American Journal of Hematology

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES OPEN ACCESS

Acute Myeloid Leukemia: 2025 Update on Diagnosis,

Risk-­Stratification, and Management
Shai Shimony | Maximilian Stahl | Richard M. Stone

Department of Medical Oncology, Dana-­Farber Cancer Institute, Boston, Massachusetts, USA

Correspondence: Shai Shimony ([email protected]) | Richard M. Stone ([email protected])

Received: 22 November 2024 | Revised: 23 January 2025 | Accepted: 25 January 2025

Keywords: AML diagnosis | AML therapy | AML-­molecular diagnosis and therapy | measureable residual disease in AML | neoplasia-­myeloid leukemias
and dysplasias

ABSTRACT
Disease Overview: Acute myeloid leukemia (AML) is a bone marrow stem cell cancer that is often fatal despite available
treatments. Diagnosis, risk assessment, monitoring, and therapeutic management of AML have changed dramatically in the
last decade due to increased pathophysiologic understanding, improved assessment technology, and the addition of at least 12
approved therapies.
Diagnosis: The diagnosis is based on the presence of immature leukemia cells in the blood, and/or bone marrow or less often in
extra-­medullary tissues. New biological insights have been integrated into recent classification systems.
Risk Assessment: The European Leukemia Network has published risk classification algorithms for both intensively and non-­
intensively treated patients based on cytogenetic and on molecular findings. Prognostic factors may differ based on the thera-
peutic approach.
Monitoring: Our increasing ability to quantify lower levels of measurable residual disease (MRD) potentially allows better
response assessment, as well as dynamic monitoring of disease status. The incorporation of MRD findings into therapeutic
decision-­making is rapidly evolving.
Risk Adapted Therapy: The availability of 12 newly approved agents has been welcomed; however, optimal strategies incorpo-
rating newer agents into therapeutic algorithms are debated. The overarching approach integrates patient and caregiver goals of
care, comorbidities, and disease characteristics.

1   |   Introduction Furthermore, novel insights regarding AML biology have im-

pacted our ability to diagnose, prognosticate, and monitor pa-
Acute myeloid leukemia (AML) is a disease arising from un- tients with AML [2, 22–24].
controlled proliferation of clonal hematopoietic cells [1, 2]. It
comprises 1% of all new cancer cases in the United States. AML
is diagnosed mainly at older age (median age at diagnosis of 2   |   Updates in Diagnosis
68 years) [3] and has an estimated 5-­year OS of 32% (up to 50% in
young patients and less than 10% in patients older than 60) [4, 5]. In 2022 the WHO fifth edition [22] and the International
However, these outcomes do not fully encompass the dramatic consensus criteria (ICC) [23] AML classification systems
change in the therapeutic landscape, with the approval of 12 were published, each integrating novel molecular find-
new drugs or combination regimens since 2017 [6–21] (Table 1). ings and highlighting biologically-­
defined and clinically

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© 2025 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.

American Journal of Hematology, 2025; 0:1–32 1 of 32

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relevant AML subtypes. We will discuss similarities and differ- ontogeny and are associated with poor prognosis when treated
ences between the two systems, as well as the challenges and les- with intensive chemotherapy [43]. However, the definition of
sons learned since these classifications were introduced. “secondary” differs between classifications. The WHO defined
AML myelodysplasia-­related (AML-­MR) which includes one of
Of note, acute promyelocytic leukemia (APL), usually asso- the following: (1) a clinical history of MDS or MDS/MPN, (2)
ciated with a PML::RARA translocation, is a unique clinico- cytogenetics typical of MDS, or (3) molecularly defined based
pathological AML entity that accounts for 5%–10% of AML on the presence of one of eight secondary ontogeny defin-
[25, 26]. APL is generally initially treated with a combination ing mutations. In contrast, ICC included two separate entities
of all trans-­retinoic acid (ATRA) and arsenic trioxide (ATO), of secondary AML: molecularly defined (termed AML with
with additional chemotherapy for those with WBC > 10 K/μL. myelodysplasia-­ related gene mutations) and cytogenetically
This entity has an excellent prognosis, especially in compar- defined (termed AML with myelodysplasia-­related cytogenetic
ison to other non-­A PL AML subtypes [27–33]. In this review, abnormalities). Furthermore, in the ICC, a clinical history of
we will not discuss APL management; AML will refer to non-­ prior MDS or MDS/MPN is used to annotate the diagnosis of
APL AML. AML, rather than being considered a separate entity. In addi-
tion, the molecular and cytogenetic abnormalities considered
Both ICC and WHO fifth edition molecularly defined abnor- MDS-­defining differ slightly between the two classifications.
malities that allow a diagnosis of AML even at relatively low For example, a RUNX1 mutation is included as myelodysplasia-­
marrow blast counts. In addition to RUNX1::RUNX1T1 and defining in the ICC definition, but not in the WHO 2022 criteria,
CBFB::MYH11, NPM1 is recognized by both classifications as an (Figure 1 and Table 2).
AML-­defining mutation, due to the rarity of NPM1 mutations
in myelodysplastic syndromes (MDS) and the rapid progression Both classification systems incorporated special consideration
seen in most patients previously defined as MDS with NPM1 for prior cytotoxic exposure and genetic predisposition. In
mutation [34, 35]. The WHO delineates CEBPA-­mutated AML as the WHO classification, those were reclassified under a new
an entity including either biallelic CEPBA mutation (irrespective diagnostic category called secondary myeloid neoplasms en-
of mutation type) or a monoallelic in-­frame basic leucine zip- compassing either myeloid neoplasms arising after cytotoxic
per region (bZIP) mutated gene. The ICC definition of CEBPA-­ therapeutics, or those which possess a defined germline pre-
mutated AML only requires the presence of the bZIP alteration. disposition. In the ICC classification, these were considered as
This addition is due to the discovery that the in-­frame mutations qualifiers or annotations to an AML diagnosis rather than a sep-
in C-­terminal bZIP C-­terminus region have distinct clinical and arate diagnostic category (Figure 1).
molecular characteristics: younger age, higher white blood cell
counts, and enrichment in co-­mutations of GATA2 and NPM1. Therapy-­related AML is traditionally associated with worse
The presence of bZIP in-­frame mutation is associated with fa- prognosis [43], although it was not officially integrated into
vorable response and improved survival [36–38]. BCR::ABL1 the ELN prognostic criteria as adverse risk. Recent discoveries
was added as a formal AML defining lesion, with the require- demonstrated that mutations in TP53 [44–46] and related genes
ment of blasts ≥ 20% rather than ≥ 10%, to differentiate from such as PPM1D [47, 48] drive chemoresistance and dismal out-
CML in accelerated phase. comes. Indeed, the biological characteristics of leukemia gener-
ally outweigh clinical history. For example, those who develop
The WHO and ICC classifications employ different blast APL after exposure to chemotherapy for another cancer are ex-
thresholds to define AML in certain situations: There is no pected to do well [49].
minimum threshold in the WHO criteria for AML with defin-
ing genetic abnormalities (with the exception 20% required for With recent advances in molecular diagnosis and analysis, more
AML with BCR::ABL1 and AML with CEBPA bZIP mutation); individuals than previously with myeloid malignancies (even
the ICC requires at least 10% blasts in the bone marrow or pe- those who present at advanced ages) are now recognized to have
ripheral blood for defining AML with recurrent genetic abnor- an inherited germline predisposition [50]. Thus, it has been ad-
malities (with the exception of ≥ 20% in AML with BCR::ABL1 vocated that MDS and/or AML patients with certain molecular/
or with prior MDS/MPN, e.g., chronic myelomonocytic leuke- cytogenetic lesions, a syndromic presentation with a myeloid
mia [CMML]). For all other AML subgroups, the 20% blasts malignancy, or a suggestive family history undergo a genetic
threshold was retained by the WHO. However, The ICC in- analysis of unaffected tissue to assess for a germline predispo-
troduced a new category of MDS/AML comprising those with sition [51].
10%–19% blasts in the bone marrow or peripheral blood, in
recognition of the similarities in biology and prognosis be- For example, mutations in DDX41 are the most common genetic
tween such patients and those with ≥ 20% myeloblasts [39–42]. predisposition in MDS and AML in adults [52, 53], with germ-
Whether a patient who has an AML defining-­genetic lesion line pathogenic variants carrying an increased risk for MDS or
with a relatively low blast count responds to therapy similarly AML found in ~1:430 people in European adults [54, 55]. The
to those with the same lesion and higher blasts count remains occurrence of AML in those with a germline mutation in DDX41
to proven prospectively. is generally thought to involve a “second-­hit” via a mutation in
the other allele [56]. AML with DDX41 germline mutations have
The definition of AML with myelodysplasia related changes unique clinical characteristics: male predominance, presenta-
(MRC) was not included in either classification system. Instead, tion in the seventh decade, low peripheral blood leukocyte and
both WHO and ICC introduced categories with molecular and bone marrow blast counts, and intensive chemotherapy or vene-
cytogenetic abnormalities that define functional secondary toclax based-­regimen-­responsiveness, yielding a more favorable

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 TABLE 1    |    Drugs and/or combinations recently approved by the FDA for AML with selected trials.

Drug Mechanism Approved indication FDA approval date Approved regimen Other selected trials

GO [13, 120, 217] CD33-­directed antibody ND CD33-­positive AML 09/01/2017 ND – with

combinationa • AMLSG 0909: ICE+ATRA+/-­GO
drug conjugate intensive chemotherapy [257]
• NCRI AML 18 trial: 7 + 3+ GO (1
vs. 2 doses) [126]
• NCRI AML 19 trial: GO+
FLAG-­I DA versus GO+ DA; second
randomization for single versus
fractionated GO [258]

R/R CD33 positive adults R/R – monotherapy

CPX-­351 [7, 133] Liposomal daunorubicin ND t-­A ML or AML-­MRC (defined 08/03/2017 Monotherapy for • CPX-­351 in patients with t-­
and cytarabine by clinical history, morphologic induction and AML or AML-­MRC age < 60 years
changes, or cytogenetics) consolidation (NCT04269213)
• NCRI AML 19 trial (HR arm):
CPX-­351 vs. FLAG-­I DA in HR ND-­
AML [136]
• CPX-­351 + ven, Ivo or midostaurin
in ND-­A ML patients (NCT04075747)
[259]
• Low dose CPX-­351 + ven in ND-­
AML (NCT04038437) [260]
• CPX-­351 + ven in R/R AML
(NCT03629171) [261]

Enasidenib [10] IDH2 inhibitor R/R IDH2 mutated AML 01/08/2017 Monotherapy • HMA + Ena as single arm or versus
HMA in IDH2-­mutated ND-­A ML
[181, 216]
• Ena versus conventional therapy in
older R/R AML [215]
• Ena + ven for IDH2-­mutated AML
(NCT04092179) [262]
• Ena + intensive induction
chemotherapy for IDH2-­mutated
ND-­A ML (NCT02632708) [146], NCT
03839771)
• ASTX727 + ven + Ena for IDH2
mutated R/R AML (NCT04774393)

(Continues)

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 TABLE 1    |    (Continued)

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Drug Mechanism Approved indication FDA approval date Approved regimen Other selected trials

Ivosidenib [8, 9, 15] IDH1 inhibitor R/R IDH1-­mutated AML R/R − 07/20/2018 R/R—Monotherapy • Ivo + intensive chemotherapy
ND—Combination for IDH1 mutated-­N D-­A ML
ND IDH1-­mutated AML ND
therapy with azacitidine (NCT02632708) [146], NCT03839771)
age ≥ 75 years/comorbidities, not Monotherapy −05/02/2019
or monotherapy • ASTX727 + ven + Ivo for IDH1
fit for intensive chemotherapy Combination—05/25/2022
mutated-­R /R AML (NCT04774393)
• Ivo + ven +/− aza in AML
(NCT03471260) [208]
• CPX-­351 + Ivo for IDH1 mutated-­-
R/R AML (NCT04493164)

Olutasidenib [19, IDH1 inhibitor R/R IDH1-­mutated AML 12/01/2022 Monotherapy

210]

Midostaurin [6] FLT3 inhibitor ND FLT3-­mutated AML 04/28/2017 With “7 + 3” and • Midostaurin as maintenance
HIDAC consolidation therapy post-­A lloSCT [263]
• Crenolanib versus Midostaurin
added to induction chemotherapy
for FLT3-­mutated ND-­A ML
(NCT03258931)

Gilteritinib [12] FLT3 inhibitor R/R FLT3-­mutated AML 11/21/2018 Monotherapy • Gilteritinib + ven in R/R FLT3-­
mutated AML [206]
• Gilteritinib + ven + HMA
in FLT3-­mutated AML: (with
azacitidine) [189], (with ASTX727—
NCT05010122) [264]
• CPX-­351 + gilteritinib in FLT3-­
mutated R/R AML (NCT05024552)
• Gilteritinib vs. Midostaurin added
to “7 + 3” in FLT3-­mutated ND-­A ML
(NCT04027309, NCT03836209)
• MORPHO study—Gilteritinib
versus placebo as maintenance post-­
alloSCT in FLT3-­mutated AML [156]

Quizartinib [20] FLT3 inhibitor ND FLT3-­mutated AML 07/20/2023 With “7 + 3” and • 7 + 3 + Quizartinib versus Placebo
HIDAC consolidation in patients with ND FLT3-­I TD
negative AML (NCT06578247)
• CPX-­351 with quizartinib in FLT3-­
ITD mutated-­A ML (NCT04128748)
• aza + ven + quizartinib in ND unfit
FLT3-­I TD-­mutated AML [265]

(Continues)

American Journal of Hematology, 2025

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 TABLE 1    |    (Continued)

Drug Mechanism Approved indication FDA approval date Approved regimen Other selected trials

Venetoclax [11, 17, BCL2 inhibitor ND-­A ML age ≥ 75 years/comorbidities, 11/21/2018 Combination + • FLAG-­I DA + ven in ND-­A ML [139]
18, 165] not fit for intensive chemotherapy decitabine, aza or LDAC or ND and R/R AML [224]
“7 + 3” + ven in AML [141]
(NCT03709758) [142]
Clad + ven + LDAC/aza
in ND-­A ML [168]
Clad + IDA+ ara-­C + ven
in ND-­A ML [143]
Ven in combination with
reduced intensity conditioning
for AlloSCT [266]
HMA + ven as maintenance
therapy post-­A lloSCT (“VIALE-­T,”
NCT04161885) or post-­chemotherapy
(“VIALE-­M,” NCT04102020)

CC486 [14] Oral DNMT inhibitor ND-­A ML patients aged 55 ≥ as 09/01/2020 Monotherapy • CC486 as maintenance post-­
post-­intensive induction therapy in AlloSCT [263], (NCT04173533)
patients who achieved remission • CC486 + ven as maintenance
after conventional chemotherapy
(NCT04102020)
• CC486 + ven in AML
(NCT04887857, NCT05287568) [267,
268]

Glasdegib [16] Hedgehog pathway inhibitor ND-­A ML age ≥ 75 years/comorbidities, 11/21/2018 In combination • CPX-­351+ Glasdegib in t-­A ML or
not fit for intensive chemotherapy with LDAC AML-­MR (NCT04231851)
• “7 + 3”/aza with vs. without
glasdegib in ND-­A ML [184]

Revumenib [21, 222] Menin inhibitor R/R KMT2A rearranged 11/15/2024 Monotherapy AUGMENT-­102 (NCT05326516):
acute leukemia Chemotherapy + revumenib
in R/R AML
NCT05886049: 7 + 3+
revumenib in ND AML
SAVE (NCT05360160):
Decitabine/cedazuridine
+ venetoclax + revumenib
in ND and R/R AML
Abbreviations: 7 + 3—daunorubicin plus cytarabine; AlloSCT—allogeneic stem cell transplantation; AML—acute myeloid leukemia; AML-­MRC—acute myeloid leukemia with myelodysplastic related changes; ara-­C—cytarabine;
ATRA—all trans retinoic acid; aza—azacitidine; CD—cluster of differentiation; clad—cladribine; DNMT—DNA methyltransferase; Ena—enasidenib; FLAG-­I DA—fludarabine, cytarabine, G-­C SF, idarubicin; FLT3i—FLT3
inhibitor; GO—gemtuzumab ozogamicin; HIDAC—high dose cytarabine; HMA—hypomethylating agents; HR—high risk; ICE—Idarubicin, cytarabine, etoposide; ida—idarubicin; IDH—isocitrate dehydrogenase; Ivo—ivosidenib;
LDAC—low dose cytarabine; ND—newly diagnosed; R/R—relapse or refractory; t-­A ML—therapy related AML; ven—venetoclax.
a Approved as a single agent in patients with ND-­A ML as well, but rarely used as monotherapy.

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FIGURE 1    |    Comparison between WHO fifth versus ICC AML definitions. * ≥ 20% blasts are required for AML definition. Colors reflect similar
subgroups between classifications. AML—acute myeloid leukemia; ICC—international consensus classification; MDS—myelodysplastic syndrome;
MPN—myelodysplastic neoplasm; WHO—world health organization.

prognosis than matched patients with wild type DDX41 [57–59]. 3   |   Updates in Risk Stratification
Forthcoming discoveries of additional germline predisposition
syndromes will likely increasingly impact treatment strategies, The European leukemia network (ELN) 2022 guidelines incor-
such as donor selection for allogeneic stem cell transplant, de- porate knowledge from novel molecular findings and recent
cisions regarding the choice of the optimal transplant condi- trial results. The main changes compared with the ELN 2017
tioning regimen, or the fashion in which family members are [63] are (Table 3):
evaluated and monitored [60].
• The FLT3 internal tandem duplication (ITD) allelic ratio
While advances in AML diagnosis could aid in optimizing (AR) is no longer considered in risk classification. Patients
individualized therapy, the two novel classification systems with FLT3-­I TD-­mutated AML are assigned to the interme-
challenge communication between health care profession- diate group, irrespective of the AR or presence of an NPM1
als, especially pathologists, treating clinicians, and patients. mutation. The reasons for this change include the effect of
In the last few years, numerous comparisons between the FLT3 inhibitors on outcomes of patients with FLT3-­I TD-­
two classifications have been conducted and there are calls mutated AML [6, 12, 20, 64] and integration of MRD into
for a unified diagnostic approach [61, 62]. The similarities be- decision-­making [65, 66].
tween the two classification systems exceed the differences.
• AML with myelodysplasia-­related gene mutations (as de-
Nonetheless, the clinician has the responsibility to synthesize
lineated by ICC) is now defined as an adverse risk entity,
the biological, clinical, and personal data while considering
which is delineated by the presence of a pathologic variant
the available literature to make a treatment decision. Clearly,
in one or more of ASXL1, BCOR, EZH2, RUNX1, SF3B1,
the diagnosis alone, whether using the ICC or WHO algo-
SRSF2, STAG2, U2AF1, or ZRSR2 genes [2, 43]. These mu-
rithms cannot be the sole factor in such a decision. Further,
tations do not confer adverse risk in patients with favorable
the ICC recommends that the molecular tests be available in
risk-­defining aberrations.
3–5 days; this goal is aspirational for many centers around
the world. While the integration of novel molecular find- • NPM1-­mutated AML with adverse cytogenetic abnormali-
ings is likely to improve diagnostic accuracy and promote ties is now classified as adverse risk. This change is based
biologically-­based therapy, we should also consider the appli- on a meta-­analysis that evaluated additional cytogenetic
cability and generalizability of recommendations for the en- abnormalities in patients with NPM1-­mutated AML [67].
tire healthcare community, as a major goal is to optimize care The exact role of additional molecular abnormalities (other
of patients worldwide. than FLT3-­I TD) in patients with NPM1-­mutated AML is not

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 TABLE 2    |    Major differences between WHO fifth AML and the ICC AML classifications.

Major differences in AML classification systems

WHO fifth AML classification ICC AML classification Main differences
Structure
1. Two groups—AML defined by genetic abnormalities. Hierarchical diagnosis of AML with recurrent Two groups definition (WHO)
2. AML is defined by differentiation. Requires exclusion of AML with defined genetic abnormalities = > mutated TP53 (VAF > 10%) versus hierarchical order (ICC)
genetic alterations, MPAL, myeloid neoplasm pCT, and history of proven = > AML with myelodysplasia-­related gene
MPN. mutations = > AML with myelodysplasia-­related
cytogenetic abnormalities = > AML NOS
Blast threshold (bone marrow or peripheral blood)
AML defined by genetic abnormalities does not require any blast threshold AML with recurrent genetic abnormalities Different blasts thresholds.
(except for AML with BCR::ABL1, AML with biallelic/single bZIP mutations in requires 10% blasts (except AML with BCR::ABL1 New definition of MDS/
CEPBA mutation and AML-­MR which require 20%). or prior MDS/MPN requires 20%). AML in ICC criteria.
AML defined by differentiation requires 20% blasts. Other subtypes are defined as MDS/AML
(blasts 10%–19%) or AML (blasts ≥ 20%).
AML-­MR versus AML with myelodysplasia-­related gene mutations/cytogenetic abnormalities (formerly known as part of AML-­
MRC definition)
Cytogenetic: del(5q)/t(5q); −7/del(7q)/t(7q); del(11q); del(12p)/t(12p); −13/ Cytogenetic: del(5q)/t(5q)/add(5q); −7/del(7q); +8; del(12p)/ Modest difference in molecular
del(13q); del(17p)/t(17p)/iso(17q); idic(X)(q13) or Complex karyotype (≥ 3 t(12p)/add(12p); iso(17q), −17/add(17p) or del(17p); del(20q); and cytogenetic definitions.
abnormalities). idic(X)(q13) or Complex Karyotype (≥ 3 abnormalities) Significance and interpretation
Molecular: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, UAKF2, ZRSR2. Molecular: ASXL1, BCOR, EZH2, SF3B1, SRSF2, of prior MDS diagnosis
Prior history of MDS or MDS/MPN accounts for AML-­MR STAG2, U2AF1, ZRSR2 and RUNX1.
Prior history of MDS or MDS/MPN accounts
as a qualifier and not a separate group
Prior History of MDS or MDS/MPN, prior cytotoxic therapy, germline disposition
New definition of secondary myeloid neoplasm (separate from AML Diagnostic qualifiers in addition to AML group— Different categorization
defined groups above)— • Therapy-­related of clinical or pathological
• Myeloid neoplasms post cytotoxic therapy (pCT). • Progression from MDS or MDS/MPN characteristics
• Myeloid neoplasms associated with germline predisposition • Germline predisposition
Note: Major differences are bolded and highlighted in the right column.
Abbreviations: AML—acute myeloid leukemia; AML-­MR—AML myelodysplasia-­related; AML-­MRC—AML with myelodysplasia-­related changes; ELN—European leukemia network; ICC—international classification; MDS—
myelodysplastic syndrome; MPAL—mixed phenotype acute leukemia; MPN—myeloproliferative neoplasm; pCT—post-­c ytotoxic therapy; WHO—World Health Organization.

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TABLE 3    |    ELN 2022 risk classification for patients treated with NPM1 in the presence of otherwise adverse-­risk defining
intensive chemotherapy. mutations [68–72].

Risk category Genetic abnormality • The favorable prognosis of CEPBA-­mutant AML depends
solely on an in-­frame mutations affecting the bZIP region,
Favorable t(8;21)(q22;q22.1)/RUNX1::RUNX1T1a
irrespective of whether mono-­or bi-­allelic mutations are
inv (16)(p13.1q22) or t(16;16) present [36–38].
(p13.1;q22)/CBFB::MYH11a
• Additional disease-­defining cytogenetic abnormalities now
Mutated NPM1 without FLT3-­I TDb considered as adverse risk—include t(3q26.2;v) involv-
ing the MECOM gene and t(8;16)(p11;p13) associated with
bZIP in-­frame mutated CEBPAc
KAT6A::CREBBP, as they were also shown to be associated
Intermediate FLT3-­I TD (irrespective of allelic with dismal long term overall survival [73, 74].
ratio or NPM1 mutation)
• AMLs with hyperdiploid karyotypes with multiple trisomies
t(9;11)(p21.3;q23.3)/MLLT3::KMT2Ad (or polysomies) are no longer considered to be equivalent
Cytogenetic and/or molecular to a complex karyotype and are excluded from the adverse
abnormalities not classified risk group, as such patients with only numerical cytogenetic
as favorable or adverse changes without structural abnormalities have better sur-
vival outcome compared to patients with three or more cy-
Adverse t(6;9)(p23;q34.1)/DEK::NUP214 togenetic changes with structural abnormalities [75].
t(v;11q23.3)/KMT2A rearranged
(excluding KMT2A-­PTD) However, the guidelines are largely based on intensively treated
patients up to 60 years. A recent study generated a prognostic
t(9;22)(q34.1;q11.2)/BCR::ABL1 score for older patients, aged 60 and older based on the NCRI-­
(8;16)(p11;p13)/KAT6A::CREBBP AML 18 and HOVON-­SAKK cohorts [76]. Four distinct groups
(favorable, intermediate, poor and very poor) were identified
inv (3)(q21.3q26.2) or t(3;3) based on clinical (Male, WBC ≥ 20*109/L cells, age > 65 years)
(q21.3;q26.2)/GATA2, MECOM(EVI1) and genetic (monosomal karyotype, TP53, RUNX1, FLT3-­I TD,
t(3q26.2;v)/MECOM(EVI1)-­rearranged ASXL1, and DNMT3A mutations) characteristics. The proposed
classification improved calibration compared with the ELN
−5 or del(5q); −7; −17/abn(17p) 2022 in a derivation and internal validation cohort. In addition,
Complex karyotype (change in they demonstrated that alloSCT was associated with improved
definition)e; Monosomal Karyotypef survival in the very poor and intermediate group, a trend toward
improved survival in the poor group, and no improvement in the
Mutated ASXL1, BCOR,
favorable group. In the two latter groups, the benefit of reduced
EZH2, RUNX1, SF3B1, SRSF2,
non-­relapse mortality with alloSCT was offset by higher non-­
STAG2, U2AF1, or ZRSR2g
relapse mortality associated with alloSCT. These results should
Mutated TP53 (variant be validated in external cohorts for their generalizability.
allele frequency ≥ 10%)
Abbreviation: ELN—European leukemia network.
However, both of these criteria were derived from patients
Source: Modified from Döhner et al. ELN 2022 recommendations, tab. 6 [24]. treated with intensive chemotherapy, with multiple studies
aThe presence of KIT or FLT3 mutations does not alter risk category.
bAML with NPM1 and adverse risk cytogenetic abnormalities is defined as
demonstrating the limited prognostic role of the ELN 2022
adverse risk. criteria in patients who are treated with less-­intensive ther-
cOnly in-­f rame mutations affecting the basic leucine zipper (bZIP) region of apies, mainly venetoclax-­based regimens [59]. For example, a
CEBPA, irrespective of whether they occur as monoallelic or biallelic mutations, recent study in patients treated with a hypomethylating agent
have been associated with favorable outcomes.
dThe presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent (HMA) plus venetoclax demonstrated that an AML-­M R muta-
adverse-­r isk gene mutations. tion does not confer an inferior prognosis [77]. Thus, the ELN-­
eComplex karyotype: ≥ three unrelated chromosome abnormalities in the
2022 schema must be considered in the context of the specific
absence of other class-­defining recurring genetic abnormalities; excludes
hyperdiploid karyotypes with three or more trisomies (or polysomies) without treatment received. Based on analysis of the prospective ran-
structural abnormalities.
f Monosomal karyotype: presence of two or more distinct monosomies (excluding
domized VIALE-­A plus the previous phase Ib trial involving
X or Y), or one single autosomal monosomy in combination with at least one
HMA plus venetoclax, a 4-­gene signature risk score classified
structural chromosome abnormality (excluding core-­binding factor AML). patients into three prognostic groups: (1) those with TP53
g AML with NPM1 and one of these adverse molecular abnormalities do not alter
mutations were included in a lower benefit group; (2) those
risk category currently.
without TP53 but harboring a FLT3-­I TD, NRAS or KRAS mu-
tations were intermediate; (3) those without any of these 4 mu-
tations were favorable (median OS 5.5, 12.1 and 26.5 months,
yet defined; currently, those with concomitant NPM1 and respectively) [78]. A retrospective study based on this classifier
myelodysplasia gene mutations and even TP53 mutations demonstrated similar results [79], thereby enabling the devel-
are still considered favorable (although there is conflict- opment of new ELN risk criteria for patients with AML treated
ing data); However, since publication of the ELN 2022 risk with lesser-­intensive therapies (Table 4) [80]. Nevertheless,
criteria, several studies questioned the favorable impact of one should note that the combination of HMA plus venetoclax

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TABLE 4    |    ELN 2024 risk classification for patients treated with to most patients with AML, the latter requires the knowledge
less-­intensive chemotherapy. of specific diagnostic cytogenetic abnormalities or mutations
and is commonly available for tracking patients with CBF or
Risk category Genetic abnormality
NPM1 mutations. Other increasingly used techniques are next-­
Favorable Mutated NPM1 (FLT3-­I TDwt, generation sequencing (NGS) [83, 84] and digital droplet PCR
NRAS wt, KRAS wt, TP53wt) (ddPCR; each of the latter can be sensitive down to about 1/106)
[85]. The ELN recommendations from 2021 focus on the stan-
Mutated IDH2 (FLT3-­I TDwt,
dardization of MFC-­MRD and RT-­qPCR MRD thresholds, MRD
NRASwt, KRAS wt, TP53wt)
response definition, and use of MRD in clinical decision-­making
Mutated IDH1a (TP53wt) [66]. Currently, the level of detection recommended by ELN is
1/103 or lower. However, as measurement becomes more sen-
Mutated DDX41b
sitive over time and data from clinical trials are generated, the
Other cytogenetic and/or molecular use and interpretation of MRD assessment is expected to evolve.
abnormalitiesc (FLT3-­I TDwt,
NRAS wt, KRAS wt, TP53wt) The prognostic value of MRD, no matter how measured, is well
established, both in patients treated with intensive and less-­
Intermediate Other cytogenetic and/or molecular
intensive chemotherapy. In a study including 346 patients with
abnormalitiesc (FLT3-­I TDpos and/or
an NPM1 mutation, MRD measured by RT-­qPCR for this gene
NRASmut, and/or KRASmut, TP53wt)
with a threshold of 0.1% after two cycles of intensive chemother-
Adverse Mutated TP53 apy was found to be an independent prognostic factor (MRD
Note: The classification does not apply to patients with prior hypomethylating positivity HR for death: 4.38; 95% CI: 2.57 to 7.47; p < 0.001)
agent exposure. [86]. Another key trial in 430 intensively treated patients eval-
Source: Modified from Döhner et al. ELN 2022 recommendations, tab. 1, [80].
aThe favorable risk applies specifically to patients treated with azacitidine + uated the utility of MRD in CR after two chemotherapy cycles
ivosidenib, irrespective of the presence of activating signaling gene mutations. using an NGS panel with a cut-­off ≥ 0.02% for positivity [87].
bIdentification of a DDX41 mutation at near-­heterozygous frequency should
Patients with persistent MRD positivity, excluding mutations in
prompt consideration of germline DDX41 mutation.
cFor many cytogenetic and molecular abnormalities, single or as co-­aberrations, DNMT3A, TET2, and ASXL1, which are often present in clonal
no data are currently available; they are tentatively categorized as favorable and hematopoiesis, had higher 4-­year relapse rates than those with
intermediate risk depending on the absence or presence of activating signaling undetectable MRD (55.4% vs. 31.9%; hazard ratio [HR], 2.14;
gene mutations.
p < 0.001), as well as worse 4-­year overall survival (41.9% vs.
66.1%; HR for death, 2.06; p < 0.001). In addition, NGS contrib-
uted additive prognostic value compared to MFC-­MRD alone, in
is widely used today in a broader and more heterogenous that patients who were negative by both had the lowest rate of
population than was included in the VIALE-­A trial. A recent relapse (73% when both were positive, ~50% when either MFC-­
real-­world study from the UK in patients treated with veneto- MRD or NGS-­MRD were negative and 27% when both were
clax plus azacitidine (n = 587) or low dose cytarabine (LDAC; negative, p < 0.001). In a systematic review and meta-­analysis of
n = 67) demonstrated that the new ELN 2024 performed bet- MRD as prognostic tool in AML among 11 151 patients treated
ter compared to the ELN 2022, (C-­index of 0.568 vs. 0.542) intensively, the average OS HR for achieving MRD negativity
[81]. However, the prognostic value was still sub-­optimal. A was 0.36 (95% CI: 0.33–0.39) and the 5 year OS was 68% versus
large retrospective study in three academic centers (n = 279) 34% among patients who achieved MRD negativity versus those
suggested a re-­classification: favorable (mutated NPM1, IDH1, who did not [88].
IDH2, DDX41, and wild-­type N/KRAS, PTPN11, FLT3-­I TD,
TP53), intermediate (mutated FLT3-­I TD, NRAS, or other mu- The prognostic value of MRD in non-­intensively treated pa-
tations not classified and wild-­t ype KRAS, PTPN11, and TP53) tients has also been demonstrated. Among patients who were
and adverse risk (mutated KRAS, PTPN11, or TP53). The re- treated with azacytidine and venetoclax in the VIALE-­A trial,
classification was verified in the external UK cohort (n = 430) in patients who achieved composite complete remission (cCR)
[82]. Thus, the generalizability of the ELN 2024 risk criteria is defined as complete (CR) or complete responses with incom-
still not clear. Furthermore, although DDX41-­mutated AML plete count recovery [CRi]), the achievement of MFC-­M RD
is categorized as favorable risk irrespective of co-­mutations, negativity (< 0.1%) was associated with better outcomes com-
there is limited data on TP53 co-­mutation and its clinical pared to those who failed to have responses at such a deep
implication. level. The median DOR, EFS, and OS were not reached in
patients with MRD negativity with 12-­month estimates for
DOR, EFS, and OS in this group of 81.2%, 83.2%, and 94.0%.
4   |   Updates in MRD Measurement and In cCR patients with MRD positivity, the median DOR, EFS,
Monitoring and OS were 9.7, 10.6, and 18.7 months, corresponding to 12-­
month DOR, EFS and OS estimates of 46.6%, 45.4%, and 67.9%,
MRD (minimal or measurable residual disease) is a biomarker respectively. In a COX regression multivariable analysis ad-
used for prognostic, predictive, monitoring, and response as- justing for age, cytogenetics and type of AML (de novo vs.
sessment in AML. The two most commonly used technologies secondary), MRD negativity by MFC was independently pre-
to evaluate MRD are multiparameter flow cytometry (MFC) and dictive for improved OS (HR for mortality 0.285; 95% CI: 0.159
real-­time quantitative PCR (RT-­qPCR), each of which can detect to 0.510; p < 0.001) [89]. A recent study among NPM1-­mutated
one malignant cell in 10 4. While the former may be applicable patients treated with HMA + VEN demonstrated that MRD

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negativity (defined as 0 NPM1 copies per 100 ABL1 at the end recommendation. Moreover, even with such close serial mon-
of cycle 4) was associated with superior OS and EFS as well itoring, surprises are not uncommon. Relapse can occur in up
as a lower cumulative incidence of relapse than in those who to 30% of patients with MRD negativity [86, 87] and not all
remained MRD positive at that time point (at 2-­year 84% vs. patients with MRD positive disease will relapse, especially
46%), EFS (at 2-­year 84% vs. 20%) and cumulative incidence of those with low level PCR-­M RD in patients with NPM1 or CBF
relapse CIR (at 2-­year 72% vs. 10%) [90]. mutations [94, 95] (although relapse by flow without clinical
relapse was shown to carry the same adverse prognosis as
The peri-­transplant setting is a critical time for MRD evaluation. morphological relapse) [96].
Decisions about the relative utility of consolidation chemother-
apy and post-­transplant maintenance often need to be made at While the value of MRD as prognostic marker is well estab-
this juncture. However, the prognostic importance of MRD de- lished, there are no guidelines or wide acceptance on MRD
tection in the pre-­transplant setting is impacted by diagnostic utility as a predictive marker to aid in therapeutic decision-­
features. For example, in one study of patients aged ≥ 60 years making. However, several studies have demonstrated the
treated with intensive chemotherapy followed by reduced-­ use of MRD measurement as a guide to decide between
intensity conditioning (RIC) allogeneic hematopoietic stem cell post-­remission alloSCT versus consolidation chemotherapy.
transplantation (alloSCT), MRD negativity, measured by NGS A prospective trial suggested that with the persistence of
and defined as lack of any non-­DNMT3A or TET2 mutation, was RUNX1::RUNX1T1 transcripts after two cycles of chemother-
associated with better leukemia free survival (LFS) in a uni- apy should indicate the need for alloSCT even in this “favor-
variable model compared with MRD positivity [91]. However, able” subtype of AML [97]. Results from an important recently
MRD was no longer prognostic in a multivariable model, mainly published study from the United Kingdom may aid in guiding
due to its association with diagnostic genetic characteristics, in- utilization of alloSCT in patients with NPM1-­mutated AML
cluding MDS-­associated gene mutations, TP53 mutations, and treated with intensive chemotherapy. In 737 patients with
high-­risk karyotype. Similar results emphasizing the impact of NPM1-­mutated AML who were treated on the NCRI AM17
baseline cytogenetic and molecular characteristics compared and AML19 studies and achieved remission [98], consolida-
with MRD pre-­transplant was also seen when MRD was mea- tion with alloSCT in first complete remission (CR1) was bene-
sured by MFC [92]. ficial only in those who were MRD positive by PCR (sensitivity
1/10 000) for the NPM1 mutation post-­ induction (3-­ year
In a study performed in the United States, pre-­a lloSCT blood OS 61% vs. 24% with vs. without alloSCT, HR 0.39, 95% CI:
samples were obtained from the CIBMTR biobank and MRD 0.24–0.64, p < 0.001), but not in those who were MRD nega-
measured by ultra-­deep anchored multiplex PCR-­based NGS-­ tive post-­induction (79% vs. 82% with vs. without alloSCT, HR
MRD for FLT3, NPM1, IDH1/2, and KIT with error-­corrected 0.82, 95% CI: 0.50–1.33, p = 0.4). This was true even in the sub-
variant calling. Among 822 patients treated with AML who set of patients who had concomitant FLT3-­I TD mutation and
achieved CR and proceeded with alloSCT (371 in the discov- thus, considered ELN 2022 intermediate risk and traditionally
ery cohort, 451 in the validation cohort), pre-­a lloSCT NPM1, recommended for alloSCT in CR1: 3-­year OS 45% versus 18%
and/or FLT3-­I TD negativity was associated with improved with MRD positivity post-­induction; 83% vs. 76% if MRD neg-
OS, RFS, and lower relapse rates (p < 0.001 for all) compared ativity post-­induction.
with detectable presence of these mutant genes [84, 93].
MRD detectability during post-­ t herapy monitoring could
The ELN MRD guidelines recommend using qPCR for pa- prompt early treatment, but will this change disease natural
tients with NPM1 or CBF-­mutated AML (ddPCR or NGS-­M RD history? In the phase II VALDAC trial 48 patients with an
may be alternatively used, though paucity of data existed at MRD positive relapse (defined as ≥ 1 log) rise in the MRD was
the time of recommendations). For patients without an NPM1 measured by RT-­qPCR or dd-­P CR or low-­oligoblastic (defined
or CBF mutation at diagnosis, MFC-­M RD, ideally established as 5%–15% blasts) after achieving remission with intensive
at diagnosis to define the patient-­specific leukemia-­a ssociated chemotherapy were treated with LDAC plus venetoclax, to try
immunophenotype (LAIP) or different from normal (DfN), and eradicate the relapsing clone [99]. By the end of the sec-
may be used. The ELN guidelines also address the optimal ond cycle, almost half (44%) of the patients with MRD relapse
timing and tissue of MRD assessment. The diagnostic sample achieved MRD negativity and 70% of those with oligoblastic
should ideally be obtained from the bone marrow aspirate but relapse were able to achieve remission. The median OS was
can be done from peripheral blood in patients with NPM1 or not reached, with an estimated 2-­year OS of 67% in the MRD
CBF-­mutated AML whose blood has ≥ 20% peripheral blasts. cohort and 53% in the oligoblastic cohort. Although not ran-
The first post-­t reatment MRD should be measured in the mar- domized, these data suggest for potential role of MRD as a
row after two cycles of therapy (those with NPM1 and CBF surveillance marker and early intervention in those with low-­
mutant AML may have peripheral blood assessment). An burden relapsed disease.
end-­of-­treatment MRD measurement from marrow aspirate
is also recommended, although lack of data precludes firm The use of MRD in the peri-­transplant period could help de-
therapeutic recommendation based on the result. To eval- termine which patients should receive targeted maintenance
uate pre-­clinical recurrence in NPM1 or CBF mutant AML, therapy. In the phase III MORPHO trial (detailed below, under
assessments via blood every 4–6 weeks or bone marrow every “Gilteritinib” and “Post-­ remission therapy”), maintenance
3 months are recommended. The MFC-­M RD monitoring fre- gilteritinib post-­a lloSCT in patients with FLT3-­I TD AML im-
quency should be similar, but data supporting such intervals proved relapse-­ f ree survival (RFS) compared with placebo
are lacking, leading the panel to define this as an exploratory only in patients who had MRD detected using a sensitive

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PCR-­based assay for FLT3-­I TD prior to or post-­a lloSCT (HR, The incorporation of MRD as an endpoint also created new
0.515 [95% CI: 0.316 to 0.838]; p = 0.0065), but not in those definitions for time-­to-­event outcomes other than OS, such as
without detectable MRD (HR, 1.213 [95% CI: 0.616 to 2.387]; event free survival (EFSMRD), relapse free survival (RFSMRD) or
p = 0.575). cumulative incidence of relapse (CIR MRD), reflecting MRD pos-
itivity as an event. For proper interpretation of a given study,
Overall, MRD clearly has a role in the determination of prog- the MRD sample site (marrow vs. peripheral blood), technique,
nosis after initial chemotherapy, in both patients destined to and sensitivity should be provided. The practical suggestions
receive an alloSCT and in those that will be treated with con- on the ELN MRD guidelines are highly valuable, appreciated,
solidation chemotherapy. MRD testing is also emerging as and reasonable, but it must be recognized that more prospec-
predictive test to provide therapeutic guidance in various time-­ tive data will be required to increase the validity and strength
points—post-­ induction, pre-­and post-­ alloSCT; however, as of the recommendations. The developers acknowledged that
there is still no standardized method for MRD measurement revisions will be required when new data is generated, such as
and no solid prospective data guiding the integration of results that described above for NPM1 and FLT3-­I TD-­mutated AML.
into clinical management, we do not routinely utilize MRD for
surveillance and decision-­making in every patient with AML,
but we do consider the MRD findings in selected patients as 6   |   Updates on Treatments in Newly Diagnosed
part of the decision to perform allogeneic stem cell transplant AML
in first complete remission. For patients without a useful mo-
lecular diagnostic mutation at diagnosis, we routinely employ 6.1   |   General Considerations
flow cytometry, using DfN MRD technology, which generally
uses a 0.02% cut-­off [100]. For detection of NPM1 mutations or The classical paradigm to achieve cure in AML is first to in-
CBF translocations, we use PCR measurement, as previously duce CR thereby reducing the leukemia burden by several
mentioned [86, 101]. orders of magnitude, followed by post-­remission therapy in
the form of chemotherapy and/or alloSCT. The choice of the
most appropriate induction and post-­ remission therapy is
5   |   Updates in Response and Outcomes Evaluation based on multiple parameters, including patient comorbidi-
ties, past medical history including prior myeloid disease and/
The ELN 2022 response criteria retained the ELN 2017 defini- or cytotoxic chemotherapy exposure, AML cytogenetic and
tions of CR, CRi, partial remission (PR) and marrow leukemia molecular risk profile, possibly post-­therapy MRD status, as
free state (MLFS), with the addition of a new response cat- well as donor availability and patient goals of care [24, 63].
egory: CR with partial hematological recovery (CRh), which Historically, the first step for deciding on initial treatment
is defined by bone marrow blasts < 5%, absence of peripheral is based on patients ‘fitness’ for intensive therapy, with in-
blasts or extramedullary disease and partial count recovery tensive chemotherapy induction being the default for those
with ANC ≥ 500/μL and platelets ≥ 50 000/μL. CRh was used who are being deemed fit for a highly myelosuppressive/gut-­
as post hoc analysis required by the FDA for enasidenib ap- toxic approach. It is perhaps easier to delineate who should
proval [10] and has been used since as an endpoint in other not receive intensive chemotherapy than who should defin-
clinical trials; however, the exact role of CRh in predicting itively be subject to a long hospitalization with a significant
survival is yet to be defined [102]. ELN 2022 also integrated risk of treatment-­related mortality. At this time, age over 75 is
MRD status into response definitions. If MRD negative re- thought to be a relative contraindication to intensive chemo-
sponse is achieved, all CR subtypes (i.e., CR, CRi, and CRh) therapy, especially based on the known availability of effec-
should be annotated with MRD status as well, (i.e., CR MRD−, tive less intensive chemotherapy. Other than age, the FDA has
CRi MRD−, and CRh MRD−). The definition of relapse remains adopted a set of stringent criteria (poor hepatic, renal, cardiac,
bone marrow leukemia blasts ≥ 5%, any reappearance of pe- and pulmonary function) to definitively consider a patient
ripheral leukemic blasts in two samples 1 week apart or new unfit for intensive chemotherapy. The criteria, suggested by
extra-­medullary disease. A new definition of MRD failure or Ferrara et al. [103], are commonly incorporated into eligibil-
relapse is based on one of the following (if repeated within ity criteria and were validated in a large cohort of patients for
4 weeks to validate the results in a second consecutive sample predicting shorter-­term mortality after intensive chemother-
from the same tissue source, preferably bone marrow): conver- apy treatment in AML [104]. However, with multiple thera-
sion from MRD negativity to positivity by any method or copy peutics emerging in recent years, the paradigm has shifted
number increase by quantitative PCR by a factor of 10. The toward “who would benefit from intensive chemotherapy”
cutoff for MFC-­M RD negativity is < 0.1% for CD45-­expressing rather than who is deemed fit. For instance, even a ‘fit’ patient
cells using either LAIP or DfN immunophenotype. MRD neg- (of any age) with adverse risk biology might not be “appro-
ativity by qPCR is defined as cycling threshold (Ct) ≥ 40 in priate” for intensive chemotherapy due the likelihood of poor
≥ 2 of 3 replicates. Due to low relapse risk when the end of outcomes. The dilemma is most prominent in patients aged
treatment NPM1 or CBF AML qPCR is less than 2%, only val- 60–75 years, which represents the largest age group in AML,
ues above that level are considered positive [66, 94, 95, 101]. many of whom can potentially be treated with either inten-
However, the recent findings of NPM1 MRD positivity prog- sive or less-­intensive therapies in the upfront setting. We will
nostic value [71, 90, 98] have not been incorporated into these elaborate on the various therapeutic possibilities and present
guidelines and will possibly impact the threshold for MRD our approach, including an updated suggested therapeutic al-
positivity in patients with NPM1-­mutated AML. gorithm for patients in this age group.

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6.2   |   Updates on Intensive Therapy for Newly daunorubicin intensity and the additive value of second induc-
Diagnosed Patients tion in 864 patients aged 18–65 years with ND AML treated with
intensive chemotherapy [119]. In the first randomization, there
6.2.1   |   Updates on Induction Therapy was no difference in response or survival in patients treated with
60 mg/m2 compared with 90 mg/m2 (composite CR rates: 90% vs.
The backbone of intensive chemotherapy remains an anthra- 89%, p = 0.691; 3-­year OS 65% vs. 58%, p = 0.242, respectively).
cycline-­and cytarabine-­based approach [105, 106], most com- In subgroup analyses, comparable outcomes were seen across
monly as the “7 + 3” regimen using daunorubicin at a dose of patients with NPM1, FLT3-­I TD, and all ELN 2017 risk groups.
60–90 mg/m2 for 3 days and cytarabine at a dose of 100–200 mg/ In the second randomization, there was no benefit of a second
m2 for 7 days [107–110]. However, other induction regimens in induction among the 389 who achieved a good early response
use include CLAG-­M [111], G-­CLAM [112], IA [113], FLAG-­IDA (defined as < 5% blasts in the day-­14 bone marrow evaluation):
[114], and lomustine-­I A [115]. Whether any of these are ‘better’ composite CR rates 87% versus 85%; 3-­year OS 76% versus 75%
than 3 + 7 alone is unclear, though the addition of either lomus- with one vs. two inductions, respectively.
tine [115], a nucleoside analog [116], or treatment with FLAG-­
IDA [117] have each been suggested to be superior to 3 + 7 in Gemtuzumab ozogamicin (GO) is a CD33 monoclonal antibody
prospective randomized trials; however, the latter was deemed conjugated to the toxin calicheamicin. In an individual patient
too toxic for general use [118]. Moreover, several drugs were meta-­analysis of randomized control trials, improved survival
recently approved (in combination with chemotherapy) for pa- was seen among patients with AML when GO was added to 7 + 3
tients with newly diagnosed (ND) AML who are fit for inten- or FLAG-­IDA vs. no GO addition [120]. The benefit was confined
sive chemotherapy (Table 1 and Figure 2). Regarding the dose of to patients with favorable and intermediate cytogenetics (6 years
daunorubicin, in two large-­randomized trials, 90 versus 45 mg/ OS of 76 vs. 55% [OR 0.47, 95% CI: 0.31–0.74] and 39 vs. 34% [OR
m2 improved survival among younger [108] and older [109] pa- 0.84, 95% CI: 0.75–0.95], respectively). It should be noted, how-
tients, as well as in patients with specific mutations (NPM1, ever, that the OS of patients with CBF-­A ML not receiving GO
FLT3, and DNMT3A) [107]. However, there was no benefit in in the meta-­analysis was surprisingly low with a 5-­year OS sur-
term of survival among 1206 patients with AML when 90 mg/ vival of 55%. An OS advantage with GO addition was not seen
m2 was compared to 60 mg/m2 (although all patients received in any of the individual trials included in the meta-­analysis.
a second course of daunorubicin 50 mg/m2 , which could po- These issues, plus the marrow and hepatoxicity of GO, have
tentially reduce the beneficial effects of 90 vs. 60 mg/m2) [110]. caused many to question the routine addition of GO to induc-
The two-­ step randomized DAUNODOUBLE trial evaluated tion therapy. In the ALFA0701 trial which was included in the

FIGURE 2    |    Treatment algorithm for newly diagnosed patients aged < 60 years with AML fit for intensive therapy. AlloSCT—allogeneic stem cell
transplantation; AML—acute myeloid leukemia; AML-­MR—acute myeloid leukemia with myelodysplasia related changes (ELN 2017 definition);
CBF—core binding factor; ELN—European Leukemia Network; FLT3i—FLT3 inhibitors; GO—gemtuzumab ozogamycin; HMA—hypomethylat-
ing agents; MRD—measurable residual disease; ND—newly diagnosed; t-­A ML—therapy related AML; ven—venetoclax.

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meta-­analysis, the administration of fractionated dose of 3 mg/ that demonstrated improved survival among patients with ND
m2 on days 1, 4, and 7 with 7 + 3 in patients aged 50–70 years was mutant FLT3 AML aged 18–59 treated with 7 + 3 + midostau-
associated with longer EFS and OS compared with 7 + 3 alone rin versus 7 + 3 alone. The FDA approved the combination of
[13]. A post hoc analysis of the ALFA0701 trial demonstrated 7 + 3 + midostaurin for all patients with FLT3-­mutated AML
a benefit for the addition of GO in favorable and intermediate deemed eligible for intensive chemotherapy based in part on
risk groups per ELN 2017 risk criteria [121]. Additional positive data from a non-­randomized trial that included older patients
trials included in the meta-­analysis (AML-­MRC15 and NCRI-­ supporting improved outcomes versus historical cohorts in pa-
AML16) employed a single 3 mg/m2 GO dose on the first day of tients aged 60–70 (median OS 22.7 vs. 8.4 months, HR for death
induction [122, 123] and in each subsequent cycle. The AMLSG 0.47, 95% CI: 0.33–0.67, p < 0.01) [128, 129]. In addition, in a
09–09 trial was a phase III randomized study not included in the post hoc analysis of the RATIFY trial incorporating FLT3-­I TD
meta-­analysis, which evaluated the addition of GO to idarubi- allelic ratio and NPM1 mutational status, improved survival
cin, cytarabine, etoposide, and all-­trans-­retinoic acid in patients with midostaurin was seen across all ELN 2017 risk groups [64].
aged 18 years and older (median 58.8) with NPM1 positive-­A ML Resistance was associated with either loss of FLT3-­I TD with the
[124, 125]. EFS was not statistically different between the GO acquisition of mutations in signaling pathways, persistence of
arm and the standard arm (HR 0.83, 95% CI: 0.65–1.04, p = 0.1), FLT-­I TD clones, or other mechanisms [130].
with higher rates of early deaths in the GO arm (10.3% vs. 5.7%,
p = 0.05 and 20% in patients age ≥ 70 years) due to a higher Quizartinib is a highly potent type II (active only in those with
rate of infections. Subgroup analysis revealed a significant FLT3-­I TD mutations) FLT3 inhibitor that is also approved in
EFS improvement in the GO arm in females, patients younger combination with chemotherapy for patients with ND FLT3-­
≤ 70 years, and non-­FLT3-­I TD patients. The impact of GO ad- ITD-­mutated AML. The QUANTUM FIRST trial demonstrated
dition was also beneficial in achieving an MRD negative state improved OS among 539 patients up to age 75 years with ND
defined as a 3-­log reduction measured by quantitative RT-­PCR FLT3-­ITD-­mutated AML treated with 7 + 3+ quizartinib ver-
(56% vs. 41%, p = 0.01) which translated into lower relapse rates sus 7 + 3 (median 32 vs. 15 months, HR 0.78, 95% CI: 0.62–0.98,
in the GO arm versus standard therapy (4-­year cumulative inci- p = 0.03) [20]. There was a slightly higher rate of fatal events in the
dence relapse rates 29.3% vs. 45.7%, respectively. p = 0.009) [13]. quizartinib arm (11.3 vs. 9.7%), which may relate to a significant
myelosuppressive effect and/or prolonged QTc with quizartinib.
The AML-­MRC 18 trial evaluated older patients (age ≥ 60 years; Of note, in a subgroup analysis of patients ≥ 60 years, there was
n = 852) treated with intensive chemotherapy induction with ei- no survival benefit for the addition of Quizartinib (HR 0.91, 95%
ther single dose GO (at day one) or fractionated two doses (on CI: 0.66–1.26).
day one and four) of GO [126]. In the entire cohort, response
rates (CR/CRi) and survival rates were similar between those Crenolinib is a potent type I second-­generation FLT3 inhibitor
treated with single versus fractionated GO (82% vs. 81%, that was evaluated in a phase Ib-­II trial when added to tradi-
p = 0.723; 5-­year OS 24% vs. 29%, p = 0.14). However, the rate of tional 7 + 3 [131]. Among 44 patients aged 18–75 treated with this
MRD negativity in those who achieved CR (measured by MFC combination, the CR rate was 77%, with a negative MRD state
at a threshold of 0.1%) was lower in patients treated with single in 89% of those who achieved complete response. The estimated
versus fractionated GO dose (41% vs. 50%, p = 0.027). In addi- 3-­year OS in the entire group was 58% and was higher in those
tion, in a sensitivity analysis excluding patients with either TP53 aged ≤ 60 years (n = 29, 71%) versus > 60 years (n = 15, 33%).
mutations or adverse risk cytogenetics, a worse OS was observed
with single versus fractionated GO dose (5-­year OS 26% vs. 33%, In addition, ongoing trials are also evaluating the 7 + 3 + mido-
p = 0.045). This advantage was lost when patients were censored staurin versus 7 + 3 with the more potent FLT3 inhibitors gilteri-
at transplant. tinib (HOVON 156—NCT04027309, PreECOG—NCT03836209)
or crenolanib (NCT03258931).
The addition of GO to standard AML therapy prolongs sur-
vival in patients with cytogenetically favorable (e.g., CBF) Overall, there are two approved FLT3 inhibitors with 7 + 3 in
[120] AML and may be beneficial by improving EFS in NPM1-­ patients with ND FLT3-­mutated AML. In those with FLT3-­T KD
mutated/FLT3-­I TD wild-­t ype AML [125]. As noted, GO may be mutations, we use midostaurin. In patients with FLT3-­I TD mu-
administered by various schedules. Our practice, based on an tations, as there are no comparative trials between midostaurin
amalgamation of the MRC and French studies is to give one dose and quizartinib, we evaluate patient co-­morbidities and spe-
of GO at day 1, capped at 4.5 mg/m2 to all patients with CBF cific common drug-­associated side-­effects in an effort to indi-
AML and strongly consider in younger patients with NPMI mu- vidualize treatment. In addition, in patients who are expected
tant/FLT3 mutant WT AML. As the absolute value of the benefit to undergo chemotherapy-­ only consolidation without allo-
of adding GO to induction chemo in intermediate-­risk patients is SCT we favor quizartinib, because this drug was approved for
small and many of these patients receive SCT in CR1 (and would post-­remission maintenance monotherapy, while midostaurin
be subject to a higher risk of sinusoidal obstruction syndrome was not.
(SOS) due to prior GO exposure [127]) many US clinicians re-
serve the use of GO in induction for those with favorable risk CPX-­351, a liposomal formulation of daunorubicin and cytara-
cytogenetics. bine, was approved in 2017 for t-­A ML, or AML-­M RC. Approval
was based on the phase III trial in which 309 patients aged
Midostaurin is a Type I (active in patients with FLT3-­I TD and 60–75 were randomized to receive either CPX-­351 or 7 + 3 [7].
FLT3-­T KD mutations) first-­generation FLT3 inhibitor, which Patients either had t-­A ML, prior clinical diagnosis of MDS/
was approved based on the results from the RATIFY trial [6], CMML, or AML with MDS-­related cytogenetic abnormalities.

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Both CR rates and median OS were higher among patients rates of infection (51% vs. 20%, p < 0.0001), febrile neutropenia
treated with CPX-­351 versus 7 + 3: 37% versus 26% (p = 0.02) (90% vs. 54%, p < 0.0001) and length of hospitalization (41 vs.
and 9.3 months versus 6 months (HR for death 0.7, [95% CI: 15 days, p = 0.0004) were higher among patients treated with
0.6–0.9]), respectively. The median times to platelet (≥ 50 000/ CPX-­351 versus HMA + venetoclax.
μL) and absolute neutrophil counts (≥ 500/μL) recovery were
longer with CPX-­ 351 versus 7 + 3 (35 days vs. 29 days and Venetoclax, a BH3 mimetic that selectively inhibits the pro-­
36.5 days vs. 29 days, respectively), with similar infection rates apoptotic BCL2 protein and induces apoptosis in acute myeloid
(93%) in each arm but higher rates of bleeding were seen in the leukemia cells, especially in the presence of cytotoxic chemo-
CPX-­351 arm (all cause—74.5% vs. 59.6%; grade 3–5 11.8% vs. therapy [138], was approved in combination with HMA or
8.6%). Longer follow up demonstrated that the survival benefit LDAC for ND AML patients not fit for induction with intensive
was maintained (median OS 9.3 vs. 6 months, HR 0.7, 95% CI: chemotherapy based on age ≥ 75 or in ineligibility for intensive
0.55–0.91), especially among patients who received a trans- chemotherapy because of significant co-­ morbidities [11, 17].
plant and had been previously treated with CPX −351(52% vs. However, several phase I-­II trials are evaluating the efficacy and
23%, HR 0.51, 95% CI: 0.3–0.9) [132, 133]. This latter finding safety of venetoclax with Fludarabine, cytarabine, idarubicin,
suggests that CPX-­351 lead to remission at lower MRD levels and G-­CSF (FLAG-­IDA) or daunorubicin plus cytarabine in the
than 3 + 7, but this parameter was not measured during con- upfront setting. Among 45 patients with ND-­AML, FLAG-­IDA
duct of the trial. Real world evidence also demonstrated the with venetoclax yielded a composite CR rate of 89%, with 93%
efficacy of CPX-­351 among 188 patients that included 24.5% of CR patients achieving MRD negativity by multiparameter
under the age of 60 [134]. However, the exact role of CPX-­351 flow cytometry with an estimated 2-­year OS of 76% [139]. The
in the current AML landscape remains unclear. First, while CAVEAT trial demonstrated CR/CRi rates of 72% in 51 patients
the initial approval was in a population defined by either older than 60 with a seven-­day venetoclax pre-­phase followed by
clinical or cytogenetic characteristics, recent analysis of out- 5 + 2 and venetoclax for an additional 7 days. The CR/CRi rates
comes according to molecular subsets suggest a differential were remarkably high (97%) among patients with de-­novo AML
benefit CPX-­351 compared with 3 + 7. For example, patients versus 43% in patients with secondary AML [140]. Among 33
with TP53 mutations did not benefit from CPX-­351 over 7 + 3 patients aged 18–60 with ND-­AML, venetoclax in combination
[135]. The high-­r isk cohort of the UK NCRI AML19 trial en- with 7 + 3 yielded in composite CR rates of 91% with 97% MRD
rolled 187 patients with a median age of 56 years and high-­ negativity, and 1 year estimated OS of 97% [141]. In an additional
risk MDS/AML (defined by IPSS-­R or adverse cytogenetics) phase I trial evaluating 7 + 3 with venetoclax, all 11 evaluated
treated with either FLAG-­IDA (n = 82) or CPX-­351 (n = 105) patients achieved CR, most (78%) with MRD negative CR [142].
[136]. The OS was similar between arms (HR 0.78, 95% CI: Venetoclax combined with cladribine, idarubicin, and cytarabine
0.55–1.12, p = 0.12). However, in exploratory analysis of 59 pa- in 50 patients with ND AML resulted in 94% composite complete
tients harboring one or more MDS-­related gene mutation (as response, 85% at the level of MRD negativity with a 1 year OS rate
defined by ICC 2022 [23]), those treated with CPX-­351 expe- of 85% [143]. While these early results are encouraging, these
rienced improved OS compared with FLAG-­I DA (median OS regimens are highly myelosuppressive leading to significant risk
38.4 months vs. 16.3 months, HR 0.42, 95% CI: 0.21–0.85). of prolonged cytopenia and infections. Thus, until we have lon-
ger follow-­up and matched control trials, intensive chemother-
While the FDA approved CPX-­351 for patients of any age, the apy with venetoclax in the upfront setting should be evaluated
randomized trial leading to approval was limited to patients only in the context of clinical trials.
aged 60–75 years, a group expected to be enriched for AML
with adverse biology, which could potentially benefit from less Isocitrate dehydrogenase (IDH) mutations occur in 15%–20% of
intensive therapy such as HMA+ venetoclax. A multicenter patients in AML [2, 144]. IDH mutations result in the formation of
retrospective study evaluated 395 patients with molecularly the neomorphic reaction product R-­2-­hydroxyglutarate, an oncom-
defined secondary AML (by WHO fifth edition), treated with etabolite which leads to epigenetic alterations and impaired hema-
either 7 + 3 (n = 167), CPX-­351 (n = 66) or HMA + venetoclax topoietic differentiation similar to those observed when TET2 is
(n = 162) [69]. The response rates (CR/CRi) were similar be- mutated [145]. The IDH1 and IDH2 inhibitors ivosidenib and enas-
tween treatment groups (56% vs. 44% vs. 56%, p = 0.22, respec- idenib were approved as monotherapy for patients with R/R IDH-­
tively). The median OS was comparable in patients ≥ 60 years mutated AML; ivosidenib was approved in the frontline setting for
(median OS 16, 11, and 15, respectively, p = 0.54) as well as unfit patients, either as monotherapy or combined with azacitidine
among patients consolidated with transplant (2-­year OS 64% (see “non-­intensive therapy for newly diagnosed patients”). Both
vs. 60% vs. 74%, p = 0.55). In a multivariable regression model IDH inhibitors were evaluated in a phase I trial in combination
controlling for patient, disease, and treatment character- with 7 + 3 in 151 “fit” patients with IDH-­mutated AML. The CR/
istics, HMA + VEN was superior to 7 + 3 whereas CPX-­351 CRi/CRp rates were 77% with the addition of ivosidenib and 74%
was not. Another retrospective study compared outcomes of with enasidenib [146]; 39% and 23% of patients achieved mIDH1/2
217 patients who received CPX-­351 versus 437 patients who clearance by ddPCR, respectively. Overall, the combination was
received HMA + Venetoclax [137]. The OS rates were compa- tolerable with low rates of differentiation syndrome or significant
rable between groups (13 months for CPX-­351 vs. 11 months QT prolongation. Prior to the routine adoption of IDH inhibitors
for HMA + venetoclax; HR, 0.88; 95% CI: 0.71–1.08; p = 0.22), plus intensive chemotherapy in the upfront setting, we await the
even after adjusting for different baseline characteristics and results from HOVON 150, a phase III trial evaluating the benefit of
with a sensitivity analysis including only patients who were adding IDH inhibitor to 7 + 3 in fit patients with ND IDH-­mutated
eligible for the CPX-­351 randomized trial. In contrast, the AML (NCT03839771).

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 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.27625 by Cochrane Japan, Wiley Online Library on [21/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6.2.2   |   Updates on Post Remission Therapy was associated with improved OS [150]. The use of sorafenib, a
first-­generation Type II TKI (active in patients with FLT3-­I TD
After remission is achieved, post-­induction therapy is neces- mutations) was associated with lower relapse rates in the main-
sary to achieve a reasonable chance of favorable long-­term tenance trials included in the analysis [151–155]. The phase III
outcomes and possibly a cure. Generally, patients with ELN MORPHO trial compared post-­alloSCT gilteritinib (Type I sec-
favorable risk score should receive 3–4 cycles of high-­dose ond generation FLT3-­inhibitor, see below under “R/R AML”)
chemotherapy, whereas patients within the intermediate or monotherapy versus placebo in 356 patients with FLT3-­I TD
adverse risk are recommended to proceed with alloSCT [23]. AML who were transplanted at first remission. The RFS was
This is mainly based on the risk of death from relapse or re- higher in the gilteritinib arm compared with placebo, albeit with
fractory disease (high in those with non-­favorable subtypes) borderline statistical significance (HR 0.68, 95% CI: 0.46–1.005,
possibly overcoming the risk of TRM associated with allo- p = 0.0518) [156]. A pre-­specified analysis demonstrated that the
SCT. Although most patients with CBF-­A ML usually do not benefit of gilteritinib over placebo was driven by patients who
proceed with alloSCT while in CR, as mentioned earlier the had either pre-­or post-­alloSCT detectable MRD for FLT3-­I TD
benefit of alloSCT was demonstrated in a prospective trial using a PCR-­based highly sensitive test to (1*10 −6): patients
evaluating the predictive value of MRD positivity in patients with detectable MRD, HR 0.52, 95% CI: 0.32–0.84, p = 0.0065;
with RUNX1::RUNX1T1 AML after the second consolidation. patients with non-­detectable MRD (HR 1.21, 95% CI: 0.6–2.39,
Patients who had positive MRD (defined by qPCR with less p = 0.575). Additional post-­alloSCT maintenance therapies, such
than 3-­log reduction) were offered to proceed with alloSCT as HMA plus venetoclax (“VIALE-­T ”; NCT04161885) are now
and had lower relapse rates, improved disease free survival, being evaluated.
and OS when treated with alloSCT versus continuation of che-
motherapy [97]. For patients with intermediate or adverse cytogenetic risk AML
who cannot proceed with alloSCT and/or complete planned post-­
While most agree that adverse-­risk AML patients have the best remission chemotherapy, maintenance therapy with CC-­ 4 86
chance for long term survival if an allogeneic is done during (“oral azacitidine”) is useful. CC-­4 86 is an oral hypomethylating
CR1, an analysis based on MRC trials in the UK suggests that agent that was FDA approved as post-­induction therapy based
the optimal strategy in intermediate-­risk patients is to trans- on the results of the phase III QUAZAR AML-­0 01 trial [14]. The
plant only in CR2, thereby saving many (especially those with trial enrolled patients aged 55–86 with ND AML who received
MRD negativity and a relatively low chance of relapse) from un- intensive chemotherapy, achieved complete remission, and were
necessary SCT-­associated morbidity and mortality [147]. On the not candidates for alloSCT at the time of screening. Patients
contrary, a large meta-­analysis of prospective clinical trials eval- received either CC-­4 86 for 14 days in 28-­day cycles (n = 238) or
uating alloSCT at CR1 versus non-­alloSCT treatments demon- placebo (n = 234) at the end of 0, 1, or 2 consolidation cycles.
strated an OS advantage both in intermediate-­risk (HR 0.83, The median OS and RFS were better in the CC-­4 86 vs. placebo
95% CI: 0.74–0.93) as well as adverse risk (HR 0.73, 0.59–0.90) group (24.7 vs. 13.8 months, and 10.2 vs. 4.8 months, respectively
groups [148]. Recently, a post hoc analysis study of the AML-­ p < 0.001 for both). There were higher rates of side effects, such
MRC17 plus 19 trials showed that the benefit of transplant may as gastrointestinal distress (50%–65% vs. 10%–24%), neutropenia
be MRD status dependent [98]. Among 737 patients (median age (44% vs. 26%), and infections (17% vs. 8%) in the CC-­4 86 arm.
52) with NPM1-­mutated AML, patients with MRD positivity Adverse events led to drug interruption in 43% of patients. Ad
measured at CR after 2 chemotherapy cycles had improved sur- hoc analysis demonstrated improved OS and RFS irrespective
vival when consolidated with alloSCT (3-­year OS 61% vs. 24%, of MRD status at first remission, with conversion rates to MRD
p < 0.001). Conversely, those who achieved MRD negativity after negativity in 25% of patients receiving CC-­4 86 [157]. AlloSCT
two chemotherapy cycles had comparable outcome with versus is more accessible in recent years due to use of more tolerated
without alloSCT (3-­year OS 79% vs. 82%, p = 0.4). Notably, the reduced intensity conditioning [158] and an expanded pool of
lack of survival advantage with alloSCT among MRD negative donors due to improved outcomes with haploidentical alloSCT
patients persisted in the subset of patients harboring a FLT3-­I TD [159, 160]. Moreover, the use of alloSCT is more common in
co-­mutation (which are defined in the ELN intermediate-­risk older patients [161] and associated with less morbidity and TRM
group): 3-­year OS 83% versus 76%, p = 0.6. Of note, the use of [162]. Thus, the use of CC-­4 86 may be limited to only those few
FLT3 inhibitors in patients with FLT3-­I TD in those trials was patients who are initially deemed fit for intensive therapy but
limited. not for transplant.

Our general approach is still to transplant all intensively treated

adverse and intermediate patients by ELN 2022 at CR1 who 6.3   |   Updates on Non-­Intensive Therapy for Newly
have an available donor and no contraindication. With the abil- Diagnosed Patients
ity to safely conduct haploidentical alloSCT, almost all patients
have a donor [149]. The exception may be in patients with NPM1 Just a few years ago, our ability to treat older patients who are
and FLT-­I TD co-­mutations, in which case MRD may direct our not fit for intensive therapy was limited to mainly supportive
decision toward post-­ remission chemotherapy alone without care and was associated with a dismal prognosis. While decit-
alloSCT. abine or azacitidine were commonly used in older patients, it
was never clear whether these single agents were better than
Post-­transplant maintenance therapy may contribute to pro- other available therapies [163, 164]. Several drugs and combina-
longed survival. In a meta-­analysis of five randomized controlled tion therapies, especially the addition of venetoclax to low-­dose
trials, maintenance therapy versus no therapy post-­ alloSCT chemotherapy, were recently approved for this group, which

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FIGURE 3    |    Treatment Algorithm for Newly diagnosed patients with AML aged 60–75 years eligible for intensive therapy. AlloSCT—allogeneic
stem cell transplantation; AML—acute myeloid leukemia; CBF—core binding factors; ELN—European Leukemia Network; FLT3i—FLT3 inhib-
itors; GO—gemtuzumab ozogamycin; HMA—hypomethylating agents; ITD—internal tandem duplication; MRD—measurable residual disease;
ND—newly diagnosed; Ven—venetoclax.

revolutionized the treatment paradigm in AML in patients who low-­dose chemotherapy (LDAC combined with cladribine, alter-
are not fit for intensive chemotherapy induction (Table 1 and nating with azacitidine) in older patients (age ≥ 60 years) or those
Figure 3). These therapeutic agents promote prolonged survival deemed unfit for intensive chemotherapy [168]. The composite
and promote questioning the paradigm of initial intensive che- CR rate was 93%, with 84% of remitting patients achieving MRD
motherapy even for selected fit patients (Figure 4). negativity. With a median follow-­up time of 22 months, the me-
dian OS and disease-­free survival were not reached, with an es-
timated 24-­month OS of 63.5% (95% CI: 52%–78%). It should be
6.3.1   |   Venetoclax Combination Therapies noted, however, the inclusion of fit patients aged 60 or older may
have accounted in part for the promising results.
In the phase III VIALE-­A trial, azacitidine added to venetoclax
improved responses and overall survival (OS) versus azacitidine As noted earlier, the relative utility of HMA plus venetoclax
alone in patients > 75 years old or those with significant comor- versus intensive induction in younger patients without co-­
bidities (composite CR 66.4% vs. 28.3%, p < 0.001; median OS 14.7 morbidities remains unclear. The ability to achieve high CR
vs. 9.7 months, HR 0.66, 95% CI: 0.52–0.85, p < 0.001) [165]. In rates, with the majority having MRD negative responses at
the VIALE-­C trial, venetoclax was added to LDAC versus LDAC acceptable toxicity with HMA plus venetoclax may allow al-
monotherapy. The trial failed to achieve the primary OS end- loSCT, thereby may even lead to better long-­term outcomes
point (median OS 7.2. vs. 4.1 months, HR 0.75 95% CI: 0.52–1.07 [69, 169–172]. Currently, there is no published data for a prospec-
p = 0.11) [18]. This was partially due to diminished power (fewer tive comparison between HMA plus venetoclax versus intensive
patients were enrolled compared to VIALE-­A (211 vs. 431), as chemotherapy, though an ongoing phase II (NCT04801797) trial
well as inclusion of patients who received HMA as prior ther- is attempting to provide such information. A phase III multi-
apy in the VIALE-­C trial. However, in a post hoc analysis with center randomized trial conducted in nine European countries
6 months additional follow-­up, an OS advantage was seen (8.4 compared 10-­day decitabine monotherapy with 7 + 3 in 606 pa-
vs. 4.1 months, HR 0.7, 95% CI: 0.5–0.99, p = 0.04) [166]. These tients aged 60 and older with ND AML, a more favorable group
regimens are now considered standard of care for older patients generally than studied in the VIALE trial [173]. At a median
or patients not deemed fit for intensive chemotherapy, although follow-­up of 4 years, the 4-­year OS was 26% (95% CI: 21%–32%)
a subgroup analysis in patients younger than age 75 who were el- and 30% (95% CI: 24%–35%) in the decitabine and 7 + 3 groups,
igible for the trial based on significant comorbidity did not show respectively (HR 1.04, 95% CI: 0.86–1.26, p = 0.69). The rates of
a benefit for the doublet over azacitidine. Venetoclax may also be alloSCT were also comparable between groups (40% vs. 39%), as
synergistic with other lower-­dose therapies [167]. For example, well as Grades 3–5 adverse events (84% vs. 94%) or treatment-­
Kadia et al. reported on the results of venetoclax combined with related mortality (12% vs. 14%). Furthermore, the response to

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 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.27625 by Cochrane Japan, Wiley Online Library on [21/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
FIGURE 4    |    Treatment Algorithm for Newly diagnosed patients with AML ≥ 75 years or unfit for intensive therapy. AlloSCT—allogeneic stem cell
transplantation; AML—acute myeloid leukemia; ELN—European Leukemia Network; FLT3i—FLT3 inhibitors; HMA—hypomethylating agents;
IDHi—IDH inhibitor; IDH—isocitrate dehydrogenase; MRD—measurable residual disease; ND—newly diagnosed; Ven—venetoclax.

the venetoclax and HMA combination is heterogeneous, with setting [8]. The phase III AGILE trial evaluated the addition of
decreased response rates in several morphologic, cytogenetic, ivosidenib to azacitidine versus azacitidine in patients with ND
and molecular subgroups [165, 174, 175]. For example, the dura- IDH1-­mutated AML older than 75 or with comorbidities [15].
tion of response varies greatly, being only a few months in high-­ Patients were randomly assigned to azacitidine for 7 days in 28-­
risk TP53-­mutated AML and in AMLs exhibiting monocytic day cycles (n = 74) versus azacitidine and ivosidenib 500 mg daily
differentiation [174–176]. Although in VIALE-­A the addition of (n = 74). The primary efficacy endpoint, EFS, was superior in
venetoclax to HMA in TP53-­mutated AML improved composite patients randomized to the doublet compared with azacitidine
CR rates (55.3% vs. 0%, p < 0.001), no survival benefit was noted, alone (HR 0.16, 95% CI: 0.16–0.69). The median overall survival
and the combination regimen caused added toxicity. The lack of was longer in patients who received ivosidenib plus azacitidine
survival advantage of adding venetoclax to HMA in this genetic (24 months vs. 7.9 months, HR 0.44, 95% CI: 0.27–0.73). Based
subset of AML was also shown in real world studies [77, 165]. on these results, the FDA approved this combination for pa-
tients with ND IDH1-­mutated AML aged 75 and above or with
Many investigators have questioned the need to administer comorbidities. Thus, there are two effective regimens approved
28 days of venetoclax with each chemotherapy course. Several for older adults with ND IDH1-­mutated AML: azacitidine ei-
retrospective studies have suggested that venetoclax for 7 or ther with ivosidenib or with venetoclax. Favorable outcomes
14 days per cycle may be adequate, especially in frail patients were seen in a combined analysis of data from IDH-­mutated pa-
[177–179]. However, given the absence of prospective data com- tients on the VIALE-­A [165] and the phase Ib of HMA+ VEN
paring different venetoclax exposure durations, the optimal [11] trials [180]. Nonetheless, the number of patients specifically
approach remains to be determined. Since we can evaluate mar- with IDH1 mutations was low (33 in the VIALE-­A and 11 in the
row findings within 48 h, we plan to administer a full course phase-­I b trial). The question of whether to use azacitidine with
of venetoclax, but will truncate the duration if a bone marrow either venetoclax or ivosidenib remains open; some would prefer
examination done ~3 weeks after therapy initiation shows blast to ‘save’ ivosidenib as a salvage therapy (even though few if any
clearance. We further have a low threshold to shorten the du- patients on the ivosidenib trial had received venetoclax-­based
ration of venetoclax in subsequent cycles in the setting of prior therapies). Moreover, since azacitidine plus ivosidenib may be
prolonged myelosuppression and good disease control. less myelotoxic than HMA plus venetoclax, some suggest the for-
mer therapy might be more appropriate for a more frail patient.

6.3.2   |   IDH Inhibitors Although not approved for patients with IDH2-­mutated ND-­
AML, combination therapy consisting of the IDH2 inhibitor
The oral IDH1 inhibitor ivosidenib was FDA approved as mono- enasidenib plus azacitidine was evaluated in the phase II
therapy in patients with IDH1-­mutated AML, both in ND pa- AG221-­A ML-­0 05 randomized trial [181]. One hundred and
tients not eligible for intensive therapy [9], as well as in the R/R one patients (median age 75) were assigned in a 2:1 ratio to

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azacitidine with (n = 68) or without (n = 33) enasidenib. CR azacitidine (58% vs. 26.5%, p < 0.001), the median OS was simi-
rates were 54% versus 12% (p < 0.0001) in azacitidine + enas- lar between groups (9.8 months vs. 8.9 months, HR 0.92, 95% CI:
idenib versus azacitidine alone. Twelve (18%) patients in the 0.529–1.585, p = 0.75). Of note, almost half (44%) of patients in
enasidenib group experienced differentiation syndrome and the AZA arm were treated subsequently with a FLT3 inhibitor
were treated with corticosteroids. The median overall sur- versus 20% in the gilteritinib plus azacitidine arm, which might
vival was similar between groups (22 months in each), which have contributed to the perceived lack of success of this combi-
may be attributed in part to effective salvage therapies, such nation in FLT3 mutant AML in ND older adults. At present, such
as enasidenib or venetoclax-­ based therapies used in those patients should receive venetoclax plus azacitidine, although
assigned to the control arms [175]. Based on available data, phase I-­II results of doublets (FLT3-­inhibitor plus venetoclax)
we use azacitidine plus venetoclax initially in IDH2 mutant and triplet combinations (FLT3 inhibitor plus HMA and veneto-
unfit AML. clax) have been published.

For example, in a phase II trial evaluating the triplet therapy

6.3.3   |   Glasdegib of venetoclax, decitabine and FLT3 inhibitors (sorafenib, gil-
teritinib, or midostaurin) in ND unfit patients as well as R/R
The critical embryonic signaling hedgehog pathway is overex- patients, CR rates were 75% and 2-­year OS was 80% among ND
pressed in myeloid leukemia cells [182]. Based on this observa- patients [188]. A triplet combination of azacitidine, venetoclax,
tion, the hedgehog pathway inhibitor glasdegib was evaluated and gilteritinib was evaluated in a phase I-­II trial in patients
in combination with LDAC compared to LDAC alone, in pa- with FLT3-­mutated ND (n = 30) or R/R AML (n = 22) [189]. The
tients with ND AML deemed not fit for intensive chemotherapy, recommended dose of gilteritinib was 80 mg/day, and the CR/
based on age ≥ 75 or having significant comorbidities (BRIGHT CRi rates were 96% in the upfront cohort with MRD negativ-
AML 1003 study) [16]. Glasdegib was given orally 100 mg/day ity (measured by FLT3-­I TD at a threshold of 5*10 −5) was 65%.
in 28 days cycles and LDAC was administrated subcutaneous After a median follow-­up of 19.3 months, the median RFS and
for 10 days at the start of each cycle. The complete remission OS were not reached with an estimated 18-­month OS of 72%.
rates and median OS were 17% versus 2.3% (p < 0.05) and 8.8 As the data is short-­term and derived from single-­arm studies,
versus 4.9 months (HR 0.51, 80% CI: 0.39–0.67, p = 0.0004) in triplet combination therapies should be used with caution, and
the glasdegib + LDAC versus LDAC alone, respectively. This preferably within the context of a clinical trial.
trial led to the FDA approval of LDAC + glasdegib in ND pa-
tients unfit for intensive chemotherapy. Although no direct
comparison was performed, the VIALE-­A and VIALE-­C trials 7   |   Updates on Relapsed and Refractory (R/R)
demonstrated far superior outcomes with venetoclax combina- AML
tions compared to glasdegib plus low dose cytarabine, leading
to infrequent use of glasdegib in patients with ND AML deemed Relapsed or refractory AML remains a therapeutic challenge,
unfit for intensive chemotherapy. The efficacy of glasdegib with a 5-­year survival of only 10% [190, 191]. Age, duration of
with LDAC in the R/R setting was evaluated in a small ret- CR1, initial cytogenetics and previous alloSCT are prognostic
rospective study that demonstrated composite CR (CR + CRp) factors for outcome [192]. The general paradigm in R/R AML,
rates of 21% with a median OS of 3.9 months [183]. The phase at least in patients who are willing to accept more therapy for
III BRIGHT AML 1019 trial failed to demonstrate a benefit a relatively small chance of good long-­term outcomes, is sal-
for addition of glasdegib to 7 + 3 in fit patients or azacitidine vage therapy [193, 194] consolidated with alloSCT if remission
alone in unfit patients. In the intensive arm (n = 404), similar is achieved [195]. However, this concept was challenged in the
OS between 7 + 3 plus placebo versus 7 + 3 plus glasdegib was ASAP trial, which compared patients with R/R AML who had
seen (median OS 20 vs. 17.3 months, HR 1.5, 95% CI: 0.78–1.41, only one previous line of therapy and were assigned to either
p = 0.749). Similarly, in the non-­intensive arm (n = 325), com- salvage therapy with cytarabine and mitoxantrone followed
parable OS was seen with azacitidine alone or plus glasdegib by alloSCT (n = 141) or immediate alloSCT (n = 140). The OS
(median OS 10.9 vs. 10.3 months, HR 0.99, 95% CI: 0.77–1.29, was comparable between those treated with immediate al-
p = 0.969). These results question the role of glasdegib in the loSCT (4-­year OS of 46% [95% CI: 36%–55%]) compared with
treatment of ND AML [184]. salvage therapy followed by alloSCT (4-­year OS of 49% [95%
CI: 39%–59%]), p = 0.42 [196]. Given similar OS and complete
remission rates at day 56 post-­a lloSCT (79% vs. 83%), despite
6.3.4   |   Gilteritinib the study not meeting its primary endpoint of non-­inferiority,
the results suggest that immediate alloSCT may be a reason-
Gilteritinib is a type 1 s-­generation inhibitor, more potent and able approach in some patients, especially if very intensive
specific than midostaurin [185, 186]. Gilteritinib is approved conditioning is used.
for patients with R/R FLT3-­mutated AML [12] (see R/R AML)
based on the ADMIRAL trial (see below). Gilteritinib was also In patients who relapse after an alloSCT in CR1, options which
evaluated in combination with other therapies in the upfront may yield responses and potentially improve survival include
setting. In the phase III randomized LACEWING trial, patients manipulation of the immune system in order to stimulate graft
with ND FLT3-­mutated AML deemed not eligible for intensive versus leukemia effect via tapering graft versus host disease pro-
chemotherapy were randomized to azacitidine (n = 49) versus phylaxis [197], administering donor T-­cells Infusion (DLI) [198],
azacitidine with gilteritinib (n = 74) [187]. Although higher com- addition of immune checkpoint inhibitors [199] or a second al-
posite CR rates were seen with azacitidine + gilteritinib versus loSCT [200].

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FIGURE 5    |    Treatment Algorithm for patients with relapsed or refractory AML. AlloSCT—allogeneic stem cell transplantation; AML—acute
myeloid leukemia; DLI—donor lymphocyte infusion; FLT3i—FLT3 inhibitors; GO—gemtuzumab ozogamycin; HMA—hypomethylating agents;
IDH—isocitrate dehydrogenase; KMT2Ar—Lysine methyltransferase 2A gene (KMT2A) re-­arranged; MRD—measurable residual disease; R/R—
relapse or refractory; Ven—venetoclax.

There are several targeted therapies for patients with specific received prior FLT3 inhibitor therapy. The modified composite
mutations that were approved in recent years for patients with CR rate (CR + CRi + CRp + MLFS) was 75% (36% were MLFS).
R/R AML (Table 1 and Figure 5). Molecular remission by FLT3 PCR was achieved in 60% of patients
and the median OS was 10 months. Grades 3–4 cytopenias were
common (80%) with prolonged myelosuppression and adverse
7.1   |   Gilteritinib events prompting venetoclax and gilteritinib dose interruptions in
51% and 48%, respectively. Triplet therapy with HMA, venetoclax,
Gilteritinib is a potent FLT3 ITD and TKD inhibitor [201]. and gilteritinib yielded a CR/CRi rate of only 27% in the R/R set-
Gilteritinib was approved as monotherapy for patients with R/R ting (with an ORR of 67%—CR + CRi + MLFS and median OS of
FLT3-­mutated AML based on the results of the ADMIRAL trial 10.5 months). Dose reductions due to myelosuppression and infec-
[12]. Patients with R/R FLT3-­mutated AML were randomized tions were common; thus, gilteritinib 80 mg daily was suggested
to either gilteritinib monotherapy (120 mg daily, n = 247) or sal- for further studies. Are the myelotoxic regimens of either gilter-
vage chemotherapy (n = 124). The median overall survival in the itinib plus venetoclax or gilteritinib plus venetoclax, and azaciti-
gilteritinib group was significantly longer than that in the che- dine better than monotherapy in R/R FLT3-­mutated AML? The
motherapy group (9.3 months vs. 5.6 months; HR 0.64; 95% CI: doublet or triplet might be appropriate as a bridge to transplant,
0.49–0.83; p < 0.001) and side effects were less common in the whereas initial or subsequent monotherapy might be more real-
gilteritinib group vs. chemotherapy. In a follow up analysis at istic for long-­term use. A real-­world retrospective study demon-
24 months, among the 40 patients in the gilteritinib arm who re- strated comparable response rates and overall survival between
ceived alloSCT and were treated with gilteritinib as post-­alloSCT gilteritinib monotherapy versus gilteritinib plus venetoclax (53%
maintenance, the cumulative relapse rates were 0% and 18.6% vs. 65%, p = 0.51, 59% vs. 42%, p = 0.11) [207]. However, early sal-
among patients who achieved CR/CRh or composite CR, respec- vage with gilteritinib plus venetoclax versus any other gilteritinib-­
tively, which may suggest a role for gilteritinib as post-­AlloSCT based approach was associated with the best outcome (p = 0.031),
in the advanced disease maintenance [202]. Of note, only 12% which suggests that earliest use (i.e., first line for R/R AML) of
of patients in the AMDIRAL study had prior FLT3 inhibitor ex- combination therapy with gilteritinib may be beneficial.
posure. However, the benefit of gilteritinib in patients with prior
exposure to FLT3 inhibitor was demonstrated both in a post hoc
analysis of the ADMIRAL and the phase I-­II CHRYSALLIS trial 7.2   |   IDH Inhibitors
[203], as well in real world data [204, 205]. In a phase Ib-­II trial
gilteritinib was combined with venetoclax in 61 patients (56 with The IDH1 inhibitor ivosidenib was approved as monotherapy
FLT3 mutation) with R/R AML [206], with 64% of patients having for patients with IDH1-­mutated R/R AML [8]. Lachowiez et al.

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presented data from a phase Ib-­II trial in patients with IDH1-­ at a dose of 3 mg/m2 on days 1, 4, and 7, mainly based on the re-
mutated MDS (n = 9), ND-­A ML (n = 14) or R/R AML (n = 8) who sults from the phase II MYELOFRANCE-­1 trial, which demon-
were treated with venetoclax and ivosidenib +/−azacitidine strated 26% CR rates with a median RFS of 11 months [217]. Due
[208]. The response rates were high (composite CR rate 90%); to its modest efficacy, as well as association with higher risk
63% of AML patients attained MRD negativity. The Median EFS of SOS [127] in patients which optimally would proceed with
and OS were 36 months (95% CI: 23-­NR) and 42 months (95% CI: AlloSCT, the use of GO in this setting is limited.
42-­NR), respectively. Although promising, these results should
be compared to the outcome in patients treated with either
HMA plus venetoclax or ivosidenib alone. It should be noted that 7.4   |   Menin Inhibitors
the ivosidenib approval for R/R AML was prior to HMA plus
venetoclax broad usage. That, alongside a retrospective study 11q23 translocations are found in 5%–10% of adults with AML
demonstrating minimal efficacy of ivosidenib post-­H MA plus [218] and confer an adverse prognosis, except for the intermediate
venetoclax [209], questions the utility of ivosidenib in patients risk are associated with self-­renewal of hematopoitetic stem cells
who were treated with venetoclax-­based therapies. k t(9;11)(p21.3;q23.3)/MLLT3::KMT2A translocation [23]. These
cytogenetic rearrangements are associated with self-­ renewal
Olutasidenib is a selective IDH1 inhibitor which was recently of hematopoitetic stem cells and elicit increased expression of
approved for R/R IDH1-­mutated AML based on a phase I-­II trial homeobox (HOX) genes, which are also dysregulated in NPM1-­
[19, 210]. In the phase I portion of the trial, 78 patients with mutated AML [219]. The scaffold protein menin, which is encoded
AML (n = 65; 17 ND and 48 R/R) or intermediate, high, or very by the MEN1 gene, binds to KMT2A and is crucial for its func-
high-­risk MDS (n = 13, 7 treatment naïve and 6 R/R) per IPSS-­R tion [220]. The FDA approved revumenib (SNDX−5613) for R/R
received olutasidenib as monotherapy (n = 32) or in combination KMT2A rearranged AML based on the results of AUGMENT-­101,
with azacitidine (n = 46). Among patients with R/R AML who a phase I single agent clinical trial in KMT2A-­rearranged and
received Olutasidenib monotherapy or combination therapy, NPM1-­mutated R/R AML [221]. The CR/CRh rate were 30% and
9/22 (41%) and 12/26 (46%) achieved an overall response, respec- 22.8% with a median OS of 7 months and 8 months in the entire
tively. The estimated median OS in R/R AML was 8.7 months cohort and in KMT2A rearranged cohort, respectively [21, 222].
(95% CI: 2.5-­non-­reached) with monotherapy and 12.1 months Asymptomatic prolongation of the QT interval was identified as
(95% CI: 4.2-­non reached) with combination therapy. The rate the only dose-­limiting toxicity; differentiation syndrome (all grade
of differentiation syndrome was 13%, similar to that associated 2) was reported in 16% of patients. Additional menin inhibitors, as
with other IDH inhibitors [211]. Overall, the CR + CRh rates monotherapy and in combination, are now being evaluated (see
among 147 patients with R/R IDH1-­mutated AML was 35% below “Selected investigational therapies”).
(51/147) [212]. In addition, 29/86 (34%) transfusion-­dependent
patients became RBC and platelet transfusion independent. A
recent small case series of single-­agent olutasidenib described 7.5   |   Venetoclax Plus Chemo Salvage
16 patients with R/R IDH1-­mutated AML who were previously
treated with venetoclax based therapy: 4/16 (25%) achieved CR Intensive chemotherapy-­only regimens for R/R include mitox-
and one (6%) CRh [213]. However, the exact role of this drug antrone plus etoposide and cytarabine, high-­dose cytarabine
is not yet known, as most of the patients on the approval trial alone, cytarabine plus clofarabine, or fludarabine plus ida-
received neither HMA plus venetoclax nor HMA plus ivosid- rubicin, cytarabine, and G-­CSF. None is clearly “best” [223].
enib upfront, each of which is now considered reasonable initial Venetoclax was combined with intensive chemotherapy in an ef-
therapy for older patients unfit for intensive chemotherapy. fort to improve outcomes for these challenging to-­treat patients.
In a phase Ib/II trial, DiNardo et al. reported results of FLAG-­
The IDH2 inhibitor enasidenib was FDA approved for patients with IDA plus venetoclax in patients with R/R AML. The composite
IDH2-­mutated R/R AML based on the results of a phase II single-­ CR rates were 61%–75%, and 1 year OS estimate of 68% [224].
arm study [10]. However the phase III trial IDHENTIFY in patients AlloSCT was crucial for long-­term survival, with a landmark
with IDH2-­mutated R/R AML aged ≥ 60 years treated with enas- analysis in the R/R group demonstrating improved survival
idenib versus either HMA monotherapy, intermediate (0.5–1.5 g/ among patients consolidated with alloSCT versus chemother-
m2) or low dose cytarabine (20 mg BID) or supportive care failed to apy alone (median OS not reached vs. 7 months, p = 0.009). As
meet its primary endpoint of OS improvement (median OS 6.5 vs. expected, patients with R/R AML harboring TP53 mutation
6.2 months, HR 0.86, p = 0.23) [214, 215]. There was an improve- had a dismal prognosis (OS 7 months). As these combinations
ment in EFS (4.9 vs. 2.6 months, HR 0.68, p = 0.008) and red blood are highly myelosuppressive, all patients received anti-­bacterial
cell transfusion independence (31.7% vs. 9.3%). Combination ther- quinolone, anti-­f ungal, and anti-­v iral therapy prophylaxis, and
apy with enasidenib was also evaluated in a small case series in the length of venetoclax was amended during trial from 14 to
the R/R setting, either as doublet with azacitidine or triplet ther- 7 days. Real-­world data with this regimen demonstrated inva-
apy, suggesting a possible benefit for the triplet versus the doublet: sive bacteremia in half of the patients and fungal infection in
(1 year OS 67% vs. 20%, HR 0.26, 95% CI: 0.09–0.97, p = 0.08) [216]. one-­third [225]. The substantial risk of infections requires vigi-
lant monitoring and prompt treatment when early signs of such
problems occur.
7.3   |   Gemtuzumab Ozogamycin
Although not approved for in R/R AML, venetoclax with
GO is a CD33 monoclonal antibody conjugated to calicheamicin. HMA was evaluated in real-­world studies, with response rates
It was (re-­)approved for patients with R/R AML as monotherapy of 31%–60% [226, 227]. Though conclusions are tentative given

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indirect comparisons, response rates seem higher with HMA trial (azacitidine + sabatolimab compared to azacitidine alone
and venetoclax compared to HMA alone (16% CRi [228]), but in patients with higher risk MDS and CMML) failed to show
overall survival is similar (6.1–6.8 months vs. 6.7 months, re- an OS improvement [233]. Lastly, the E-­selectin inhibitor up-
spectively). The phase II VALDAC study prospectively evalu- roleselan, designed to disrupt the leukemia stem cell-­n iche
ated the utility of venetoclax (600 mg/day) plus LDAC (20 mg/ interaction which showed promise in combination with che-
m 2/day on days 1–10) in 48 patients (median age 68 years) motherapy in an uncontrolled trial [234], failed to improve
with AML who previously received intensive chemotherapy, OS in combination with chemotherapy in patients with R/R
achieved morphologic remission and experienced either MRD AML (NCT03616470) [235]. The phase II/III trial of che-
relapse (considered as ≥ 1 log10 increase; n = 26) or oligoblastic motherapy +/-­uproleselan in ND-­A ML older than 60 years
relapse (defined as 5%–15% bone marrow blasts; n = 22) [99]. (NCT03701308) has completed accrual but results are not yet
AlloSCT at first remission was considered part of the initial available.
therapy. In the MRD cohort by the end of second cycle a log10
reduction was achieved in 69% and overall, 46% achieved There are many drugs being developed against novel pathways.
MRD negativity. In the oligoblastic cohort, CR/CRh/CRi were Efforts involving monotherapies and combinations directed
achieved in 73%. Overall, 21 (44%) patients were successfully against two exciting targets: menin, and CD123, are detailed
bridged to alloSCT. The estimated 2-­year OS was 67% and in Table 5. Highly promising results have been demonstrated
53% in the MRD and oligoblastic cohorts, respectively. Albeit with menin inhibitors in AMLs harboring either a transloca-
requiring conformation in a larger study, this study demon- tion in the lysine histone methyltransferase KMT2A gene on
strates the importance of MRD surveillance and potential chromosome 11q23 or a mutation in NPM1 and already lead,
early intervention. as mentioned, to revumenib's approval. Alongside revumenib,
a multitude of different menin inhibitors are currently in vari-
The best salvage for those who fail to respond or progress after ous stages of clinical trial development either as monotherapy
HMA plus venetoclax, the most used upfront therapy in unfit or in combination with chemotherapy or HMA + veneto-
older patients with AML, is unclear. A small retrospective study clax. These include ziftomenib, bleximenib [236], BMF-­219,
showed dismal outcomes (median OS 4.2 months) with IDH in- DS1594 and DSP 5336. A phase I trial of the menin inhibi-
hibitors or FLT3 inhibitors in the relevant mutational context tor ziftomenib in KMT2A-­rarranged and NPM1-­mutated R/R
post HMA plus venetoclax [209]. A recent study by Chin et al. AML (KOMET-­ 0 01) demonstrated a CR/CRh rate of 25%
demonstrated that intensive salvage chemotherapy after HMA [237]. Importantly, MEN1 resistance mutations in response to
plus venetoclax yielded CR/CRi rates of 37% and a median OS of menin inhibitors have been observed in a significant propor-
7.2 months. However, it should be noted that the median age of tion of patients on early menin inhibitor trials. The spectrum
this cohort was 65 (with interquartile range of 50–68) and were of resistance mutations, as well side effects such as differen-
fit enough to receive intensive chemotherapy, which represents tiation syndrome, seem to differ based on the specific menin
only a small fraction of patients treated with less-­intensive che- inhibitor used [238, 239]. Ongoing clinical trials will examine
motherapies [229]. the combination of menin inhibitor with intensive chemother-
apy, HMA + venetoclax and targeted therapy in both ND and
R/R AML.
8   |   Updates on Selected Investigational Therapies
Multiple immune therapies are under development including
Despite marked improvements in AML management, outcomes antibody-­drug conjugates, bispecific T cell engaging antibodies
are still unsatisfactory, especially in patients with high-­risk dis- and chimeric antigen receptor T (CART) cells directed against
ease. In the last year, several phase III trials involving the addi- a multitude of different antigens including CD123, CD33, and
tion of promising drugs to standard therapy failed to yield a new CD70 [240, 241]. However, none of the tested immune therapies
approval. have yet led to new drug approval yet as clinical trials to date
have demonstrated limited efficacy and concerning toxicities
The combination of azacitidine with the anti-­CD47 mono- such as cytokine release syndrome (CRS) and neurotoxicity.
clonal antibody magrolimab, which binds to a “don't eat me
signal” warding off anti-­tumor immunity yielded high re- Tagraxofusp and Pivekimab sunirine are two agents directed
sponse rates, particularly in TP53 mutant MDS/AML [230]. toward CD123, the IL3 receptor alpha chain. Tagraxofusp rep-
Magrolimab was then tested in prospective randomized tri- resents a truncated diphtheria toxin bound to IL-­3. Pivekimab
als including magrolimab + azacitidine versus azacitidine in sunirine is an antibody-­d rug conjugate with an indolinoben-
higher-­r isk MDS (ENAHNCE, NCT0431388), magrolimab + zodiazepine pseudodimer antibody drug payload. Tagraxofusp
azacitidine versus venetoclax + azacitidine or intensive che- in combination with azacitidine + venetoclax showed a prom-
motherapy in patients with TP53-­mutated AML (ENHANCE ising CR/CRi rate of 59% in ND-­A ML patients with adverse
2, NCT04778397) and magrolimab + azacitidine + venetoclax risk ND-­A ML (50% with mutations in TP53) [242]. Capillary
versus placebo + azacitidine + venetoclax in ND-­A ML patients leak syndrome (CLS) occurred in 18.9% of patients (5 grade 2,
not fit for intensive therapy (ENHANCE 3, NCT05079230) but 1 grade 3, 1 grade 4). Median overall survival and progression-­
in each study OS on the magrolimab arms was not superior to free survival were 14 months and 8.5 months, respectively.
standard of care [231, 232]. Second, clinical development of Pivekimab sunirine was tested as a single-­a gent therapy every
the anti-­T IM-­3 antibody sabatolimab, a novel immune check- 3 weeks in patients with R/R AML [243]. Infusion reactions
point inhibitor, in AML (STIMULUS-­A ML1, NCT04150029) occurred in 31% of patients but they were mainly grade 1/2
was discontinued after the phase III trial STIMULUS-­M DS2 (one grade 3 led to discontinuation) and limited to the first

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TABLE 5    |    Selected investigational drugs for acute myeloid leukemia.

Target Drug Regimens Population Early efficacy outcomes Selected ongoing trials
Menin KO-­539 (ziftomenib) Monotherapy KMT2A rearranged or NPM1-­ CR/CRh—25% KOMET- ­0 07 (NCT05735184):
(KOMET-­0 01) [237] mutated R/R AML ND-­A ML and R/R AML
7 + 3 + ziftomenib
aza + ven + ziftomenib
KOMET- ­0 08 (NCT06001788):
Ziftomenib in combination
with FLAG-­IDA, LDAC, or
gilteritinib for the treatment
of patients with R/R AML
JNJ-­75276617 (bleximenib) Monotherapy [236, 269] ORR 40%–50% As monotherapy (NCT04811560).
Combination with chemotherapy
(NCT05521087).
Combination aza + ven
(NCT05453903).
CD123 Tagraxofusp Tagraxofusp + ND AML not fit for intensive therapy ORR—69% Phase II in ND AML
HMA + venetoclax [242] CR/CRi—59% Tagraxofusp + HMA + venetoclax
(NCT06456463)
IMGN632 (Pivekimab sunirine) Monotherapy [243] R/R AML ORR—21% Phase Ib/II in both
CR/CRi/CRh—17% ND and R/R AML
IMGN632 + HMA + venetoclax
(NCT04086264)
Flotetuzumab (CD123/CD3) Monotherapy [244] R/R AML CR/CRi/CRh—30% Phase I trial of second
generation MGD024 in R/R
AML [270] (NCT05362773)
Abbreviations: AML—acute myeloid leukemia; aza—azacitidine; CR—complete remission; CRh—complete remission with partial hematologic recovery; CRi—complete response with incomplete count recovery; FLAG-­I DA—
fludarabine, cytarabine, G-­C SF, idarubicin; HMA—hypomethylating agent; LDAC—low dose cytarabine; ND—newly diagnosed; ORR—overall response rate; R/R—relapse or refractory; ven—venetoclax.

American Journal of Hematology, 2025

10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.27625 by Cochrane Japan, Wiley Online Library on [21/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.27625 by Cochrane Japan, Wiley Online Library on [21/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
cycle; veno-­occlusive disease was observed in 3 patients but at 9.1   |   Disease and Treatment-­Driven
higher doses than the recommended phase II dose which led
to a 17% CR/CRi/CRh rate. Both antibody-­d rug conjugates are 1. The most common cause of death in patients with AML is
currently being evaluated further in combination with HMA persistent/relapsed disease.
plus venetoclax in larger phase II trials (NCT06456463 and
2. Certain AML subtypes may have differential responses to
NCT04086264).
different therapy modalities (e.g., TP53-­mutated AML is
poorly responsive to chemotherapy, subtypes with mono-
Flotetuzumab which binds to CD3ε on T cells and CD123 was
cytic differentiation may be less responsive to HMA plus
the first of the bispecific T cell engaging antibody to be tested
venetoclax, and AML with AML-­MR mutations may be
in AML in a multicenter, open-­label phase I/II trial in 88 R/R
more sensitive to venetoclax based therapies.).
AML patients [244]. Among 30 patients treated at the recom-
mended phase dose, the complete remission (CR)/CR with 3. Consider whether the patient may become eligible for
partial hematological recovery (CRh) rate was 26.7%. The alloSCT.
most frequent adverse events were grade 1–2 infusion-­related
4. Many treatment options, particularly newly approved
reactions and cytokine release syndrome (CRS). A 10-­gene
drugs which present regulatory and financial challenges,
immune signature predicted response to flotetuzumab. An
may be only available to a subset of AML patients, based on
immune-­ infiltrated IFN-­ γ–dominant tumor microenviron-
geographic and resource considerations.
ment was associated with a more likely response. However
flotetuzumab's development was discontinued in favor of a
second generation bispecific T cell engaging antibody named
9.2   |   Patient-­Driven
MGD024 [245], which has a longer half-­life, thereby promot-
ing ease of administration and potentially minimizing CRS
1. Goals of care should be discussed early on and guide the
risk (NCT05362773).
decision on best treatment for the patient.
One common issue with CD123 and CD33 targeting approaches 2. Age by itself should not solely guide any treatment modal-
is that AML blasts do not have either a truly leukemia-­specific ity, especially if curative intent is pursued.
dispensable antigen such as CD19 on B cells. For comparison,
3. A comprehensive evaluation of comorbidities should be
antibody-­directed therapy in acute lymphoblastic leukemia has
conducted prior to the decision on treatment strategy.
led to the approval of a bispecific antibody, an antibody drug
AML-­related comorbidities should not be an absolute con-
conjugate, and three chimeric antigen receptor T cell products.
traindication to aggressive (or any) therapy.
However, while CD123 and CD33 are abundantly expressed on
AML blasts, these antigens are also present on normal hemato- 4. Older patients should undergo some form of Geriatric
poietic stem and progenitor cells which could result in signif- Assessment. Although there is no standard assessment
icant myelotoxicity. Second, a recent publication suggests that [250], such evaluations can reveal vulnerabilities that are
the cytokines released by activated T-­cells may promote AML not detected in routine clinical practice [251], predict mor-
growth, suggesting that AML cells may be intrinsically resistant bidity, mortality, and therapeutic toxicities [252–255] and
to these approaches [246]. One creative approach to allow CAR increase the rates of goals of care/end of life discussion [256].
T cell persistence without the unwanted prolonged myeloabla-
tion effect is to genetically edit out a surprisingly dispensable Our proposed therapeutic algorithms are based on our experi-
CAR target antigen (e.g., CD33 or CD45) from a donor allograft ence and our interpretation of the available data. They should be
using CRISPR/Cas9 technology and then give CAR T cells or considered a framework for the busy clinician.
an ADC directed against this now “leukemia specific” antigen
[247, 248] (NCT04849910).
10   |   Conclusion

9   |   Choosing a Treatment Strategy In recent years, our knowledge about AML has expanded ex-
ponentially. Through novel pathophysiological discoveries, the
A key question in choosing therapy for an AML patient was therapeutic landscape has changed dramatically. As we enter
traditionally the consideration of eligibility or “fitness” for an the era of personalized medicine in AML with numerous smaller
intensive 3 + 7-­type regimen. However, the availability of ge- cohorts that vary by disease, treatment, and response character-
netically targeted therapies and especially the broad usage of istics, we should aim as a community to collaborate regarding
less-­intensive therapies, has shifted the dilemma to the relative data and clinical trials.
likelihood of benefit from intensive chemotherapy. For example,
it may be that perfectly fit patients with mutated-­TP53 may not
benefit from intensive chemotherapy regimen [249] or even the Acknowledgments
addition of venetoclax to HMA [77]. Thus, the therapeutic deci-
The authors have nothing to report.
sion is based on patient age, comorbidities, goals of care, disease
characteristics, and perhaps on physician experience. We herein
provide some principles that could guide the clinicians thinking Ethics Statement
about how to treat an AML patient. The authors have nothing to report.

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Conflicts of Interest Leukaemia (ALFA-­0701): A Randomised, Open-­Label, Phase 3 Study,”
Lancet 379, no. 9825 (2012): 1508–1516.
R.M.S. reports grants and personal fees from Abbvie, personal fees
from Actinium, grants and personal fees from Agios, personal fees from 14. A. H. Wei, H. Döhner, C. Pocock, et al., “Oral Azacitidine
Argenx, grants from Arog, personal fees from Astellas, personal fees Maintenance Therapy for Acute Myeloid Leukemia in First Remission,”
from AstraZeneca, personal fees from Biolinerx, personal fees from New England Journal of Medicine 383, no. 26 (2020): 2526–2537.
Celgene, personal fees from Daiichi-­Sankyo, personal fees from Elevate,
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