Current Oncology Reports (2021) 23:120

https://doi.org/10.1007/s11912-021-01108-9

LEUKEMIA (A AGUAYO, SECTION EDITOR)

3+7 Combined Chemotherapy for Acute Myeloid Leukemia: Is It Time

to Say Goodbye?
Kenny Tang 1 & Andre C Schuh 1 & Karen WL Yee 1

Accepted: 16 February 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the
relevance of conventional treatment approaches, such as daunorubicin and cytarabine (“3+7”) induction chemotherapy, has been
challenged. We review the AML risk stratification, the efficacy of the newly approved drugs, and the role of “3+7”.
Recent Findings Treatment of AML is becoming more niched with specific subtypes more appropriately treated with
gemtuzumab, midostaurin, and CPX-351. Although lower intensity therapies can yield high response rates, they are less efficient
at preventing relapses. The only curative potential for poor-risk AML is still an allogeneic stem cell transplant.
Summary The number of AML subtypes where 3+7 alone is an appropriate therapeutic option is shrinking. However, it remains
the backbone for combination therapy with newer agents in patients suitable for intensive chemotherapy.

Keywords Acute myeloid leukemia . cytarabine . CPX-351 . Daunorubicin . Midostaurin . gemtuzumab ozogamicin .
Venetoclax

Introduction general treatment approach has remained largely unchanged

Acute myeloid leukemia (AML) is an aggressive, genetically
heterogeneous group of malignant disorders characterized by
infiltration of the bone marrow, blood, and other tissues by
clonally related myeloblasts. AML is cured in 35–40% of
patients ≤ 60 years of age and in 5–15% of patients >60 years.
Although the cytogenetic heterogeneity of AML has been
recognized for more than 30 years, the molecular heterogene-
ity of this disease has only become increasingly apparent over
the past 15 years [1, 2, 3••, 4, 5, 6••, 7]. Nonetheless, the
This article is part of the Topical collection on Leukemia
* Karen WL Yee
karen.yee@uhn.ca
Kenny Tang
kenny.tang@uhn.ca
Andre C Schuh
andre.schuh@uhn.ca
1 we would argue that in spite of these advances, “3+7” will be
Division of Medical Oncology and Hematology, University Health
Network – Princess Margaret Cancer Centre, 610 University Avenue,
700 U 6th Floor, Toronto, Ontario M5G 2M9, Canada
over the last 50 years. Although there is no standard induction
regimen for patients with untreated AML who are suitable for
intensive therapy, the most widely used regimen has been
daunorubicin (DNR) intravenously for 3 days and cytarabine
at a dose of 100–200 mg/m2 intravenously by continuous
infusion for 7 days (i.e., 3+7) [8, 9•]. This regimen produces
a complete remission (CR) in 60–80% of younger adults with
5-year overall survival (OS) of ~ 40% [10–12]. Among older
adults (≥ 60 years), 40–60% will achieve a CR, but most will
relapse with few surviving beyond 2 years [13, 14].
Most patients with AML who achieve a CR will eventually
relapse due to the existence of subpopulations of AML cells
resistant to standard chemotherapy. A smaller subset of patients
will not achieve a CR. Attempts to overcome or prevent resis-
tance have led to the development of drugs targeting specific
mechanisms of resistance to be administered with traditional
intensive (e.g., 3+7 backbone) and lower intensity chemother-
apy regimens or as single or combination targeted therapies.
While the recent approval of multiple new drugs for the treat-
ment of AML is changing conventional treatment approaches,
and their successes have raised the notion that “‘3+7’ is dead”,
with us for the foreseeable future (Table 1) [15••, 16••, 17, 18••,
19••, 20, 21, 22••, 23, 24••, 25••].
 120 Page 2 of 13 Curr Oncol Rep (2021) 23:120

In this article, we will review the AML risk stratification,
the efficacy of the newly approved drugs, and finally discuss
why these new drugs are not yet able to replace “3+7”.
Risk Stratification of AML
In recent years, the European LeukemiaNet (ELN) risk cate-
gory, based on cytogenetics and mutational status of specific
genes, has become the most widely used risk classification
system to guide AML treatment-making decisions (Table 2)
[3••]. However, there remain a number of questions
concerning the ELN genetic categories. FLT3-ITD mutations
are associated with poor OS and a higher risk of relapse [7, 26,
27]. While ELN defines the risk of patients based on both
NPM1 mutational status and FLT3-ITD allelic burden, i.e.,
low FLT3-ITD: FLT3WT allelic ratio (< 0.5) vs high allelic
ratio (> 0.5), the prognostic significance of FLT3-ITD allelic
burden has not been consistently demonstrated [28, 29]. This
may be due, in part, to lack of a standardized assay. However,
the prognostic impact of FLT3-ITD mutations in a NPM1-
mutated patient is also modified by co-occurrence of other
mutations. For example, the effect of a FLT3-ITD mutation
on OS may be more pronounced in patients with concomitant
NPM1 and DNMT3A mutations as opposed to an isolated
NPM1 mutation, regardless of the FLT3-ITD allelic ratio
[30]. Therefore, the significance of the FLT3-ITD allelic ratio
and its role in guiding treatment decisions (e.g., allogeneic
stem cell transplant (alloSCT) in a patient with a low FLT3-
ITD allelic ratio) and/or determining prognosis remains
unclear. Similarly, RUNX1 [6••, 31–34] and ASXL1 [6••,
35, 36, 37–41] mutations, in the absence of favorable
genetic risk features, have been shown to be independent
prognostic factors predicting an inferior response rate and
OS in some, but not all, studies.
Other prognostic factors that contribute to prediction of
outcome are not necessarily captured in the ELN risk catego-
ries, including a history of antecedent hematological disorders

Table 1 Recent drug approvals for first-line therapy for AML

Drug Indication Regulatory status Reference

Intensive therapy – first line

CPX-351 (liposomal Treatment of adults with newly diagnosed therapy-related AML (t-AML) FDA (2017); EMA Lancet 2018 [15••]
daunorubicin + or AML with myelodysplasia-related changes (AML-MRC)a (2018)
cytarabine)
Gemtuzumab Treatment of newly diagnosed CD33-positive AML in adults in FDA (2017); EMA Castaigne 2012;
ozogamicin (GO) combination with daunorubicin and cytarabine for adults with newly (2018); HC (2019) Lambert 2019
diagnosed AML, except acute promyelocytic leukemia (APL)b [16••, 17]
Midostaurin For use with standard cytarabine and daunorubicin induction and FDA (2017); EMA Stone 2017 [18••]
cytarabine consolidation for the treatment of adults with newly (2017); HC (2017)
diagnosed FLT3-mutated AMLa,c,d
Less intensive therapy – first line
Ivosidenib For newly-diagnosed AML with a susceptible IDH1 mutation, as detected FDA (2019) Roboz 2020 [19••]
by an FDA-approved test, in patients who are at least 75 years old or who
have comorbidities that preclude the use of intensive induction
chemotherapy
Venetoclax (VEN) + Venetoclax in combination with AZA or DEC or LDAC for the treatment FDA (accelerated 2018; DiNardo 2018,
azacitidine (AZA) of newly diagnosed AML in adults who are > 75 years, or who have regular 2020); HC 2019, 2020 [20,
comorbidities that preclude use of intensive induction chemotherapy (2020) 21, 22••]
Venetoclax (VEN) + Venetoclax in combination with AZA or DEC or LDAC for the treatment FDA (accelerated 2018; DiNardo 2018, 2019
decitabine (DEC) of newly diagnosed AML in adults who are > 75 years, or who have regular 2020) [20, 21]
comorbidities that preclude use of intensive induction chemotherapy
Venetoclax (VEN) + Venetoclax in combination with AZA or DEC or LDAC for the treatment FDA (accelerated 2018; Wei 2019, 2020 [23,
low-dose cytarabine of newly diagnosed AML in adults who are > 75 years, or who have regular 2020); HC 24••]
(LDAC) comorbidities that preclude use of intensive induction chemotherapy (2020)
Low-dose cytarabine For use in combination with LDAC, for newly diagnosed AML in patients FDA (2018); EMA Cortes 2019 [25••]
(LDAC) + glasdegib who are > 75 years or who have comorbidities that preclude intensive (2020); HC (2020)
induction chemotherapy

EMA European Medicine Agencies; FDA US Food and Drug Administration; HC Health Canada
a
No age restriction; b EMA approval for age > 15 years; c drug is FDA approved for use with a companion diagnostic, the LeukoStrat CDx FLT3
mutation assay, which is used to detect the FLT3 mutation in patients with AML; d for patients in complete response, the EMA has approved midostaurin
as single agent maintenance therapy
Curr Oncol Rep (2021) 23:120 Page 3 of 13 120

Table 2 2017 ELN risk

classification of AML (Dohner
et al. 2017) [3••]
Risk category Genetic abnormality
Favorable t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD
Mutated NPM1 with FLT3-ITDlow†
Biallelic mutated CEBPA
Intermediate Mutated NPM1 and FLT3-ITDhigh†
Wild-type NPM1 without FLT3-ITD (without adverse-risk genetic lesions)
Wild-type NPM1 with FLT3-ITDlow† (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡
Cytogenetic abnormalities not classified as favorable or adverse
Adverse t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (EVI1)
−5 or del(5q); −7; −17/abn(17p)
Complex karyotype,§ monosomal karyotype||
Wild-type NPM1 and FLT3-ITDhigh†
Mutated RUNX1¶
Mutated ASXL1¶
Mutated TP53#
†
Low low allelic ratio (< 0.5); high high allelic ratio (> 0.5)
‡
The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations
§
Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring
translocations or inversions, that is, t(8;21), inv [16] or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or
t(3;3); t(9;22)
||
Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional
monosomy or structural chromosome abnormality (excluding core-binding factor AML)
¶
These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML
subtypes.
#
TP53 mutations are significantly associated with AML with complex and monosomal karyotype.

(e.g., myelodysplastic syndrome [MDS], myelodysplastic Newly Approved Drugs

syndrome/myeloproliferative neoplasm, myeloproliferative
neoplasm [MPN]) or prior exposure to cytotoxic chemother-
apy or radiation for treatment of other disorders or malignan-
cies [5, 42–48]. Some of these genetic abnormalities and/or
clinical variables have been captured in a proposed genomic
classification of AML [6••] in the updated 2016 World
Health Organization (WHO) classification of myeloid
neoplasm and acute leukemia [5]. However, this classifi-
cation system is not without controversy. For example,
both therapy-related myeloid neoplasms and AML with
myelodysplasia-related changes (AML-MRC) portend a
poor prognosis. However, recent data indicate not only
that morphologic criteria for AML-MRC may not carry
the same weight as cytogenetic and mutational criteria,
but that there is significant heterogeneity in outcomes of
these patients and that specific subgroups may benefit
preferentially from different therapies [49].
Intensive Therapy
Gemtuzumab ozogamicin (GO) plus 3+7
Gemtuzumab ozogamicin (GO) is a humanized antibody con-
jugated with the toxin calicheamicin that targets CD33. The
Acute Leukemia French Association (ALFA)-0701 study in
280 older patients with de novo treatment-naïve (TN) AML
demonstrated a survival benefit when GO 3 mg/m2 was ad-
ministered in 3 fractionated doses on days 1, 4, and 7 in con-
junction with 3+7 induction chemotherapy compared to stan-
dard 3+7 induction alone (OS2y 53.2% vs 41.9%; P = 0.0368)
(Table 3) [16••, 17]. This was attributable to fewer relapses in
patients with favorable- or intermediate-risk cytogenetics.
Thirty-three percent of patients had an NPM1 mutation and
6% CEBPA mutations. FLT3-ITD allelic frequency and
RUNX1, ASXL1, and TP53 mutational analysis were not
 120 Page 4 of 13 Curr Oncol Rep (2021) 23:120

Table 3 Outcomes with intensive regimens

CPX-351 GO + 3+7 Midostaurin + 3+7

(N = 153) (N = 139) (N = 360)
Phase 3 Phase 3 Phase 3
Lancet 2018 [15] Castaigne 2012; Stone 2017 [18]
Lambert 2019 [16••, 17]

Characteristics
Median age, y (range) 67.8a 62.8 (59.3–66.8)b 48.6 (18–60.9) d
Age > 75y Not provided but no patients > 75 y 0b 0d
De novo AML 41 (26.8%) 139 (100%) Not provided
Therapy-related AML (tAML) 30 (19.6%) 0c 0c
Secondary AML (sAML) 82 (53.6%) 0c Not provided
Prior HMA 21 (13.7%) 0c 0
Cytogenetic risk group
Good 7 (4.9%) 3 (2%) 16/269 (5.9%)
Intermediate 64 (44.8%) 91 (65%) 231/269 (85.9%)
Poor 72 (50.3%) 28 (20%)d 22/269 (8.2%)
Gene mutations
FLT3-ITD/TKD 22/138 (15.9%) FLT3-ITD 22/137 (16%) FLT3-ITD 279 (77.5%) /
FLT3-TKD 81 (22.5%)
IDH1/2 Not provided Not provided Not provided
TP53 Not provided Not provided Not provided
Outcomes
CR + CRi
All 73 (47.7%; CR 37.3%) CR + CRp 113 (81%; CR 73%) CR 212/360 (59%); expanded
CR 244/360 (68%)
tAML 14/30 (46.7%; CR 36.7%) Not applicable Not applicable
sAML 36/82 (43.9%: CR 32.9%) Not applicable Not provided
Poor risk cytogenetics 31/72 (43.1%; CR 34.7%) 14/28 (50%; CR not provided) Not provided
Prior HMA 18/50 (36%; CR 26%) Not applicable Not applicable
FLT3-ITD/TKD 15/22 (68.2%; CR 54.5%) FLT3-ITD 21/22 CR 212/360 (59%); expanded
(95.5%; CR not provided) CR 244/360 (68%)
IDH1/2 Not provided Not done Not provided
TP53 Not provided Not done Not provided
Median duration of response, mos (95% CI) 6.93 Not specified Not specified
Median follow-up, mos 20.7 47.6 59
Median OS, mos (95% CI) 9.56 (6.60–11.86) 27.5 (21.4–45.6) 74.7 (31.5-not reached)
30-day mortality 5.9% 3.8% Not specified

CI confidence interval; CR complete remission; CRp CR with incomplete platelet recovery; CRi complete remission with incomplete count recovery; GO
gemtuzumab ozogamicin; HMA hypomethylating agent; mos months
a
Eligible age for enrolment onto study: 60–75 y; b eligible age for enrolment onto study: 50–70 y; c this group of patients were not eligible for the study;
d
cytogenetics not available in 17 patients (12%); d eligible age for enrolment onto study: 18- <60 y

performed. There was no difference in composite CR (CR +
CR without platelet recovery [CRp]) or CR rates (81% vs
75%; P = 0.25 and 73% vs 72%; P = not significant [NS])
between the 2 groups. On long-term follow-up, although OS
favored GO, this was no longer statistically significant (medi-
an OS 27.5 months vs 21.8 months; P = 0.16) [17]. Subgroup
analysis demonstrated a survival benefit for FLT3-ITD-mutat-
ed AML patients. The most common side effect of GO when
used with 3+7 was hemorrhage and infection. Persistent
thrombocytopenia was more common in the GO arm (20.4%
vs 2%). Veno-occlusive disease/sinusoidal obstruction syn-
drome (VOD/SOS), including after alloSCT, was observed
in 4.6% patients in the GO arm and 1.5% patients in the
control arm (P = 0.165) [17]. Thirty-nine patients received
an alloSCT in first CR or CRp (17 in the GO arm; 22 in the
control arm), whereas 46 patients received an alloSCT without
Curr Oncol Rep (2021) 23:120
achieving a CR or CRp (2 GO arm; 9 control arm) or after
relapse (13 GO arm; 22 control arm).
An individual patient data meta-analysis of 3325 patients
from 5 randomized trials [16••, 50–53] demonstrated an im-
proved 5-year OS with GO, irrespective of patient age, due to
decreased risk of relapse [54]. The benefit was observed in
patients with favorable (survival difference 20.7%; odds ratio
[OR] 0.47; 95% CI: 0.31–0.73; P = 0.0006) or intermediate-
risk karyotype (survival difference 5.7%; OR 0.84; 95% CI:
0.75–0.95; P = 0.005), but not in adverse-risk patients.
Overall, 29% and 20% of patients had NPM1 and FLT3-ITD
mutations. Information on other gene mutations was not pro-
vided. There was no survival benefit observed with GO in
patients with secondary AML (sAML), FLT3-ITD, or NPM1
mutations. Doses of 3 mg/m2 were associated with equal ef-
ficacy and less toxicity than higher doses.
As a proportion of patients with ELN intermediate risk
AML may require an alloSCT, the concern of developing
VOD/SOS may influence choice of induction therapy. In an
attempt to mitigate this risk, investigators in the ALFA-0701
study recommended an interval of 2 months between the last
dose of GO and alloSCT [16••]. A retrospective safety analy-
sis of clinical trial data identified 99 (11.4%) cases of VOD/
SOS among 870 GO-treated patients (221 of whom received
alloSCT) [55]. Rates of VOD/SOS were 3% when GO was
administered at doses < 6 mg/m2 as monotherapy or with non-
hepatotoxic agents and 28% when administered with 6-
thioguanine (a hepatotoxic agent), 15% when administered
as monotherapy at doses of 9 mg/m2, and between 15–40%
if alloSCT was performed within 3 months of GO. Death from
VOD/SOS occurred in 60% of the cases. The European
Society for Blood and Marrow Transplantation (EBMT) and
the Center for International Blood and Marrow Transplant
Research (CIBMTR) documented VOD/SOS incidences of
4% and 8% among patients who previously received GO prior
to alloSCT and concluded that the incidence was not higher
than a matched control group [56, 57].
Midostaurin Plus 3+7
Midostaurin is a small molecule multikinase inhibitor with
activity against FLT3. FLT3 mutations occur in approximately
30% of cases of AML (~ 20–25% FLT3-ITD; ~ 7% FLT3-
TKD) [7, 58]. The RATIFY trial evaluated midostaurin/
placebo (PBO) administered with 3+7 followed by 4 cycles
of consolidation therapy with midostaurin/PBO and high-dose
cytarabine, then a 1-year midostaurin/PBO maintenance phase
in 717 younger patients with TN FLT3-mutated AML
(Table 3) [18••, 59]. Patients with therapy-related AML (t-
AML) and patients with sAML who had received therapy
for preceding MDS were ineligible. CR rates were comparable
between the 2 arms (58.9% vs 53.5%; P = 0.15), but were
increased in the midostaurin arm when all CRs reported within
Page 5 of 13 120
30 days of ending protocol therapy were considered (68% vs
59%; P = 0.04). Midostaurin improved OS (74.7 months vs
25.6 months; OS4y 51.4% vs 44.3%; P = 0.009) in both FLT3-
TKD- and FLT3-ITD-mutated (high [> 0.7] and low [0.05–
0.7] allele burden) AML, regardless of whether patients re-
ceived alloSCT. Analyses of subgroups according to FLT3
subtype and FLT3-ITD allelic burden showed that OS did
not differ significantly according to treatment regimen within
each subgroup. As only a small proportion of patients received
maintenance, the benefit of midostaurin maintenance is un-
clear. Twenty-eight percent of patients in the midostaurin
arm received an alloSCT in first CR compared with 22.7%
in the PBO arm (P = 0.10).
The phase 2 German-Austrian AMLSG 16-10 trial ad-
ministered midostaurin with 3+7 followed by alloSCT and
single agent midostaurin maintenance in 286 patients (age
18–70 years) with FLT3-ITD-mutated AML (88% de
novo, 8% sAML and 5% t-AML) [60]. Patients with core
binding factor (CBF) AML were excluded. The composite
CR (CR + CR with incomplete count recovery [CRi]) rate
was 76.4% (CR 49.3%). The 2-year event-free survival
and OS were 39% and 34%, respectively, for all patients
and 53% and 46%, respectively, for the older patients.
Seventy-three percent of patients underwent alloSCT.
This demonstrated the safety and efficacy of midostaurin,
at least in patients up to age 70.
CPX-351 (VYXEOS™ (Cytarabine: Daunorubicin) Liposome
for Injection)
CPX-351 is a liposomal formulation of cytarabine and DNR
fixed at a 5:1 molar ratio within 100-nm diameter liposomes
[61, 62]. A randomized phase 3 trial compared CPX-351 with
3+7 in 309 older patients with TN high-risk AML (i.e., t-
AML, sAML (preceding MDS or chronic myelomonocytic
leukemia (CMML)), or AML-MRC) [15••]. The overall re-
sponse rate (ORR: CR + CRi) was higher with CPX-351
compared with 3+7 (47.7% vs 33.3%; P = 0.016) with CR
rates of 37.3% and 25.6% in favor of CPX-351 (P = 0.04).
With a median follow-up of 20.7 months, median OS was
increased in patients treated with CPX-351 (9.56 months vs
5.95 months; P = 0.003; OS2y 31.1% vs 12.3%). Subgroup
analyses demonstrated improved OS compared with 3+7 in
patients with wild-type FLT3, t-AML, sAML, and favorable/
intermediate karyotype. There was no survival benefit ob-
served in patients who had prior hypomethylating agent
(HMA) exposure or unfavorable cytogenetics. Mutational
analysis of CEBPA and NPM1 genes was performed, but no
information has been provided. CPX-351 may not be effective
in patients with TP53 mutations [63–65]. The toxicity profile
(including incidence of reduced ejection fraction) of CPX-351
was similar to that seen with 3+7 except for more prolonged
neutropenia and thrombocytopenia in the CPX-351 arm. The
 120 Page 6 of 13
30-day mortality was 5.9% with CPX-351 and 10.6% with 3+
7 (P = 0.149). Quality of life (QoL) analysis was not per-
formed, but a post-hoc Quality-Adjusted Time without
Symptoms of Disease and Toxicity (Q-TWiST) analysis dem-
onstrated improved clinical benefit with CPX-351 over 3+7
[66]. Thirty-four percent of patients in the CPX-351 arm
underwent alloSCT compared with 25% in the 3+7 arm
(P = 0.098) with less non-relapse mortality [67]. Although
this study excluded patients with MPN in blast phase
(MPN-BP), CPX-351 has yielded responses in this group
of patients [65]. A phase 3 randomized trial comparing
CPX-351 with 3+7 in adult patients with ELN defined
intermediate or adverse genetic risk AML is ongoing
(NCT03897127) [68].
Less Intensive Therapy
Venetoclax and Azacitidine
Venetoclax (VEN) is a selective BH3-mimetic that targets
B cell lymphoma 2 (BCL-2) resulting in programmed cell
death. The phase 3 VIALE-A trial comparing VEN and
azacitidine (AZA) with PBO and AZA in 433 patients with
TN AML who were not suitable for intensive chemotherapy
(as defined by age and/or comorbidities) confirmed an im-
proved median OS in favor of VEN + AZA (14.7 months vs
9.6 months; P < 0.001) (Table 4) [22••]. Patients with MPN-
BP or prior HMA exposure were excluded. Patients in the
VEN + AZA arm received a median of 7 treatment cycles
compared to 4.5 in the control arm. Composite CR (CR +
CRi) and CR rates were higher with VEN + AZA compared
with PBO + AZA (66.4% [CR 36.7%] vs 28.3 % [CR 17.9%];
P < 0.001). Median time to first response (either CR or CRi)
was 1.3 months vs 2.8 months, respectively. Composite CR
before initiation of cycle 2 was achieved in 43.4% of patients
receiving VEN + AZA vs 7.6% in those receiving PBO +
AZA. Subgroup analysis demonstrated higher composite CR
rates with VEN + AZA compared with PBO + AZA in the
following: (a) IDH1/2 mutated (75.4% vs 10.7%; P < 0.001);
(b) FLT3-ITD/TKD mutated (72.4% vs 36.4%; P = 0.02); (c)
TP53 mutated (55.3% vs 0%; P < 0.001); (d) therapy-related
and/or secondary AML (t/s-AML; 66.7% vs 22.9%; P not
specified); and (e) poor-risk cytogenetics (52.9% vs 23.2%;
P not specified). In patients with composite CR, measurable
residual disease (MRD) negativity occurred in 24.4% of pa-
tients receiving VEN + AZA compared with 7.6% in the con-
trol arm (P not specified). OS was improved in favor of VEN
+ AZA compared with the control arm in IDH1/2-mutated
AML (OS1y 66.8% vs 35.7%; P < 0.001), t/s-AML (median
16.4 months vs 10.6 months; P not specified), and AML with
poor-risk cytogenetics (median 7.6 months vs 6 months; P not
specified). Infections of any grade, including febrile neutrope-
nia, were higher in the VEN + AZA group compared with
Curr Oncol Rep (2021) 23:120
control (84% and 42% vs 67% and 19%, respectively); how-
ever, incidence of pneumonia was comparable between the 2
arms (17% vs 22%, respectively). Tumor lysis syndrome
(TLS; all laboratory) was reported in 1% of patients in the
VEN + AZA arm and none in the control arm. Only 2 patients
in the VEN + AZA arm and 1 patient in the control arm
received an alloSCT after discontinuing assigned study treat-
ment. Mortality at 30 days was the same between the 2 groups
(7% vs 6%). There was no observed difference between the 2
groups with respect to QoL.
Although no patients with CBF AML or MPN-BP were
included in this trial, responses have been observed in patients
with MPN-BP and CBF AML [70, 71]. Furthermore, high
response rates and long remission durations appear to be as-
sociated with NPM1 or IDH2 mutations, with resistance asso-
ciated with emergence of FLT3 or RAS mutations, biallelic
TP53 loss [72], and/or monocytic subclones via loss of
BCL-2 expression and increased dependency on MCL-1 for
oxidative phosphorylation and survival [73]. Outcomes for
patients with AML who did not respond, or lost response, to
front-line VEN and HMAs have a median OS of 2.4 months
[74].
Venetoclax and Low-Dose Cytarabine
The phase 3 VIALE-C study evaluated VEN and low dose
cytarabine (LDAC) compared with PBO and LDAC in 211
patients with TN AML who were not suitable for intensive
chemotherapy (as defined by age and/or comorbidities)
(Table 4) [24••]. Patients with MPN-BP or who had prior
cytarabine exposure were excluded. Median treatment dura-
tion was 3.9 months, and median number of cycles adminis-
tered was 4 in the VEN + LDAC arm compared with 1.7
months and 2, respectively, in the control arm. Median OS
at the planned analysis was not statistically different between
the 2 arms (7.2 months vs 4.1 months; P = 0.11). There were
several imbalances in baseline characteristics (i.e., sAML, pri-
or hematologic disorder-related secondary AML, and poor-
risk cytogenetics) as well as increased administrative censor-
ing in the VEN + LDAC arm compared to control arm (i.e.,
enrolment was ongoing 3.4 months before the pre-planned OS
analysis; censoring of patients still alive at time of analysis and
who had not reached the median OS by study cut-off date
happened more frequently in the VEN + LDAC arm [12%
vs 6%]). Hence, a longer-term unplanned analysis with an
additional 6 months of patient follow-up was performed and
demonstrated an improved median OS in favor of VEN +
LDAC (8.4 months vs 4.1 months; P = 0.04). Composite
CR (CR + CRi) rates were higher in patients receiving VEN
+ LDAC than PBO + LDAC (48% [CR 27%] vs 13% [CR
7%]; P < 0.001). Composite CR before initiation of cycle 2
was achieved in 34% of patients receiving VEN + LDAC
compared with 3% in those receiving PBO + LDAC (P <
Curr Oncol Rep (2021) 23:120 Page 7 of 13 120

Table 4 Outcomes with less intensive agents/regimens

VEN + AZA VEN + LDAC LDAC + glasdegib Ivosidenib Enasidenib

(N = 286) (N = 143) (N = 88)b (N = 34) (N = 39)
Phase 3 Phase 3 Phase 2 Phase 1 Phase 1/2
DiNardo 2020 [22] Wei 2020 [24] Cortes 2019 [25] Roboz 2020 [19••] Pollyea 2019 [69]

Characteristics
Median age, y (range) 76 (59–91) 76 (36–93) 77 (63–92)b 76.5 (64–87) 77 (58–87)
Age > 75y 174 (61%) 82 (57%) 53 (60.2%)b 19 (56%) 24 (62%)
De novo AML 214 (75%) 85 (59%) Not provided 8 (24%) Not provided
Therapy-related AML 26 (9%) 6/58 (10%) Not provided 3 (9%) 2 (5%)
(tAML)
Secondary AML (sAML) 46 (16%) 52/58 (90%) Not provided 23 (68%) 23 (59%)
Prior HMA 0 28 (20%) 13 (14.8%)b 16 (47%) Not provided
Cytogenetic risk group
Good 0 1 (1%) Good/Intermediate 0 0
52
Intermediate 182 (64%) 90 (63%) (59.1%)b 24 (71%) 19 (49%)
Poor 104 (36%) 47 (33%) 36 (40.9%)b 9 (26%) 10 (26%)
Gene mutations
FLT3-ITD/TKD 29/206 (14%) 20/112 (18%) 8/61 (13%)b 1/33 (3%) 2/34 (6%)
IDH1/2 61/245 (25%) 21/112 (19%) 22/61 (36%)b IDH2 2/33 (6%) IDH1 1/34 (3%)
TP53 38/163 (23%) 22/112 (20%) Not provided 3/33 (9%) 3/34 (9%)
Outcomes
CR + CRi
All 190/286 (66.4%; 69/143 (48%; CR 27%) 19/78 (24%; CR CR + CRh 14/33 CR + CRi 8/39
CR 36.7%) 17.9%) (42.4%; CR 30.3%) (20.5%; CR 18%)
tAML s/tAML 48/72 s/tAML 21/58 (36%; CR Not provided Not provided Not provided
(66.7%) 16%)
sAML Not provided Not provided CR 3/23 (13%)
Poor risk cytogenetics 55/104 (52.9%) 13/47 (28%; CR 17%) CR 5/36 (13.9%)b Not provided Not provided
Prior HMA Not applicable 7/28 (25%; CR 7%) Not provided CR + CRh 4/15 (26.7%; Not provided
CR 20%)
FLT3-ITD/TKD 21/29 (72.4%) 9/20 (45%; CR25%) ORR 2/8 (25%)b 0 0
IDH1/2 46/61 (75.4%)a 12/21 (57%; CR 38%) ORR 7/22 IDH2 0 IDH1 0
(31.8%)b
TP53 21/38 (55.3%) 4/22 (18%; CR 5%) Not provided CRh 1/3 (33%) 0
Time to response, mos 1.3 (0.6–9.9) for Before initiation cycle 2: Not provided 2.8 (1.9–4.6) for CR 5.6 (3.4–12.9) for CR
(range) CR + CRi 34% for CR +CRi
Median duration of 17.5 (13.6-NR) for Not provided 9.9 (0.03–28.8) for NR (proportion in CR at NR (3.7-NR) for CR
response, mos (95% CI) CR + CRi CRb 1y 77.8%)
Median follow-up, mos 20.5 Planned: 12 21.7b 23.5 8.4
Unplanned: 18
Median OS, mos (95% CI) 14.7 (11.9–18.7) Planned: 7.2 (5.6–10.1) 8.3 (6.6–9.5) 12.6 (4.5–25.7) 11.3 (5.7–15.1)
Unplanned: 8.4 (5.9–10.1)
30-day mortality 21/286 (7%) 18/143 (13%) 5/84 (6%)b Not provided 3/39 (8%)

CI confidence interval; CR complete remission; CRh CR with partial hematologic improvement; CRi complete remission with incomplete count
recovery; HMA hypomethylating agent; MDS myelodysplastic syndrome; mos months; NR not reached; ORR overall response rate (CR + CRi +
morphologic leukemic-free state [MLFS]); OS overall survival; y year
a
CR + CRi for IDH1 mutated 13/23 (56.5%) and for IDH2 mutated 34/40 (85%); b includes 10 patients with MDS

0.001). Subgroup analysis demonstrated higher composite CR AML (36% vs 4%; P not specified); and (d) poor-risk cytoge-
rates with VEN + LDAC compared with placebo + LDAC in netics (28% vs 10%; P not specified). There was no difference
the following: (a) IDH1/2 mutated (57% vs 33%; P not spec- in median OS in the different subgroups between the 2 treat-
ified); (b) TP53 mutated (18% vs 0%; P not specified); (c) t/s- ment arms. In patients with co-existing FLT3 and NPM1
 120 Page 8 of 13
mutations, median OS was 10.2 months in the PBO arm and
not yet reached in the VEN + LDAC arm (P not specified).
The outcomes for patients with FLT3-ITD/TKD-mutated
AML were comparable between the 2 arms. In patients with
composite CR, MRD negativity as determined by flow cytom-
etry occurred in 6% of patients receiving VEN + LDAC com-
pared with 1% in the control arm. Grade > 3 febrile neutrope-
nia and serious pneumonias were comparable between the 2
arms (32% and 13% vs 29% and 10%, respectively). TLS was
observed in 8 patients (6%; 4 clinical and 4 laboratory) in the
VEN + LDAC arm and none in the control arm. No patient
received alloSCT after study therapy. The 30-day mortality
rate was the same between the 2 groups (13% vs 11%).
There was no observed difference between the 2 groups with
respect to QoL.
Glasdegib and Low-Dose Cytarabine
Glasdegib is a selective oral inhibitor of the hedgehog signal-
ing pathway by binding to smoothened (SMO). A randomized
phase 2 study evaluated LDAC with or without glasdegib in
132 patients with newly diagnosed AML or higher risk MDS
unsuitable for intensive chemotherapy (as defined by age and/
or comorbidities) (Table 4) [25••]. Patients could not have
preceding chronic myeloid leukemia and needed to be > 55
years. The proportion of patients with t/s-AML was not re-
ported. Median treatment duration was low in both arms (2.7
months vs 1.5 months, respectively). Median OS was 8.8
months with LDAC + glasdegib and 4.9 months with LDAC
alone (P = 0.0004) with 1-year OS of 39.5% and 9.5%, re-
spectively. The composite CR (CR + CRi) rates in patients
with AML were higher in the LDAC + glasdegib arm com-
pared to single agent LDAC (24% [CR 17.9%] vs 10.5% [CR
2.6%]; P < 0.05 for CR). Febrile neutropenia occurred in
35.7% of patients treated with LDAC + glasdegib and
24.4% with LDAC. Dysguesia and muscle spasms occurred
in 25% and 22.6%, respectively, in patients receiving LDAC
+ glasdegib compared with 2.4% and 4.9%, respectively, in
the control arm. On subgroup analysis, ORR (CR + CRi +
morphological leukemia free state (MLFS) for patients with
AML and CR + marrow CR for those with MDS) favored
LDAC + glasdegib in the following: (a) IDH1/2 mutated
(31.8% vs 0%; P = NS); (b) FLT3-ITD/TKD mutated (25%
vs 0%; P not specified); (c) RUNX1 mutated (36% vs 0%; P =
NS); and (d) poor-risk cytogenetics (13.9% vs 5.3%; P not
specified). There was no difference in response rates for
TP53-mutated AML. Outcomes for t/s-AML were not report-
ed. Only 1 patient in the LDAC + glasdegib arm and none in
the control arm received an alloSCT after discontinuing
assigned study treatment. The 30-day mortality rate for pa-
tients with AML was 6.7% in the LDAC + glasdegib arm
and 13.9% in the LDAC only arm.
Curr Oncol Rep (2021) 23:120
Ivosidenib
Ivosidenib is an oral, small molecule inhibitor of mutant
isocitrate dehydrogenase 1 (IDH1). Mutations in the IDH1
gene occur in ~ 6–10% of AML [7]. Ivosidenib monotherapy
induced durable remissions in 34 patients with newly diag-
nosed mutated IDH1 AML not eligible for intensive chemo-
therapy who were treated as part of a phase 1 study (Table 4)
[19••, 75]. Sixty-eight percent had secondary AML [12% had
preceding MPN]. Differentiation syndrome occurred in 18%
of patients, but did not require treatment discontinuation.
Grade > 3 febrile neutropenia and QTc prolongation
occurred in 2 (6%) patients each. The composite CR (CR +
CR with incomplete hematologic recovery [CRh]) was 42.4%
(CR 30.3%). None of the patients achieving a CR/CRh had a
FLT3 mutation. IDH1 mutation clearance occurred in 9/14
(64%) of patients achieving CR+CRh (CR 50%; CRh
100%). Median duration of response had not been reached
with 77.8% of patients remaining in CR at 1 year. The median
time to CR was 3.7 months. After a follow-up of 23.5 months,
median OS was 12.6 months. Three (9%) patients received an
alloSCT.
Enasidenib
Enasidenib is an oral inhibitor of mutant IDH2 proteins. IDH2
mutations occur in 6–19% of AML [7]. Thirty-nine patients
with newly diagnosed IDH2-mutated AML were treated with
enasidenib monotherapy on a phase 1/2 trial (Table 4) [69,
76]. Twenty-three (59%) patients had secondary AML arising
from prior MDS, CMML, or MPN. Differentiation syndrome
occurred in 13% of patients and QTc prolongation in 10%.
The composite CR (CR + CRp) was 20.5% (CR 18%). None
of the patients with FLT3 or TP53 mutations achieved a re-
sponse. Median duration of response had not been reached.
Median OS was 11.3 months. Three (8%) patients received an
alloSCT. Although there is no FDA approval for enasidenib in
the front-line setting at this time, it is approved in the relapsed/
refractory AML setting.
Evolving Treatment Strategies Based on Risk
Group
The recent drug approvals, on the most part, irrespective of
age, have created challenges in deciding which is the most
appropriate therapy if several overlapping treatment options
are available (Tables 1 and 5). These newer therapies highlight
the need for timely identification of cytogenetic abnormalities
and genetic mutations. Despite the availability of these new
drugs, there continues to be a lack of highly effective therapy
in patients with adverse/poor-risk AML, including RUNX1-
and ASXL1-mutated AML (Tables 3, 4, and 5).
Curr Oncol Rep (2021) 23:120
Table 5 First-line treatment strategies for patients with AML who are suitable for intensive therapy
Risk group Genetic abnormality or 2016 WHO classification
Favorable Core binding factor (CBF)
Intermediate FLT3-TKD mutation (exclusive of adverse/poor risk cytogenetics)
Intermediate risk cytogenetics (exclusive of therapy-related or
secondary AML or AML-MRC)
Adverse/poor TP53 mutation
Adverse/poor risk cytogeneticsd
MPN-BC
FLT3-ITD mutation (exclusive of adverse/poor risk cytogenetics)
Therapy-relatede or secondary AML or AML-MRC
AML-MRC AML with myelodysplasia-related changes; AZA azacitidine; DEC decitabine; FLAG-Ida fludarabine, cytarabine, G-CSF, and idarubicin;
GO gemtuzumab ozogamicin; MEC mitoxantrone, etoposide and cytarabine; MPN-BC myeloproliferative neoplasm in blast crisis; VEN venetoclax
a
Patients should be enrolled onto clinical trials if possible; b transplant eligible patients; c may be off-label use; d for AML-MRC with poor risk
cytogenetics, administration of CPX-351 would also be appropriate; e for CBF administration of 3+7 + GO would also be appropriate
AlloSCT is routinely recommended in first CR for trans-
plant eligible patients with poor-risk AML, as it is potentially
curative. Intensive chemotherapy regimens other than 3+7
have been utilized in an attempt to increase the CR rates and
eligibility for alloSCT. Subgroup analyses in randomized tri-
als with 3+7 have demonstrated CR rates of 51–65% in youn-
ger patients (age < 60 years) and 34–56% in older patients
(age > 60 years) with poor-risk cytogenetics; however, OS is
poor in both age groups [9, 11, 12, 14]. Published studies
comparing different regimens have not been powered to dem-
onstrate significant differences in outcomes in poor-risk sub-
groups [9•]; however, in exploratory ad hoc analyses,
flavopiridol (alvocidib), cytarabine, and mitoxantrone
(FLAM) yielded higher CR rates in patients with > 1 poor-
risk feature compared with 3+7 (61% vs 34%; P = 0.04) [77].
Also, the UK MRC AML15 trial compared 2 induction
courses of fludarabine, cytarabine, G-CSF, and idarubicin
(FLAG-Ida) (n = 635) with daunorubicin and cytarabine with
etoposide (ADE) (n = 633) in the front-line setting in patients
with TN AML [78]. FLAG-Ida was associated with a signif-
icantly higher CR rate after 1 cycle of induction therapy (77%
vs 67%; P < 0.001) with improved RFS (45% vs 34%; P =
0.01), overall and in subgroups, but there was no OS benefit.
Based on the higher CR rate after 1 induction, several centers
have adopted FLAG-Ida as front-line therapy for patients with
poor-risk AML in order to enable more of these patients to
proceed to alloSCT [79].
More effective and less toxic treatments could deliver more
patients to transplant who otherwise might not respond to
first-line therapy, relapse before reaching transplant, or devel-
op treatment-related complications that impair their ability to
receive an alloSCT (Tables 3, 4, and 5). Therapy with single
agent LDAC, AZA, and decitabine (DEC) in patients with de
novo or sAML has yielded low CR rates (range, 8–20%)
[80–83]. Among the newly approved lower intensity
Page 9 of 13 120
First-line therapya
3+7 + GO
3+7 + midostaurin
3+7 + GO; intensive regimens (e.g., FLAG-Ida, MEC)b
VEN + AZA (DEC)c; intensive regimens (e.g., FLAG-Ida, MEC)b
VEN + AZA (DEC)c; intensive regimens (e.g., FLAG-Ida, MEC)b
VEN + AZA (DEC)c; intensive regimens (e.g., FLAG-Ida, MEC)b
3+7 + midostaurin
CPX-351b; intensive regimens (e.g., FLAG-Ida, MEC)b
regimens/agents, faster and higher CR rates and/or MRD neg-
ativity appear to be achieved with VEN + AZA (Table 4),
including in HMA-naïve patients with poor-risk cytogenetics
and t/s-AML. Although patients with MPN-BP were excluded
from most of the studies [15••, 17, 18••, 22••, 24••] due to their
extremely poor response to intensive chemotherapy [46, 84],
VEN-based therapies may be effective in this group of pa-
tients [71]. The high response rates of VEN + HMA compared
with contemporary intensive chemotherapy and other lower
intensity regimens with low rates of early deaths/induction
deaths and/or infections have led to more off-label use of these
regimens in higher-risk patients for whom alloSCT is deemed
appropriate (Tables 3, 4, and 5) [85, 86, 87, 88]. However,
limited data is available for outcomes (such as relapse risk and
OS) when VEN + HMAs are administered as a bridge to
alloSCT [87, 88]. A phase 2 trial is examining the safety and
tolerability of VEN + AZA in younger patients (< 60 years)
with ELN defined poor-risk AML compared to historical con-
trols who received induction chemotherapy (NCT03573024)
[89]. Ultimately, a randomized prospective trial will be re-
quired to determine the most effective strategy in this high-
risk group of patients who are eligible for intensive chemo-
therapy and alloSCT.
Why It Is Not Time to Say Goodbye to “3+7”
The number of AML subtypes where “unadulterated” 3+7
(i.e., 3+7 alone) is an appropriate therapeutic option is shrink-
ing. A meta-analysis demonstrated a small incremental surviv-
al benefit with the addition of GO to 3+7 for intermediate-risk
cytogenetics (excluding t/s-AML or AML-MRC) with no im-
pact on CR rates; hence, administration of 3+7 without GO
may be warranted in patients with risk factors for VOD/SOS.
AML subtypes where there is no longer a role for treatment
 120 Page 10 of 13
with 3+7 only include t/s-AML, FLT3-mutated AML, and
CBF AML. However, unlike for acute promyelocytic leuke-
mia, where there is a high CR and cure rate with all-trans
retinoic acid and arsenic trioxide [90], there is no curative
non-chemotherapeutic treatment option for patients with other
subtypes of AML. The lower intensive therapies, including
VEN + HMA, may be very effective in remission induction,
but they are not very effective at preventing relapse.
Therefore, 3+7 will remain the intensive chemotherapy back-
bone onto which newer therapies have been/will be added to
manage specific subsets of AML (e.g., quizartinib
(NCT02668653), gilteritinib (NCT02236013), and
venetoclax (NCT03709758)).
Conclusion
The treatment of AML has been propelled into the foreground
in the last 5 years with the approval of multiple new drugs.
These are exciting times for treating clinicians as they have an
unprecedented number of therapeutic options at their disposal,
but at the same time, AML treatment is becoming increasingly
complex. Naturally, the relevance and value of intensive che-
motherapeutic regimens have been challenged as our under-
standing of the underlying pathobiology of AML pathogene-
sis expands and the spotlight turns towards targeted therapies.
As highlighted in this review, 3+7 continues to play a pivotal
role in AML treatment, especially in patients < 60 years, and
will remain a cornerstone of AML therapy for individuals who
are suitable for intensive chemotherapy, at least until there are
randomized, head-to-head trials that demonstrate a clear supe-
riority of novel therapies over the 3+7 backbone. Currently,
clinical trials are attempting to augment the established effica-
cy of 3+7/intensive chemotherapy regimens though combina-
tion with novel therapies. It will be fascinating to see how well
combinations of targeted, lower intensity therapies perform
against traditional intensive chemotherapy regimens in the
front-line setting. Until then, it would be premature to say
goodbye to 3+7 chemotherapy altogether.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Declarations
Conflict of Interest KWLY consulted for and/or received honorarium
from Novartis, F. Hoffmann La Roche, Takeda, Pfizer, TaiHo, Bristol-
Myers Squib/Celgene, Paladin, Astex, and Otsuka. Received research
funding from Astex, Novartis, Forma Therapeutics, Jazz, Onconova, F.
Hoffmann La Roche, Genentech, and Tolero. ACS has consulted for and/
or received honoraria from and/or received research support from
AbbVie, Agios, Amgen, Astellas, Celgene/BMS, GlycoMimetics, Jazz,
Novartis, Paladin, Pfizer, and Teva.
Curr Oncol Rep (2021) 23:120
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