3 mutated acute myeloid leukemia. Blood. 2016;128:
449-452.
52. Löwenberg B, Pabst T, Maertens J, et al. Therapeutic value of clofar-
abine in younger and middle-aged (18-65 years) adults with newly
diagnosed AML. Blood. 2017;129:1636-1645.
53. Halpern AB, Othus M, Huebner EM, et al. Phase 1/2 trial of GCLAM
with dose-escalated mitoxantrone for newly diagnosed AML or other
high-grade myeloid neoplasms. Leukemia. 2018 Apr 17. https://doi.
org/10.1038/s41375-018-0135-8.
54. Wei AH, Tiong IS. Midostaurin, enasidenib, CPX-351, gemtuzumab
ozogamicin, and venetoclax bring new hope to AML. Blood. 2017;
130:2469-2474.
55. Lazenby M, Gilkes AF, Marrin C, et al. The prognostic relevance of
flt3 and npm1 mutations on older patients treated intensively or
non-intensively: a study of 1312 patients in the UK NCRI AML16
trial. Leukemia. 2014;28:1953-1959.
56. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemo-
therapy for acute myeloid leukemia with a FLT3 mutation. N Engl J
Med. 2017;377:454-464.
57. Larson RA, Mandrekar SJ, Sanford BL, et al. An analysis of mainte-
nance therapy and post-Midostaurin outcomes in the international
prospective randomized, placebo-controlled, double-blind trial
(CALGB 10603/RATIFY [alliance]) for newly diagnosed acute mye-
loid leukemia (AML) patients with FLT3 mutations. Blood. 2017;
130:145.
58. Röllig C, Serve H, Huttmann A, et al. Addition of sorafenib versus pla-
cebo to standard therapy in patients aged 60 years or younger with
newly diagnosed acute myeloid leukaemia (SORAML): a multicentre,
phase 2, randomised controlled trial. Lancet Oncol. 2015;16:
1691-1699.
1289
59. Serve H, Krug U, Wagner R, et al. Sorafenib in combination with
intensive chemotherapy in elderly patients with acute myeloid leuke-
mia: results from a randomized, placebo-controlled trial. J Clin Oncol.
2013;31:3110-3118.
60. Levis M. The current therapeutic landscape of FLT3 inhibitors. Blood
Adv. 2017;1:1944.
61. Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor
of FLT3 with activity against resistance-conferring point mutants.
Blood. 2014;123:94-100.
62. Gallipoli P, Giotopoulos G, Tzelepis K, et al. Glutaminolysis is a meta-
bolic dependency in FLT3 ITD acute myeloid leukemia unmasked by
FLT3 tyrosine kinase inhibition. Blood. 2018;131:1639-1653.
63. Walter RB, Appelbaum FR, Estey EH, et al. Acute myeloid leukemia
stem cells and CD33-targeted immunotherapy. Blood. 2012;119:
6198-6208.
64. Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin
(Mylotarg) as a single agent for molecularly relapsed acute promyelo-
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
cytic leukemia. Blood. 2004;104:1995-1999.
65. Larson RA, Sievers EL, Stadtmauer EA, et al. Final report of the effi-
cacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients
with CD33-positive acute myeloid leukemia in first recurrence. Can-
cer. 2005;104:1442-1452.
66. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab
ozogamicin to induction chemotherapy in adult patients with acute
myeloid leukaemia: a meta-analysis of individual patient data from
randomised controlled trials. Lancet Oncol. 2014;15:986-996.
67. Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab Ozogamicin ver-
sus best supportive Care in Older Patients with Newly Diagnosed
Acute Myeloid Leukemia Unsuitable for intensive chemotherapy:
results of the randomized phase III EORTC-GIMEMA AML-19 trial. J
Clin Oncol. 2016;34:972-979.
68. Olombel G, Guerin E, Guy J, et al. The level of blast CD33 expression
positively impacts the effect of gemtuzumab ozogamicin in patients
with acute myeloid leukemia. Blood. 2016;127:2157-2160.
69. Khan N, Hills RK, Virgo P, et al. Expression of CD33 is a predictive
factor for effect of gemtuzumab ozogamicin at different doses in
adult acute myeloid leukaemia. Leukemia. 2017;31:1059-1068.
70. Laszlo GS, Harrington KH, Gudgeon CJ, et al. Expression and func-
tional characterization of CD33 transcript variants in human acute
myeloid leukemia. Oncotarget . 2016;7:43281-43294.
71. Lamba JK, Chauhan L, Shin M, et al. CD33 splicing polymorphism
determines Gemtuzumab Ozogamicin response in De novo acute
myeloid leukemia: report from randomized phase III Children's oncol-
ogy group trial AAML0531. J Clin Oncol . 2017;35:2674-2682.
72. Gale RE, Popa T, Wright M, et al. No evidence that CD33 splicing
SNP impacts the response to GO in younger adults with AML treated
on UK MRC/NCRI trials. Blood. 2018;131:468-471.
73. Walter RB. Investigational CD33-targeted therapeutics for acute
myeloid leukemia. Expert Opin Investig Drugs. 2018;27:339-348.
74. Nikanjam M, Capparelli EV, Lancet JE, et al. Persistent cytarabine
and daunorubicin exposure after administration of novel liposomal
formulation CPX-351: population pharmacokinetic assessment. Can-
cer Chemother Pharmacol. 2018;81:171-178.
75. Lancet J, Uy G, Cortes J, et al. CPX-351(cytarabine and daunorubicin)
liposome for injection vs. conventional cytarabine plus daunorubicin
in older patients with newly diagnosed secondary acute myeloid leu-
kemia. J Clin Oncol . 2018;36(26):2684-2692.
76. Lancet JE, Hoering A, Uy GL, et al. Survival following allogeneic
hematopoietic cell transplantation in older high-risk acute myeloid
leukemia patients initially treated with CPX-351 liposome injection
versus standard Cytarabine and Daunorubicin: subgroup analysis of a
large phase III trial. Blood. 2016;128:906-906.
77. Uy GL, Lancet JE, Cortes JE, et al. Multivariate efficacy analysis of a
randomized, phase 3 study of CPX-351 versus 7+3 in older adults
with treatment-related acute myeloid leukemia (AML) or AML with
myelodysplasia-related changes. Blood. 2017;130:2647-2647.
78. Nardi V, Winkfield KM, Ok CY, et al. Acute myeloid leukemia and
myelodysplastic syndromes after radiation therapy are similar to de
novo disease and differ from other therapy-related myeloid neo-
plasms. J Clin Oncol. 2012;30:2340-2347.
/
ESTEY
FIGURE 7 Outcomes in people according to whether they had persistence of NPM1 mutations (MRD-positive) in blood after initial 2 cycles of
chemotherapy (see reference 96)
mutations could be divided into those associated with ARCH7 (ie,
mutations in DNMT3a, TET2, and ASXL1) and others. The ARCH-
related mutations were often present in varying allele frequencies
(VAF) suggesting presence in >5% of marrow cells consistent with
presence of non-leukemic clones. Non-ARCH mutations were found
1281
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in 28% of patients and usually in VAF consistent with MRD. Persis-
tence of non-ARCH, but not ARCH, mutations were associated with
higher cumulative incidence of relapse and shorter survival and
relapse-free survival. These associations were also found in a “valida-
tion” population and were independent of ELN 2017, age, number of
/
1290
79. Walter RB, Othus M, Orlowski KF, et al. Unsatisfactory efficacy in
randomized study of reduced-dose CPX-351 for medically less fit
adults with newly diagnosed acute myeloid leukemia or other
high-grade myeloid neoplasm. Haematologica. 2018;103:e106-e109.
80. DiNardo CD, Pollyea DA, Jonas BA, et al. Updated safety and effi-
cacy of Venetoclax with Decitabine or Azacitidine in treatment-
naive, elderly patients with acute myeloid leukemia. Blood. 2017;130:
2628-2628.
81. Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of Venetoclax
with low-dose Cytarabine in treatment-naive, elderly patients with
acute myeloid leukemia unfit for intensive chemotherapy: 1-year
outcomes. Blood. 2017;130:890-890.
82. Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in acute
myeloid leukemia and myelodysplastic syndromes. N Engl J Med.
2016;375:2023-2036.
83. Paschka P, Schlenk RF, Weber D, et al. Adding dasatinib to intensive
treatment in core-binding factor acute myeloid leukemia-results of
the AMLSG 11-08 trial. Leukemia. 2018 Apr 17. https://doi.org/10.
1038/s41375-018-0129-6 In press.
84. Marcucci G, Geyer S, Zhao W, et al. Adding KIT inhibitor Dasatinib
(DAS) to chemotherapy overcomes the negative impact of KIT
mutation/over-expression in Core binding factor (CBF) acute myeloid
leukemia (AML): results from CALGB 10801 (alliance). Blood. 2014;
124:8.
85. Cancer Genome Atlas Research Network, Ley TJ, Miller C,
et al. Genomic and epigenomic landscapes of adult de novo acute
myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
86. Bruker B, Byrd J, Levine R. Beat AML. http://www.lls.org/beat-aml/
beat-aml-master-trial-more-information.
87. Estey E, Levine RL, Löwenberg B. Current challenges in clinical devel-
opment of “targeted therapies”: the case of acute myeloid leukemia.
Blood. 2015;125:2461-2466.
88. Montalban-Bravo G, Huang X, Naqvi K, et al. A clinical trial for
patients with acute myeloid leukemia or myelodysplastic syndromes
not eligible for standard clinical trials. Leukemia . 2017;31:318-324.
89. Jaramillo S, Benner A, Krauter J, et al. Condensed versus standard
schedule of high-dose cytarabine consolidation therapy with pegfil-
grastim growth factor support in acute myeloid leukemia. Blood Can-
cer J. 2017;7:e564.
90. Löwenberg B. Sense and nonsense of high-dose cytarabine for acute
myeloid leukemia. Blood . 2013;121:26-28.
91. Thomas X, de Botton S, Chevret S, et al. Randomized phase II study
of Clofarabine-based consolidation for younger adults with acute
myeloid leukemia in first remission. J Clin Oncol. 2017;35:
1223-1230.
92. vlisen AK, Oest A, Bendtsen MD, et al. Stringent or nonstringent
complete remission and prognosis in acute myeloid leukemia: a Dan-
ish population-based study. Blood Adv. 2018;2:559-564.
93. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable
residual disease in AML: a consensus document from the European
LeukemiaNet MRD working party. Blood. 2018;131:1275-1291.
94. Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of
flow cytometric minimal residual disease detection in acute myeloid
leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol.
2013;31:3889-3897.
95. Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell
transplantation for acute myeloid leukemia: time to move toward a
minimal residual disease-based definition of complete remission? J
Clin Oncol. 2016;34:329-336.
96. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual
disease in standard-risk AML. N Engl J Med. 2016;374:422-433.
97. Jourdan E, Boissel N, Chevret S, et al. Prospective evaluation of gene
mutations and minimal residual disease in patients with core binding
factor acute myeloid leukemia. Blood. 2013;121:2213-2223.
98. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal
residual disease in acute myeloid leukemia. N Engl J Med. 2018;378:
1189-1199.
99. Getta BM, Devlin SM, Levine RL, et al. Multicolor flow cytometry
and multigene next-generation sequencing are complementary and
highly predictive for relapse in acute myeloid leukemia after
ESTEY
allogeneic transplantation. Biol Blood Marrow Transplant. 2017;23:
1064-1071.
100. Morita K, Kantarjian HM, Wang F, et al. Clearance of somatic muta-
tions at remission and the risk of relapse in acute myeloid leukemia. J
Clin Oncol. 2018 Jun 20;36(18):1788-1797.
101. Boddu P, Jorgensen J, Kantarjian H, et al. Achievement of a negative
minimal residual disease state after hypomethylating agent therapy
in older patients with AML reduces the risk of relapse. Leukemia.
2018;32:241-244.
102. Othus M, Wood BL, Stirewalt DL, et al. Effect of measurable ('mini-
mal') residual disease (MRD) information on prediction of relapse and
survival in adult acute myeloid leukemia. Leukemia. 2016;30:
2080-2083.
103. Salk JJ, Schmitt MW, Loeb LA. Enhancing the accuracy of
next-generation sequencing for detecting rare and subclonal muta-
tions. Nat Rev Genet . 2018;19:269-285.
104. Terwijn M, Zeijlemaker W, Kelder A, et al. Leukemic stem cell fre-
quency: a strong biomarker for clinical outcome in acute myeloid leu-
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
kemia. PloS one. 2014;9:e107587.
105. Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treat-
ment response measured by flow cytometric residual disease detec-
tion in older patients with acute myeloid leukemia. J Clin Oncol.
2013;31:4123-4131.
106. stgård LSG, Lund JL, Norgaard JM, et al. Impact of allogeneic stem
cell transplantation in first complete remission in acute myeloid leu-
kemia: a national population-based cohort study. Biol Blood Marrow
Transplant. 2018;24:314-323.
107. Wheatley K, Gray R. Commentary: Mendelian randomization—an
update on its use to evaluate allogeneic stem cell transplantation in
leukaemia. Int J Epidemiol. 2004;33:15-17.
108. Freeman SD, Hills RK, Virgo P, et al. Measurable residual disease at
induction redefines partial response in acute myeloid leukemia and
stratifies outcomes in patients at standard risk without NPM1 muta-
tions. J Clin Oncol . 2018;36:1486-1497.
109. Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with
acute myeloid leukemia who did not undergo transplantation in first
remission. J Clin Oncol. 2013;31:1293-1301.
110. Zhu HH, Zhang XH, Qin YZ, et al. MRD-directed risk stratification
treatment may improve outcomes of t(8,21) AML in the first com-
plete remission: results from the AML05 multicenter trial. Blood.
2013;121:4056-4062.
111. Elsawy M, Sorror ML. Up-to-date tools for risk assessment before
allogeneic hematopoietic cell transplantation. Bone Marrow Trans-
plant. 2016;51:1283-1300.
112. Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a
clinical measure of biologic age before allogeneic hematopoietic cell
transplantation. J Clin Oncol. 2014;32:3249-3256.
113. Appelbaum FR. Impact of allogeneic hematopoietic cell transplanta-
tion on the outcome of older patients with acute myeloid leukemia.
Best Pract Res Clin Haematol. 2017;30:320-326.
114. Muffly L, Pasquini MC, Martens M, et al. Increasing use of allogeneic
hematopoietic cell transplantation in patients aged 70 years and
older in the United States. Blood . 2017;130:1156-1164.
115. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allo-
geneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:
2091-2101.
116. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus
reduced-intensity hematopoietic cell transplantation for acute mye-
loid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35:
1154-1161.
117. Fasslrinner F, Schetelig J, Burchert A, et al. Long-term efficacy of
reduced-intensity versus myeloablative conditioning before alloge-
neic haemopoietic cell transplantation in patients with acute myeloid
leukaemia in first complete remission: retrospective follow-up of an
open-label, randomised phase 3 trial. Lancet Haematol. 2018;5:
e161-e169.
118. Kroger N, Iacobelli S, Franke GN, et al. Dose-reduced versus stan-
dard conditioning followed by allogeneic stem-cell transplantation
for patients with myelodysplastic syndrome: a prospective random-
ized phase III study of the EBMT (RICMAC trial). J Clin Oncol. 2017;
35:2157-2164.
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1282
FIGURE 8 Relation between relapse and MRD as detected by MFC and NGS (see reference 98)
courses needed to attain CR/CRi, and when in the 21 day to 4 month
window testing was done. It remains unclear whether persistence of
some non-ARCH related mutations is more prognostic than persis-
tence of others; VAF thresholds for positivity may vary by gene.
Examining the 340 of the 430 adults in whom MFC as well as
NGS testing was performed, Jongen-Lavrenic et al. found concor-
98
dance between MFC and NGS in 69%. In the discordant cases, NGS
was positive in about 60% and MFC in about 40%. Combining NGS
and MFC appeared to improve the sensitivity/predictive value of a
positive MRD test (Figure 8). 98 Similar results have been reported for
prediction of post HCT relapse by Getta et al, 99 while Morita
et al. reported post-treatment clearance of mutations might help strat-
ify MFC negative patients according to risk of relapse.100
The great majority of the results noted above have been obtained
after “intensive” therapy  HCT. However, Boddu et al. have sug-
gested persistence of MFC-detected MRD after 3 months in CR or
CRi is associated with relapse after therapy with azacitidine or decita-
bine in a population whose median age was 75 years (Supporting
101
Information Figure 4). Nonetheless, while it is clear detection of
MRD provides invaluable information, at least after intensive therapy
 HCT, addition of MFC status at time of CR to pretreatment vari-
ables had only modest quantitative effect on assessing chance of
relapse, 102 suggesting the likely need to consider changes in MRD
over time rather than MRD at only a single instance, to develop new
103
means for MRD detection for example, “duplex sequencing” or
analysis of leukemia “stem cells” 104 and to use these methods in
ESTEY
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
complementary fashion. These approaches might improve the predic-
tive value of a positive MRD test (PPV) for subsequent morphologic
relapse which averages about 80% and the predictive value of a nega-
tive MRD test for remaining in CR (NPV) which is approximately 60%-
80%, that is, 20%-40% of patients deemed MRD negative will relapse,
with PPV higher and NPV lower in older patients 105 and perhaps after
less intense therapy (see figure 1 in reference 101). But even today, it
is clear MRD detection using PCR and MFC has a role in modifying
post-remission therapy, previously based solely on pretreatment vari-
ables, for example, ELN 2017. Indeed, the recognition by ELN 2017 of
CR with MRD as distinct entity18 implies the desirability of treating it
in different fashion than CR without MRD. Allogeneic HCT provides
an example.
5.2 | Allogeneic HCT
Without accounting for MRD, HCT in CR1 is often recommended for
fit patients, usually age <70, with ELN 2017 intermediate- and
adverse-, but not favorable-risk disease. For example, stgård
et al. used the Danish Acute Leukemia Registry assuring virtual com-
plete data collection on virtually all 1031 adults with intermediate—or
adverse-risk cytogenetics age <70 who entered CR between 2000
and 2014, of whom 19% received HCT in CR1. 106 As expected, HCT
patients tended to be younger with fewer comorbidities but more
often had adverse cytogenetics. A total of 70%-75% of patients
received at least 1 “consolidation” chemotherapy course, with 40% of
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119. Deeg HJ, Stevens EA, Salit RB, et al. Transplant conditioning with
Treosulfan/Fludarabine with or without Total body irradiation: a ran-
domized phase II trial in patients with myelodysplastic syndrome and
acute myeloid leukemia. Biol Blood Marrow Transplant. 2018;24:
956-963.
120. Jurcic JG, Rosenblat TL. Targeted alpha-particle immunotherapy for
acute myeloid leukemia. Am Soc Clin Oncol Educ Book. ASCO 50th
Annual Meeting. 2014;34:e126-e131.
121. Appelbaum FR. Alternative donor transplantation for adults with
acute leukemia. Best Pract Res Clin Haematol . 2014;27:272-277.
122. Tsai SB, Rhodes J, Liu H, et al. Reduced-intensity allogeneic trans-
plant for acute myeloid leukemia and myelodysplastic syndrome
using combined CD34-selected Haploidentical graft and a single
umbilical cord unit compared with matched unrelated donor stem
cells in older adults. Biol Blood Marrow Transplant. 2018;24:
997-1004.
123. Lee SJ, Logan B, Westervelt P, et al. Comparison of patient-reported
outcomes in 5-year survivors who received bone marrow vs periph-
eral blood unrelated donor transplantation: long-term follow-up of a
randomized clinical trial. JAMA Oncol . 2016;2:1583-1589.
124. Milano F, Appelbaum FR, Delaney C. Cord-blood transplantation in
patients with minimal residual disease. N Engl J Med. 2016;375:
2204-2205.
125. Estey E, Gale RP. Acute myeloid leukemia therapy and the chosen
people. Leukemia. 2017;31:269-271.
126. Pagel JM, Othus M, Garcia-Manero G, et al. Feasibility of allogeneic
hematopoietic cell transplantation among high-risk AML patients in
first complete remission: results of the transplant objective from the
SWOG (S1203) randomized phase III study of induction therapy
using standard 7+3 therapy or Idarubicin with high-dose Cytarabine
(IA) versus IA plus Vorinostat. Blood. 2016;128:1166-1166.
127. Mawad R, Gooley TA, Sandhu V, et al. Frequency of allogeneic
hematopoietic cell transplantation among patients with high- or
intermediate-risk acute myeloid leukemia in first complete remission.
J Clin Oncol. 2013;31:3883-3888.
128. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for
patients with AML in first complete remission. Blood. 2016;127:
62-70.
129. Schlenk RF, Taskesen E, van Norden Y, et al. The value of allogeneic
and autologous hematopoietic stem cell transplantation in prognosti-
cally favorable acute myeloid leukemia with double mutant CEBPA.
Blood. 2013;122:1576-1582.
130. Othus M, Mukherjee S, Sekeres MA, et al. Prediction of CR following
a second course of ‘7+3’ in patients with newly diagnosed acute
myeloid leukemia not in CR after a first course. Leukemia. 2016;30:
1779-1780.
131. Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of
patients with acute myeloid leukemia refractory to 1 cycle of
high-dose cytarabine-based induction chemotherapy. Blood. 2010;
116:5818-5823. quiz 6153.
132. Walter RB, Othus M, Löwenberg B, et al. Empiric definition of eligi-
bility criteria for clinical trials in relapsed/refractory acute myeloid
leukemia: analysis of 1,892 patients from HOVON/SAKK and
SWOG. Haematologica. 2015;100:e409-e411.
133. Thol F, Schlenk RF, Heuser M, et al. How I treat refractory and early
relapsed acute myeloid leukemia. Blood . 2015;126:319-327.
134. Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for
adult patients with acute myeloid leukemia in first relapse. J Clin
Oncol. 2005;23:1969-1978.
135. Wong TN, Miller CA, Klco JM, et al. Rapid expansion of preexisting
nonleukemic hematopoietic clones frequently follows induction ther-
apy for de novo AML. Blood . 2016;127:893-897.
136. Roboz GJ, Rosenblat T, Arellano M, et al. International randomized
phase III study of elacytarabine versus investigator choice in patients
with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014;
32:1919-1926.
137. Kantarjian HM, DiNardo CD, Nogueras-Gonzalez GM, et al. Results
of second salvage therapy in 673 adults with acute myelogenous leu-
kemia treated at a single institution since 2000. Cancer . 2018;124:
2534-2540.
1291
138. DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with
the BCL2-inhibitor venetoclax in combination therapy for relapsed
and refractory acute myeloid leukemia and related myeloid malignan-
cies. Am J Hematol. 2018;93:401-407.
139. Feldman EJ, Lancet JE, Kolitz JE, et al. First-in-man study of
CPX-351: a liposomal carrier containing cytarabine and daunorubicin
in a fixed 5:1 molar ratio for the treatment of relapsed and refractory
acute myeloid leukemia. J Clin Oncol. 2011;29:979-985.
140. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2
relapsed or refractory acute myeloid leukemia. Blood . 2017;130:
722-731.
141. Fathi AT, DiNardo CD, Kline I, et al. Differentiation syndrome associ-
ated with Enasidenib, a selective inhibitor of mutant Isocitrate dehy-
drogenase 2: analysis of a phase 1/2 study. JAMA Oncol . 2018;4(8):
1106-1110.
142. Paschka P, Schlenk R, Weber D, et al. Outcome of patients with
refractory or relapsed AML with IDH1 and IDH2 mutations after
conventional salvage therapy: a study of the German-Austrian AML
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
study group; 21 st congress of the European Hematology Association.
Copenhagen. 2016; Abstract S809. Leukemia. 2018 Apr 17. https://
doi.org/10.1038/s41375-018-0129-6.
143. Stein EM, Garcia-Manero G, Rizzieri DA, et al. The DOT1L inhibitor
pinometostat reduces H3K79 methylation and has modest clinical activ-
ity in adult acute leukemia. Blood. 2018 Jun 14;131(24):2661-2669.
144. DiNardo C, Stein E, de Botton S, et al. Durable remissions with ivosi-
denib in IDH1-mutated relapsed or refractory AML. New Engl J Med.
2018;378:2386-2398.
145. Stein EM, DiNardo CD, Mims AS, et al. Ivosidenib or Enasidenib com-
bined with standard induction chemotherapy is well tolerated and
active in patients with newly diagnosed AML with an IDH1 or IDH2
mutation: initial results from a phase 1 trial. Blood. 2017;130:726-726.
146. Quek L, David M, Kennedy A, et al. Clonal heterogeneity in differen-
tiation response and resistance to the IDH2 inhibitor Enasidenib in
acute myeloid leukemia. Blood. 2017;130:724-724.
147. Lichtenegger FS, Krupka C, Kohnke T, et al. Immunotherapy for
acute myeloid leukemia. Semin Hematol. 2015;52:207-214.
148. Daver N, Boddu P, Garcia-Manero G, et al. Hypomethylating agents in
combination with immune checkpoint inhibitors in acute myeloid leuke-
mia and myelodysplastic syndromes. Leukemia. 2018;32:1094-1105.
149. Middeke JM, Herbst R, Parmentier S, et al. Long-term follow-up and
impact of comorbidity before allogeneic hematopoietic stem cell
transplantation in patients with relapsed or refractory acute myeloid
leukemia-lessons learned from the prospective BRIDGE trial. Biol
Blood Marrow Transplant. 2017;23:1491-1497.
150. Chen X, Xie H, Wood BL, et al. Relation of clinical response and mini-
mal residual disease and their prognostic impact on outcome in acute
myeloid leukemia. J Clin Oncol. 2015;33:1258-1264.
151. Craddock C, Labopin M, Robin M, et al. Clinical activity of azacitidine
in patients who relapse after allogeneic stem cell transplantation for
acute myeloid leukemia. Haematologica. 2016;101:879-883.
152. Mielcarek M, Storer BE, Flowers ME, et al. Outcomes among patients
with recurrent high-risk hematologic malignancies after allogeneic
hematopoietic cell transplantation. Biol Blood Marrow Transplant.
2007;13:1160-1168.
153. Zhou Y, Wood BL, Walter RB, et al. Is there a need for morphologic
exam to detect relapse in AML if multi-parameter flow cytometry is
employed? Leukemia. 2017;31:2536-2537.
SUPPORTING I NFORMATION
Additional supporting information may be found online in the Sup-
porting Information section at the end of the article.
How to cite this article: Estey EH. Acute myeloid leukemia:
2019 update on risk-stratification and management. Am
J Hematol. 2018;93:1267–1291. https://doi.org/10.1002/ajh.
25214
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ESTEY
FIGURE 9 Effect of HCT in CR1 on survival. HR <1.0 indicates HCT better than continued chemotherapy. Adjusted HR accounts for age (up to
70 years), PS, comorbidities, de novo vs secondary AML and cytogenetics (see reference 106)
chemotherapy-only and 24% of HCT patients receiving two such
courses, corresponding to a median time from CR of to HCT of about
4 months. Two-thirds of transplanted patients received reduced
intensity conditioning (RIC), the remainder myeloablative conditioning
(MAC); approximately half the donors were matched siblings (MSD),
the remainder matched unrelated (MUD). Using Mantel-Byar method-
ology and landmark analyses to account for the “guarantee time” HCT
patients, but not chemotherapy only patients, must live before
107
HCT, cumulative incidence of relapse was lower, and survival and
relapse-free survival longer, in HCT recipients with either intermedi-
ate or adverse cytogenetics or age <60 or 60-69 (Figure 9). Median
follow up was 2.2 years in all patients, with relapses occurring in 49%
and deaths in 68% of chemotherapy patients vs 24% and 42% for
HCT patients. Median RFS was 293 days (interquartile range
142-910) for chemotherapy only vs 1067 (IQ range 397-2696) for
HCT with median survival times of 476 days (IQ 167-1589) and 1173
(IQ 474-2859)
Might accounting for MRD affect the recommendation for HCT
in ELN adverse or intermediate but not “favorable” patients? Specifi-
cally, it seems plausible the presence of MRD might be used to
“upstage,” and the absence of MRD to “downstage,” the pretreatment
ELN risk score, although it appears the influence of MRD status may
be less in the ELN adverse risk group. 108 More attention would be
given the possibility of allogeneic HCT in upstaged patients and less in
down-staged patients (Table 5). For example, patients in the ELN
2017 “favorable” group pretreatment but who have MRD after
2 cycles of therapy, as assessed by MFC or PCR, have risk of morpho-
logic relapse within 1-2 years of approximately 50%, not dramatically
different than the 60% seen in patients initially in the ELN adverse
group but who have no MRD after 2 cycles. The risk of nonrelapse
mortality (NRM) patients/physicians might be willing to accept after
HCT depends not only on the risk of relapse without HCT but on the
degree to which HCT might reduce this risk. It is generally accepted
HCT reduces relapse risk, as in stgärd et al.106 and numerous other
publications. It is also well-known pre HCT MRD is highly associated
with post HCT relapse, much as is the case without HCT. What seems
less clear is whether the reduction in relapse risk following HCT varies
by MRD status. Preliminary data from the NCRI group in the UK sug-
gest HCT in CR1 has a beneficial effect in intermediate risk patients in
the presence but not the absence of MRD.108 These data are in partial
accord with the NCRI's report that survival was the same in people
with intermediate risk AML regardless of whether they received HCT
1283
in CR1, at relapse, or in CR2.109 However, it has been pointed out that
Printed by [Wiley Online Library - 123.253.099.020 - /doi/epdf/10.1002/ajh.25214] at [13/02/2021].
the CR2 rate in such patients was unusually high (54%),109 suggesting
the influence of selection bias. Nonetheless, since this report included
patients with or without MRD, it suggests there, at least, may be no
need for allogeneic HCT in intermediate risk patients without MRD
after the first two courses of therapy. Certainly, the expectation of
post-HCT NRM would need to be very low to justify HCT in such
patients. In contrast, in people in the ELN intermediate group with
MRD, ELN adverse group without, and particularly ELN adverse risk
group with MRD, higher risks of post-HCT NRM might be acceptable
given HCT's greater potential benefit. For example, Thomas
et al. demonstrated the beneficial effect of addition of clofarabine to
post-remission therapy was substantially abrogated by receipt of
HCT 91 (Supporting Information Figure 5).
Investigating the potential utility of using MRD to decide
between transplant and nontransplant approaches, Zhu et al.110
assigned patients with t(8;21) who were PCR positive after two “con-
solidation” courses (high risk) to receive HCT while PCR negative
patients (low risk) were to receive autologous HCT or further chemo-
therapy. High risk patients who received HCT had better outcomes
than high risk patients who did not, while outcomes were similar in
low risk patients regardless of whether they received HCT
(Supporting Information Figure 6). Only MRD (yes/no) and MRD
adapted therapy (yes/no) affected outcome. However, confounding
factors exist, and the study was not randomized. It remains to be seen
whether MRD-directed therapy will sufficiently reduce MRD, thus
making it possible to examine whether patients in whom such reduc-
tion, occurs, for example pre-HCT, will have better outcomes than
patients who receive HCT without prior attempts to reduce MRD.
Although there are alternatives, the hematopoietic cell transplan-
tation comorbidity index (HCT-CI) effectively estimates NRM post-
HCT.111 Although as with induction therapy, age alone even up to
75-80 appears less important than comorbidities in influencing post
HCT NRM, 112 the proportion of adults with AML receiving HCT
(approximately 30% at any time in their course), while unaffected by
age up to 70, falls considerably once age 70 is reached. 113 Nonethe-
less Muffly et al.114 have noted the increasing use of HCT for AML
patients in their 70s (Supporting Information Figure 7A) concomitant
with better survival and disease-free survival in such patients
(Supporting Information Figure 7B). The same is true for HCT in gen-
eral. 115 Attempts to improve the HCT-CI's performance include incor-
poration of frailty indices and markers of inflammation.111